Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.N1C=CC=CC=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+]([O-])=O)=[CH:29][CH:28]=1)=[O:25]>ClCCl>[C:27]1([O:26][C:24](=[O:25])[NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C
Reaction time: 13 h

Procedure:
4-(4,4,5,5-tetramethyl 1,3,2 dioxaborolan-2-yl) aniline (3 g, 0.013 mol) was dissolved in dichloromethane (350 mL) to which pyridine (1.02 g, 0.013 mol) and 4-nitrophenyl chloroformate was added. The reaction was stirred for 13 hr where TLC analysis showed consumption of all starting materials. The solution was washed with saturated NaHCO3 (3×50 mL), water (3×50 mL) and brine (3×50 mL). The organic layer was dried over Na2SO4 and solvent removed to yield a white crystalline solid [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid phenyl ester, 4.45 g, 91%. 1H NMR (CDCl3 300 MHz) δ 1.4 (s, 12H), 7.1 (brs, 1H), 7.3 (d, 2H), 7.5 (d, 2H), 7.8 (d, 2H), 8.3 (d, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[Cl-].[NH4+]>CN1CCCC1=O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClCc1ccccn1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2ccn(Cc3ccccn3)c2c1
Reaction time: 0.75 h
Yield: 81.7 %

Procedure:
—Sodium hydride (60% dispersion in oil, 15.5 g, 319 mmol) was added in portions to a solution of 6-nitroindole (23.5 g, 145 mmol) in 1-methyl-2-pyrrolidinone (1000 ml). After 45 min. stirring, 2-chloromethyl-pyridine hydrochloride (28.2 g, 174 mmol) was added in portions. Stirring was continued for 1 h and the reaction mixture was poured into a saturated aqueous solution of ammonium chloride. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 1:1→ethyl acetate) afforded 6-nitro-1-pyridin-2-ylmethyl-1H-indole (30 g).
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[NH:19][C:20]3=[O:23])=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].O>CN(C)C=O>[N:34]([CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])[NH:19][C:20]3=[O:23])=[CH:15][CH:14]=2)[CH2:8]1)=[N+:35]=[N-:36]
Reactant: CS(=O)(=O)OCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 65 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
The 2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl methanesulfonate (169.1 mg, 0.351 mmol) obtained in step C was dissolved in N,N-dimethylformamide (1.3 ml). Thereafter, sodium azide (96.2 mg, 1.33 mmol) was added to the obtained solution, and the mixture was then stirred at 65° C. for 4 hours. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1 to 3:1), so as to obtain 7-(5-azidomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (139.6 mg; yield: 93%) in the form of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].Cl[CH2:27][O:28][C:29]([N:31]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:30]>>[CH2:36]([O:35][C:33]([CH2:32][N:31]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:29]([O:28][CH2:27][O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8])=[O:30])=[O:34])[CH3:37]
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)OCCl
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)OCOc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 38.6 %

Procedure:
Using 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide 1 sodium salt (compound of Example 43(1)) and diethyl N-[(chloromethoxy)carbonyl]iminodiacetate as the raw materials, the same operation as the Example 98 gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C1(C)C=CC(S(O[CH2:21][CH2:22][Cl:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)c1cccc(OCCCl)c1
Yield: 70.6 %

Procedure:
To a solution of 3-hydroxybenzamide (21.6 g) in methyl ethyl ketone ("MEK") was added 2-chloroethyl p-toluenesulphonate (55.46 g) and potassium carbonate (16.0 g). After stirring at reflux for 6 hours, the resultant mixture was poured onto water and a colourless solid filtered off. Crystallisation from ethanol gave the title compound, (22.2 g), m.p. 125°-126°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12](Cl)(=[O:14])=[O:13])[CH:10]=2)[C:5]([Cl:16])=[CH:4][N:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:14])=[O:13])[CH:10]=2)[C:5]([Cl:16])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCCN1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H]1CCCCN1S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
1,4-Dichloro-7-isoquinolinylsulphonyl chloride (245 mg, 0.83 mmol) was added to a solution of tert-butyl 2(R)-piperidine carboxylate (153 mg, 0.83 mmol) and triethylamine (170 μl, 1.22 mmol) in CH2Cl2 (15 ml), and the reaction stirred at room temperature for 18 h. The solution was diluted with CH2Cl2, washed with 2M hydrochloric acid, saturated Na2CO3 solution and then brine, dried (MgSO4), and evaporated in vacuo. The residual oil was purified by column chromatography upon silica gel using an elution gradient of pentane-EtOAc (100:0 to 90:10), to give tert-butyl (2R)-1-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-2-piperidinecarboxylate, (290 mg, 0.65 mmol) as a colourless film.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1>C(O)C>[F:23][C:22]([S:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][NH:6][C:7]3=[O:12])=[CH:16][CH:17]=1)([F:25])[F:24]
Reactant: O=C1NCCc2c(O)cccc21
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Solvent: CCO
Product: O=C1NCCc2c(OCc3ccc(SC(F)(F)F)cc3)cccc21

Procedure:
166 mg (1.017 mmol) of 5-hydroxy-3,4-dihydroisoquinolin-1(2H)-one, 289 mg (1.068 mmol) of 1-(bromomethyl)-4-[(trifluoromethyl)sulphanyl]benzene and 365 mg (2.645 mmol) were suspended in 3 ml of ethanol and stirred under reflux for 6 h. After cooling, the insoluble constituents were filtered off and the solvent was removed under reduced pressure. The residue was dissolved in chloroform and water. The phases were separated, the organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure. The crude product was purified by chromatography (ethyl acetate:n-heptane 2:1). This gave 200 mg (54% of theory) of the desired 5-({4-[(trifluoromethyl)sulphanyl]benzyl}oxy)-3,4-dihydroisoquinolin-1(2H)-one. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 7.89 (br. s, 1H), 7.52-7.44 (m, 4H), 7.28 (t, 1H), 7.22 (d, 1H), 5.16 (s, 2H), 3.33 (dt, 2H), 2.84 (t, 2H).
Reaction SMILES: [CH2:1]([C:3]12[CH2:17][CH:7]3[NH:8][CH:9]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=41)[CH:4]2[CH2:5][CH:6]3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Li].[CH3:32][S:33][CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>>[CH2:1]([C:3]12[CH2:17][CH:7]3[NH:8][CH:9]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=41)[CH:4]2[CH2:5][C:6]3([C:37](=[O:38])[CH2:36][CH2:35][CH2:34][S:33][CH3:32])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2]
Reactant: CCOC(=O)C1CC2C3Cc4ccccc4C2(CC)CC1N3
Reactant: CSCCCC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Product: CCOC(=O)C1(C(=O)CCCSC)CC2C3Cc4ccccc4C2(CC)CC1N3

Procedure:
Following a procedure similar to that described in Examples 1 or 2, it is contemplated that reaction of ethyl 5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate with lithium diisopropylamide, followed by reaction of the resulting lithium salt with γ-methylmercaptobutyryl chloride and treatment of the resulting product with dilute mineral acid affords ethyl 5α-ethyl-3-(γ-methylmercaptobutyryl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate, which, on heating with trimethylammonium formate, affords 6(eq)-ethyl-11(eq)-(6-methylmercapto-3-oxohexyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)(=[O:17])[CH2:14][CH2:15][CH3:16].Cl.[NH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:13]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:24])=[CH:25][CH:26]=1)(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 55.9 %

Procedure:
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.801 mmol) was added to a solution of 4-butyrylbenzoic acid (154 mg, 0.801 mmol), methyl 3-aminopropanoate hydrochloride (90.8 mg, 0.881 mmol), 1-hydroxy-7-azabenzotriazole (109 mg, 0.801 mmol), and triethylamine (120 μL, 0.86 mmol) in dichloromethane (8.0 mL). The reaction was stirred at room temperature for 19 h. The reaction was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography gave methyl 3-(4-butyrylbenzamido)propanoate (124.1 mg, 56%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.2 Hz, 2H), 6.89 (br. s., 1H), 3.69-3.77 (m, 5H), 2.95 (t, J=7.2 Hz, 2H), 2.66 (t, J=5.8 Hz, 2H), 1.71-1.82 (m, 2H), 1.00 (t, J=7.43 Hz, 3H. MS (M+1): 278.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].CN(C=O)C.P(Cl)(Cl)([Cl:34])=O>>[Cl:34][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c([N+](=O)[O-])c(-c2ccccc2)[nH]c(=O)c1C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Temperature: 100 °C

Procedure:
In 6.5 ml of phosphorus oxychloride was dissolved 2.5 g of 3,4-diethoxycarbonyl-5-nitro-6-phenyl-2pyridone, followed by addition of 1 ml of DMF. The mixture was heated at 100° C. for 30 minutes. After the reaction mixture was concentrated under reduced pressure, an aqueous solution of sodium hydrogencarbonate was added to the residue for neutralization, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (eluent:ethyl acetate/hexane 1:2), to give 1.9 g of the title compound as yellow needles.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][C:8]([C:18]([F:21])([F:20])[F:19])=[C:7]([Br:22])[N:6]=1)=[O:4].[OH-].[Na+].O.Cl>C1COCC1>[Br:22][C:7]1[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][C:8]=1[C:18]([F:20])([F:19])[F:21]
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1-n1c(C)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(Br)nc1C(=O)O

Procedure:
6-Bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.9 g, 5.04 mmol) and 2M NaOH (2.52 ml, 5.04 mmol) in THF (10 ml) was stirred at RT for 1 hour. The reaction mixture was poured into water (50 ml) and the pH was adjusted to pH 4 by addition of 1M HCl. The mixture was extracted with EtOAc (2×50 ml) and the organic portion was washed with brine (30 ml), dried over MgSO4 (5 g), filtered and concentrated to give the title compound as a crystalline orange solid;
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][CH:41]=1.C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:38][CH2:39][C:40]2[S:44][CH:43]=[N:42][CH:41]=2)=[O:15])[CH:3]=1
Reactant: NCc1cncs1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(C(=O)NCc2cncs2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of Example 104A (32.5 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL) was added, followed by the addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.4 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). Then, 5-(aminomethyl)thiazole (21.7 mg, 0.19 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by the addition of diisopropyl ethyl amine (57.9 uL, 0.31 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). The mixture was shaken at room temperature overnight. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to give the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.25-1.39 (m, 3H) 4.43-4.54 (m, 2H) 4.58-4.68 (m, 2H) 7.04-7.14 (m, 1H) 7.37-7.45 (m, 1H) 8.83-9.19 (m, 1H); MS (ESI) positive ion 304 (M+H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[C:21]12([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[C:21]12([CH2:31][C:32]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:20])=[O:33])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1C
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1ccc(-c2nn(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c3ccccc23)cc1C

Procedure:
The product of Example 163A and 2-(adamantan-1-yl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.24 (s, 1H), 8.39-8.42 (m, 1H), 7.88-8.01 (m, 2H), 7.75 (dd, J=6.9, 2.1 Hz, 1H), 7.29-7.35 (m, 3H), 3.56 (s, 1H), 2.33 (s, 2H), 2.32 (s, 3H), 2.05 (d, J=3.0 Hz, 2H), 1.93-1.97 (m, 3H), 1.54-1.72 (m, 12H); MS (APCI+) M/Z 442 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[CH2:21]([O:20][C:18](=[O:19])[C:17]1[CH:23]=[CH:24][C:14]([C:11](=[O:13])[CH2:12][CH2:2][C:3](=[O:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:15][CH:16]=1)[CH3:22]
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: O=C(CBr)c1ccccc1
Product: CCOC(=O)c1ccc(C(=O)CCC(=O)c2ccccc2)cc1

Procedure:
4-(4-Oxo-4-phenyl-butyryl)-benzoic acid ethyl ester is prepared from bromoacetophenone and ethyl 4-acetyl-benzoate and following the procedure in Example 11, Step 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>C(O)C>[Cl:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:1][C:2]3[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCO
Product: COC(=O)c1cc(Nc2ccnc3cc(Cl)ccc23)cc(C(=O)OC)c1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
1,3-dimethyl 5-aminobenzene-1,3-dicarboxylate (2.09 g, 10 mmol) and 4,7-dichloroquinoline (1.98 g, 1 eq) were refluxed in 200 mL of ethanol for 3 h. The reaction mixture was then cooled to room temperature and the precipitate was removed by filtration and washed successively with a saturated aqueous solution of NaHCO3, water, ethanol and then petroleum ether to yield expected compound as a yellow powder (2.90 g, 78% yield). m/z (ESI) 371.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:16][CH:17]=O.[C:19]([O:23][C:24](=[O:43])[N:25]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:19]([O:23][C:24](=[O:43])[N:25]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:26]1[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]2=[O:1])[CH2:28][CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COC(=O)c1cc(=O)n(CC=O)c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4 mL of a chloroform solution containing methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate, 0.12 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 0.03 g of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 0.11 g of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate], to give 109 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methoxycarbonyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc(N)ccc1C
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(I)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
Methyl 5-amino-2-methylbenzoate (1.0 eq, 3.75 g) was dissolved in acetic acid (70 ml). N-Iodosuccinimide (1.0 eq, 5.27 g) was added portionwise over 60 minutes. The mixture was stirred at room temperature for 30 minutes. Acetic acid was evaporated. The residue was diluted with ethyl acetate (80 ml) and neutralized with saturated sodium carbonate (80 ml). The organic layer was washed with 1M sodium thiosulfate (2×40 ml), then water (2×40 ml) and brine (2×40 ml). The material was purified by flash chromatography on silica gel (gradient 10% to 30% ethyl acetate in hexanes) to provide methyl 5-amino-4-iodo-2-methylbenzoate as a yellow-orange solid (3.19 g, 49% yield). GCMS>95% pure, m/z 291. 1H NMR (400 MHz, DMSO, d6) δ 2.30 (s, 3H), 3.78 (s, 3H), 5.27 (br s, 2H), 7.24 (s, 1H), 7.54 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]([N:26]5[CH2:30][CH2:29][CH2:28][C@H:27]5[C:31](O)=[O:32])=[O:25])=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:36][NH:37][CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:36][N:37]([CH3:38])[C:31]([C@@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][NH:22][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:35]=[CH:34][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21])=[O:32]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N3CCC[C@H]3C(=O)O)ccc21
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-((S)-2-dimethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]amide (23 mg) was prepared by following General Procedure F starting from (S)-1-(2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetyl)-pyrrolidine-2-carboxylic acid (33 mg), dimethylamine (35 uL, 2 M in THF), HBTU (29 mg), and DIEA (17 uL). LC/MS: m/z 540.7.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH:19]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:27][CH:19]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: NC1CCCCCCC1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(NC2CCCCCCC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
(±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.549 g, 2 mmol), cyclooctylamine (0.762 g, 6 mmol) and ethanol (15 mL) were stirred at reflux under nitrogen for 20 hours. 1N NaOH (2 mL) was added and solvent was evaporated. The residual oil was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform as white powder after crystallization from acetonitrile-methanol (0.623 g, 87%); m.p. 171°-173° C.