Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([N:8]=[CH:9]3)=[N:6][C:4]([NH:5]1)=[N:3][N:2]=2.[CH:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=[C:27]([NH2:34])[CH:26]=1.NCCCC[C:40]1([OH:60])[C:53]2[O:54][C@@H:50]3[C@@:51]45[CH2:55][CH2:56][N:57]([CH3:58])[C@@H:45]([C@@H:46]4[CH:47]=[CH:48][C@@H:49]3[OH:59])[CH2:44][C:43]([C:52]5=2)=[CH:42][CH2:41]1.CCOC(OC(OCC)=O)=O>CN(C=O)C.C(N(CC)CC)C>[C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([N:8]=[CH:9]3)=[N:6][C:4]([NH:5]1)=[N:3][N:2]=2.[CH:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=[C:27]([NH2:34])[CH:26]=1.[CH:42]1[C:43]2[CH2:44][C@H:45]3[N:57]([CH2:56][CH2:55][C@@:51]45[C@H:46]3[CH:47]=[CH:48][C@H:49]([OH:59])[C@@H:50]4[O:54][C:53]([C:52]=25)=[C:40]([OH:60])[CH:41]=1)[CH3:58]
Reactant: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)CCCCN
Agent: C1=Cc2cc3nnc(nc4nc(cc5ccc(cc1n2)[nH]5)C=N4)[nH]3
Agent: CCOC(=O)OC(=O)OCC
Agent: Nc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5

Procedure:
A solution of each of the compounds obtained in Examples 31 to 39, i.e., tetraazaporphin (synthesized in Examples 1 to 9)-PABA and 3-(4-aminobutyl)morphine in DMF was treated with DEPC in the presence of triethyl amine in the same manner as described in Examples 31 to 39. Thus, tetraazaporphin-PABA-morphine combined products were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N=C=O)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(OC)c(-c3c(Br)cnn3C)c2)cc1
Yield: 78.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.031 g, 0.11 mmol) was treated with 4-methoxyphenyl isocyanate (0.016 g, 14.2 μL, 0.11 mmol, 1.0 equiv.) in CH2Cl, (2 mL), in a similar manner as described in Example 1.2 to afford Compound 4 (0.037 g, 0.086 mmol, 78%) as a white solid. LCMS m/z (%)=431 (M+H79Br, 89), 433 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.02 (s, 1H), 7.89 (s, 1H), 7.67 (dd, J=2.7, 9.0 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.42 (d, J=9.0 Hz, 2H), 7.12 (d, J=9.0 Hz, 1H), 6.85 (d, J=9.0 Hz, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-:3])=[O:2].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>CC(C)=O>[C:15]1([O:21][S:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:12])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(S(=O)(=O)Oc2ccccc2)ccc1Cl
Temperature: 25 °C
Yield: 86.4 %

Procedure:
3-Nitro-4-Chloro-benzene-sulfonic acid-phenylester was obtained by mixing 51 g of 3-nitro-4-chloro-benzene-sulfonic acid-chloride with 18.8 g of phenol in 120 ml of acetone, and by adding 28 ml of triethylamine dropwise, while cooling, at a temperature not exceeding 10° C. The mixture was continued to be stirred for several hours at room temperature, and then water was added, in which process an oil was separated which was extracted with ether. After recrystallization of the residue from methanol, 54 g of 3-nitro-4-chloro-benzene-sulfonic acid-phenylester were obtained, which had a melting point of 71° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:10][S:11](O)(=[O:13])=[O:12]>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: O=S(=O)(O)Cl
Reactant: BrCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To a solution of 2-bromoethylbenzene (10.0 g; 54 mmol) in 16 ml of chloroform placed at a temperature of 0° C. was added dropwise a solution of chlorosulfonic acid (162 mmol, 18.87 g; 10.82 ml) in 11 ml of chloroform. After 15 minutes at 0° C., the reaction was maintained at room temperature for 3 hours. The reaction mixture was poured onto ice, and the aqueous phase was extracted with chloroform. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated off to give 12.34 g of crude product, which was purified by chromatography on a column of silica, eluting with chloroform (76% yield). The product obtained was used for the following reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][C:3]=1[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21])[CH:11]=[C:12]([CH3:14])[CH3:13]>ClCCl.S(=O)(=O)(O)O>[CH3:13][C:12]1([CH3:14])[CH2:11][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=2[O-:21])[C:3]2[CH:4]=[C:5]([S:8][CH3:9])[CH:6]=[CH:7][C:2]=2[O:1]1
Reactant: CSc1ccc(O)c(C(C=C(C)C)c2cccc[n+]2[O-])c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CSc1ccc2c(c1)C(c1cccc[n+]1[O-])CC(C)(C)O2
Yield: 93.6 %

Procedure:
0.47 g of 2-[1-(2-hydroxy-5-methylthiophenyl)-3-methyl-2-butenyl]pyridine N-oxide was taken up in 10 ml of dichloromethane and stirred with 5 drops of sulphuric acid for 1 hour at 20° C. The mixture was diluted with 20 ml of dichloromethane and washed with aqueous sodium carbonate solution. The organic phase was evaporated and the residue was chromatographed on silica gel using diethyl ether/methanol (19:1) for the elution to give 0.44 g of 2-(3,4-dihydro-2,2-dimethyl-6methylthio-2H-1-benzopyran-4-yl)pyridine N-oxide in the form of a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:32])[CH2:10][C:11]2[C:12](=[O:31])[O:13][C:14]3[C:19]([C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:17]2[CH2:27][CH2:28][CH:29](O)[C:16]=2[CH:15]=3)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:32])[CH2:10][C:11]2[C:12](=[O:31])[O:13][C:14]3[C:19]([C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:17]2[CH2:27][CH:28]=[CH:29][C:16]=2[CH:15]=3)=[C:4]([C:33]([F:36])([F:34])[F:35])[CH:3]=1
Reactant: O=C(Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(O)CC3)Nc1ccc(F)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C=CC3)Nc1ccc(F)cc1C(F)(F)F
Yield: 83 %

Procedure:
A solution of N-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(8-hydroxy-2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetamide (Example 214) (250 mg) in toluene (50 ml) was combined with p-TsOH monohydrate (300 mg), and heated under reflux for 30 minutes. After the reaction solution was concentrated, the resultant residue was purified by a silica gel column chromatography (eluent: hexane-ethyl acetate=3:1) to obtain the title compound as a colorless crystal (200 mg, yield: 74%). An aliquot was recrystallized from THF to measure a melting point. Melting point: 217-218° C.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:6][CH2:5][N:4]([C:7]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=O)[CH2:3]1.[CH3:17][C:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][NH2:21]>C1(C)C=CC=CC=1>[F:1][C:2]1([F:16])[CH2:6][CH2:5][N:4]([C:7]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[N:21][CH2:20][CH2:19][C:18]([CH3:23])([CH3:22])[CH3:17])[CH2:3]1
Reactant: O=Cc1cccc(F)c1N1CCC(F)(F)C1
Reactant: CC(C)(C)CCN
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN=Cc1cccc(F)c1N1CCC(F)(F)C1

Procedure:
2-(3,3-Difluoropyrrolidin-1-yl)-3-fluorobenzaldehyde (400 mg, 1.745 mmol) was taken in toluene (15 mL) and 3,3-dimethylbutan-1-amine (176.6 mg, 234.8 μL, 1.745 mmol) was added. The reaction mixture was refluxed overnight with a Dean Stark trap to remove the water. The reaction mixture was then concentrated and used in the next step without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9].C(I)C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:7][CH2:8][O:5][C:1]([CH:2]([OH:3])[CH3:4])=[O:6].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9]
Reactant: CC(O)C(=O)O
Agent: O=C(O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CC(C)=O
Product: CCOC(=O)C(C)O
Yield: 142.6 %

Procedure:
15 g of a lactic acid/glycolic acid copolymer having a weight-average molecular weight of about 7,500 (lactic acid/glycolic acid=75/25 (mol %)) (Wako Pure Chemical Industries, Ltd.) and a 7.8 g of ethyl iodide were dissolved in 150 ml of acetone. To thus obtained solution was added 1.38 g of potassium carbonate and then the resulting mixture was refluxed for 6 hours. After the resultant solution was cooled, inorganic substances were removed by filtration and then the filtrate was concentrated under reduced pressure. The concentrate was dissolved in 100 ml of dichloromethane, washed 3 times with 100 ml of 10% ethanol-water, and then dried with magnesium sulfate. After magnesium sulfate was separated by filtration, the mixture was concentrated to dryness under reduced pressure to yield 12.5 g of the ethyl ester of lactic acid/glycolic acid copolymer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][C:31]([OH:33])=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:12]2[N:13]=[C:14]([CH3:24])[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[CH:10]=1.[C:34](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:12]2[N:13]=[C:14]([CH3:24])[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[CH:10]=1
Reactant: Cc1nc2cc([N+](=O)[O-])c(Oc3ccc(CC(=O)O)cc3Cl)cc2n1COCC[Si](C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COC(=O)Cc1ccc(Oc2cc3c(cc2[N+](=O)[O-])nc(C)n3COCC[Si](C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under an N2 atmosphere, 2-(3-Chloro-4-(2-methyl-6-nitro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-benzo[d]imidazol-5-yloxy)phenyl)acetic acid (0.376 g, 0.764 mmol) was dissolved in DMF (3 mL). Cesium carbonate (0.274 g, 0.841 mmol) was added and the reaction was stirred at room temperature for 5 min. Iodomethane (0.052 mL, 0.841 mmol) was added and the reaction was allowed to stir at room temperature for 16 h. The reaction was diluted with diethyl ether and washed with water. The layers were separated and the aqueous layer was washed with additional diethyl ether. The organics were combined, dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the residue, eluting with 10% to 30% isopropanol in hexanes, afforded the title compound. LC-MS ESI (pos.) m/z: 506.0 (M+H).
Reaction SMILES: BrBr.[S:3]([O-:7])([O-:6])(=[O:5])=[O:4].[CH3:8][C:9]1[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][NH3+:19])=[N:11][CH:12]=[CH:13][CH:14]=1.CC1C(CCCC[NH3+])=NC=CC=1>OS(O)(=O)=O.O=S(=O)=O>[CH3:8][C:9]1[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[N:11][CH:12]=[CH:13][CH:14]=1.[S:3](=[O:5])(=[O:4])([OH:7])[OH:6]
Reactant: O=S(=O)([O-])[O-]
Reactant: Cc1cccnc1CCCC[NH3+]
Agent: BrBr
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Cc1cccnc1CCCCN

Procedure:
Bromine (10 g) was added dropwise with stirring to a solution of 4-(3-methyl-2-pyridyl)butylammonium sulphate (21.3 g) obtained from 4-(3-methyl-2-pyridyl)butylamine and concentrated sulphuric acid) in 65% oleum (100 ml) at room temperature. The solution was then heated to 55° C. and stirred overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](I)=[CH:5]2.FC(F)(F)C([O-])=O.[Na+]>CN1CCCC1=O.O.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2
Reactant: Cn1c(I)cc2cc(Cl)ccc21
Agent: [Cu]I
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1ccc2cc(Cl)ccc21
Temperature: 160 °C

Procedure:
A mixture of 5-chloro-2-iodo-1-methylindole obtained from Example 3 (16.5 g, 56.6 mmole), sodium trifluoroacetate (76.2 g, 56.0 mmole) and copper (I) iodide (10.6 g, 56.0 mmole) in N-methylpyrrolidone is heated at 160° C. for about 8 hours, cooled to room temperature, diluted with water and filtered through diatomaceous earth. The filtrate is extracted with diethyl ether. The extracts are combined, washed with water, dried over MgSO4 and concentrated in vacuo to give a black oil residue. The residue is chromatographed using silica gel and 15:1 hexanes:ethyl acetate to give a yellow oil. The oil is chromatographed a second time using the same eluent and silica gel to give the title product as a yellow oil, 2.92 g (22% overall yield from 5-chloro-1-methylindole), identified by IR, 1HNMR, 13CNMR and 19FNMR analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([CH:11](O)[CH3:12])=[CH:7][C:8]=1[CH2:9][CH3:10].S(Cl)([Cl:16])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([CH:11]([Cl:16])[CH3:12])=[CH:7][C:8]=1[CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCc1cc(C(C)O)ncc1OC
Solvent: ClCCl
Product: CCc1cc(C(C)Cl)ncc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A solution of 3-methoxy-4-ethyl-6-(1-hydroxyethyl)-pyridine (236 mg, 1.3 mmol) in 5 mL of methylene chloride at 0° C. is treated with thionyl chloride (0.141 mL, 1.95 mmol) and stirred at room temperature for 1 h. The reaction is quenched with 12 mL of saturated sodium bicarbonate. The aqueous layer is extracted with 3×10 mL of methylene chloride. The combined organics are dried over potassium carbonate and concentrated in vacuo to provide 249 mg (96%) of 3-methoxy-4-ethyl-6-(1-chloroethyl)-pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:34]=[C:33]5[C:28]([CH:29]=[CH:30][C:31](=[O:35])[O:32]5)=[CH:27][CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc5ccc(=O)oc5c4)ncnc32)CC1
Yield: 15.3 %

Procedure:
4-[4-(2-Oxo-2H-chromen-7-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (6.4 mg, 16%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.09 mmol) with 7-hydroxy-coumarin (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 15 mg, 0.09 mmol) in the presence of potassium carbonate (27 mg, 0.195 mmol). Mass spectrum MH+=464.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][C:15](=[O:21])[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[C:30]([O:29][C@@H:9]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][C:15](=[O:21])[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
To the solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (5.8 mg) in THF and methanol (1.5 mL/0.5 mL) was added 1 M NaOH solution (0.6 mL). The mixture was stirred at 25° C. for 16 hours, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Concentration gave (S)-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one (4.4 mg). LCMS-ESI+ (m/z): 386.2 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[C:22]([C:23]3[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=3)=[C:21]([F:30])[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[F:30][C:21]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:19][N:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)(=[O:16])=[O:17])[C:22]=1[C:23]1[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(Cc1cn(S(=O)(=O)c2ccc(O)cc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of tert-butyl {[1-{[4-(benzyloxy)phenyl]sulfonyl}-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (360 mg) in ethyl acetate (30 mL) was added 10% palladium carbon (50% containing water, 350 mg) under a nitrogen atmosphere, and the mixture was stirred for 1 hr under a hydrogen atmosphere. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (yield 300 mg, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[BH3:24].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([O:20][CH2:19][CH2:18][CH:14]1[C:13]2[N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:10]([CH:21]([CH3:23])[CH3:22])=[N:11][C:12]=2[CH2:17][CH2:16][CH2:15]1)(=[O:35])=[O:34].[BH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCO)CCC2
Agent: B
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCOS(C)(=O)=O)CCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred suspension of Intermediate 76 (830 mg) in Dichloromethane (DCM) (40 mL), under nitrogen, was treated with triethylamine (0.501 mL) then cooled to ca. 0° C. (ice bath). Methanesulfonyl chloride (0.222 mL) was added via syringe, then the cooling bath was removed and stirring continued for 2 h. The solution was partitioned between aqueous ammonium chloride (200 ml) and DCM (200 ml). The layers were separated and the aqueous phase was further extracted with DCM (200 ml). The combined organic extracts were washed with water (200 mL), dried (Na2SO4), filtered through a hydrophobic frit and evaporated in vacuo. The crude product was purified by column chromatography (silica, 0-25% Methanol in DCM). The appropriate fractions were combined and concentrated to afford the title compound, 368 mg. LC/MS (M-BH2)-411/413, Rt 2.18 mins (5 min run, TFA modifier).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-])=O.O.Cl>C(O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCO
Product: Nc1ccc2c(c1)CCCC2
Reaction time: 18 h

Procedure:
7-Nitrotetralone (Formula 10) is dissolved in a solvent, such as ethanol or methanol, preferably ethanol (about 4 L/mole). To this solution is added water (about 400 ml/mmol), concentrated HCl (about 95 ml/mmol) and 10% palladium on carbon (about 40 g/mmol). The reaction mixture is hydrogenated at a pressure of about 30-40 psi for a period of about 12 to 24 hours, preferably about 18 hours. When the reaction is substantially complete, 2-amino-5,6,7,8-tetrahydronaphthalene of Formula 11 is isolated and purified by conventional means, preferably by preparative TLC or flash column chromatography.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[CH:5][N:4]=[N:3]1.C1C(=O)N([Cl:23])C(=O)C1>CN(C)C=O.CCOC(C)=O>[Cl:23][C:5]1[N:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1
Reactant: COC(=O)c1cc(-c2cnnn2C)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2c(Cl)nnn2C)cs1
Yield: 79.7 %

Procedure:
A solution of methyl 4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylate (500 mg, 2.24 mmol) and NCS (1196 mg, 8.96 mmol) in N,N-Dimethylformamide (DMF) (10 ml) was heated at 50° C. for 2 hr. The reaction mixture was diluted with 50 ml of EtOAc. The organic layer was washed with H2O (50 ml×2) and brine (50 ml), and then concentrated to give 460 mg of a crude mixture, which was used in next step without further separation. LCMS (ES) m/z 258.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4]Cl.[K].[Cl:8][C:9]1[CH:10]=[N:11][C:12](=[O:15])[NH:13][CH:14]=1>CN(C)C=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][N:11]1[CH:10]=[C:9]([Cl:8])[CH:14]=[N:13][C:12]1=[O:15]
Reactant: CN(C)CCCl
Reactant: O=c1ncc(Cl)c[nH]1
Agent: [K]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(Cl)cnc1=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 47 %

Procedure:
2-Dimethylaminoethyl chloride (0.016 mol) was added to the potassium salt of 5-chloropyrimid-2-one (0.012 mol) in dimethylformamide (50 ml) and the reaction mixture stirred at 80° C. for 7 h. The solvent was then evaporated at reduced pressure (1 mm Hg) and the residue was extracted with chloroform (150 ml). The chloroform solution was washed with 1 N NaOH (2×4 ml), with water (5 ml) and dried (MgSO4) before evaporation. The product was recrystallized from benzene containing a little pet. ether; yield 47%, m.p. 157° C. (Found: C, 47.87; H, 6.05 Calc. for C8H12ClN3O: C, 47.64; H, 5.99).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]1([CH3:22])[CH2:16][S:15](=[O:18])(=[O:17])[C:14]([CH3:20])([CH3:19])[C:13]([NH2:21])=[N:12]1.C(N(CC)CC)C>C(O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:11]2([CH3:22])[CH2:16][S:15](=[O:17])(=[O:18])[C:14]([CH3:19])([CH3:20])[C:13]([NH2:21])=[N:12]2)[CH:4]=1
Reactant: CC1(C)C(N)=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)CS1(=O)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)C(N)=N[C@](C)(c2cc(N)ccc2F)CS1(=O)=O
Temperature: 23 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of (R)-5-(2-fluoro-5-nitro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (950 mg, 2.88 mmol, Eq: 1.00) in ethanol (50 ml) was added at 23° C. under inert atmosphere triethylamine (292 mg, 402 μl, 2.88 mmol, Eq: 1.00) and after inertisation Pd/C 10% (307 mg, 288 μmol, Eq: 0.1). The suspension was set under hydrogen (balloon) and stirred at 23° C. for 1 hour. The catalyst was filtered off, washed three times with ethanol and a mixture of dichloromethane and methanol and evaporated the combined filtrate to give the crude and nearly pure (R)-5-(5-amino-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (760 mg, 2.54 mmol, 88.0% yield) as an off-white solid. MS (ISP): m/z=300.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(F)c1
Yield: 98.6 %

Procedure:
3-Fluorobenzaldehyde (5 g, 40.28 mmol) in pyridine (50 mL) was reacted with malonic acid (5.4 g, 52.3 mmol) and piperidine (343 mg, 4.0 mmol) at 75° C. for 12 hours to afford 6.6 g (96.9%) of the crude product which was used in the next step without further purification.