Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.ClCCl.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C.CO>[Br:22][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
1-(tert-Butyl) 2-methyl(2S,4R)-4-hydroxytetrahydro-1H-1,2-pyrroledicarboxylate (3) (2.0 g, 8.15 mmol) was weighed into an oven-dried flask and azeotropically dried using toluene. Dichloromethane (16 mL) and carbon tetrabromide (10.81 g, 8.15 mmol) were added and the solution was stirred, cooled to 0° C. and treated with triphenylphosphine (8.5 g, 32.41 mmol). The mixture was stirred for 5 h at 0° C., then methanol (1.8 mL) was added and stirring was continued overnight at room temperature. The mixture was diluted with diethyl ether (80 ml) and the resulting suspension was filtered and washed with diethyl ether (30 ml). The solvents were combined and evaporated under reduced pressure and the crude product was purified by silica gel column chromatography eluting with hexane/ethyl acetate (19:1 to 4:1, v/v) to give the title bromide (4) (1.0 g, 40%) as a colourless oil:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[OH:12]O>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: OB(O)c1cccc(F)c1F
Reactant: OO
Solvent: ClCCl
Product: Oc1cccc(F)c1F
Yield: 93 %

Procedure:
Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25° C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenol as a brown oil.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[NH:16][N:15]=1.Br[C:33]1[S:37][C:36]([N:38]([CH2:42][C@@H:43]([N:51]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)C(=O)C)=[N:35][CH:34]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:51][C@@H:43]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:42][NH:38][C:36]1[S:37][C:33]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:13])=[CH:34][N:35]=1
Reactant: Cc1n[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CC(=O)N(C[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)c1ncc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]c2ccc(-c3cnc(NC[C@@H](N)Cc4ccccc4)s3)cc12
Temperature: 150 °C
Yield: 26.6 %

Procedure:
To a solution of 1.0 mL dioxane, 0.5 mL distilled water and sodium carbonate (35.0 mg, 0.33 mmol) in a 5 mL microwave tube, were added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (32.0 mg, 0.124 mmol) and (S)-N-(5-bromothiazol-2-yl)-N-(2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropyl)acetamide (40.0 mg, 0.0826 mmol). The reaction mixture was degassed by bubbling nitrogen into the microwave tube for 30 seconds. Subsequently, tetrakis(triphenylphosphine)palladium(0) (10.0 mg, 0.0083 mmol) was added to the tube, and the mixture was heated at 150° C. in a Smith microwave synthesizer. After heating for 25 minutes, the reaction mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was evaporated off, and the resulting residue was diluted with 1.5 mL MeOH, 1.5 mL water, and 1.5 mL hydrazine. The resulting mixture was transferred to a 5 mL microwave tube and heated at 150° C. After heating for 33 minutes, silica gel (10.0 g) was added to the reaction mixture, and the mixture was concentrated to dryness. The resulting solid was directly loaded on a silica gel column and chromatography separation was performed with DCM:MeOH (97:3) as the eluant to afford the desired compound N-((S)-2-amino-3-phenylpropyl)-5-(3-methyl-1H-indazol-5-yl)thiazol-2-amine as a colorless solid (8.0 mg, 26.6%). HRMS Theoretical (M+H) 364.15904, found 364.15915.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3](O)([CH2:4]3)[CH2:2]1)[CH2:8]2.[Na].CCCCCCCC.[C:22](O)(=[O:25])[CH:23]=[CH2:24]>S(=O)(=O)(O)O.COC1C=CC(O)=CC=1.O.C1(C)C=CC=CC=1>[C:22]([O:12][C:1]12[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2)(=[O:25])[CH:23]=[CH2:24]
Reactant: C=CC(=O)O
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Agent: COc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCCCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(=O)OC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.2 %

Procedure:
Adamantyl acrylate is synthesized by the method described in JP-2001-106650-A. That is, 86.4 g (513 mmol) of 1,3-adamantane diol containing sodium in an amount of 0.05% by weight, 400 ml of toluene, 400 ml of n-octane, 108 g (1,500 mmol) of acrylic acid, 1.23 g of strong sulfuric acid, and 0.37 g p-methoxyphenol are placed in a separable flask equipped with a stirrer, a thermometer, a Dean-Stark water separator, a Dimroth condenser, an air introduction tube, and a separating valve provided on the bottom side. Reaction is conducted for five hours in a reflux state at 112° C. while inspiring a small amount of air to the flask. During the reaction, produced water is removed by using the Dean-Stark water separator. The reaction liquid is cooled down to room temperature followed by filtration of insoluble matters. 840 g of 5% by weight sodium hydroxide solution is admixed and separated. Thereafter, the organic phase is washed with 400 ml of water six times. The organic phase is condensed with a reduced pressure, filtered, and dried to obtain 83.8 g of adamantyl acrylate of white powder.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:24]=[C:23](I)[C:22](=[O:26])[NH:21][C:20]1=[O:27])(=[O:3])[CH3:2].[CH3:28][Sn:29][CH3:30].O1CCOC[CH2:32]1>>[C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:24]=[C:23]([Sn:29]([CH3:32])([CH3:30])[CH3:28])[C:22](=[O:26])[NH:21][C:20]1=[O:27])(=[O:3])[CH3:2]
Reactant: C[Sn]C
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc([Sn](C)(C)C)c(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 100 °C

Procedure:
600 mg (1.21 mmol) of the above compound 5 as a starting material, 1.42 g (4.32 mmol, 3.6 eq) of dimethyl tin (Sn2Me6) and 22 mg (0.03 eq) of bis-triphenylphosphine palladium dichloride are dissolved in 36 mL of 1,4-dioxane, with continuously stirring at 100° C. After the starting material disappears, the solution is concentrated under reduced pressure, and then purified by rapid column chromatography (EtOAc/n-hexane=1:1). A white solid product (1-(2′,3′,5′-Tri-O-acetyl-β-D-arabinofuranosyl)-5-trimethylstannylpyrimidin-2,4(3H)-dione) 6 is obtained. Its weight and yield are 500 mg and 75%, respectively.
Reaction SMILES: [F:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:32])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a stirred solution of 6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.55 g, 1.58 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (0.32 g, 1.58 mmol) in DCM (3 mL). After stirring for 2 h at 0° C., the mixture was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.50 g, 88%) as a white solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 8.02-8.06 (m, 2H), 7.77 (s, 1H), 7.61 (m, 1H), 7.37 (dd, J=8.4, 1.5 Hz, 1H), 7.01 (m, 1H), 5.48 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/z 364 (M+H)+.
Reaction SMILES: C(C1[C:13]2[C:8](=[N:9][C:10]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:11][C:12]=2[Cl:14])[N:7]([CH2:30][C:31]2[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=2)[N:6]=1)CC=C.C[N+]1([O-])CC[O:45][CH2:44]C1.[O:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Os](=O)(=O)(=O)=O.C(OCC)(=O)C.O.CC(C)=O>[Cl:14][C:12]1[N:11]=[C:10]([N:15]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[N:9]=[C:8]2[N:7]([CH2:30][C:31]3[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=3)[N:6]=[C:50]([CH2:51][CH2:52][CH:53]([OH:49])[CH2:44][OH:45])[C:13]=12
Reactant: C1CCOC1
Reactant: C=CCCc1nn(Cc2ncc(C)c(OC)c2C)c2nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc(Cl)c12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1c(C)cnc(Cn2nc(CCC(O)CO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
Osmium tetroxide (21 mg) was added to a mixture composed of the above 3-(3-butenyl)-6-di(tert-butoxycarbonyl)amino-4-chloro-1-(4-methoxy-3,5-dimethylpyridin-2-yl)methyl-1H-pyrazolo[3,4-d]pyrimidine (4.78 g), N-methylmorpholine-N-oxide (5.04 g), tetrahydrofuran (60 mL), acetone (60 mL) and water (60 mL), and the mixture was stirred at room temperature for five hours. Ethyl acetate (300 mL) and a 10% sodium thiosulfate solution (500 mL) were added to the reaction mixture, followed by further stirring for 30 minutes. The reaction mixture was separated, and the aqueous layer was extracted with ethyl acetate. Then, the combined organic layers were washed with brine. The organic layers were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the solvent was evaporated to obtain a crude product of the title compound (4.60 g, 91%) as a solid. The resulting compound was directly used for the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][CH:3]=1.[Br:10]C1C(CN2[C@@H](C)[C@@H](C3C=CC=C(OC(F)(F)F)C=3)OC2=O)=NC(SC)=NC=1>>[Br:9][C:5]1[C:6]([CH2:8][Br:10])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cccc(OC(F)(F)F)c3)[C@@H]2C)n1
Reactant: Cc1nc(Cl)ccc1Br
Product: Clc1ccc(Br)c(CBr)n1

Procedure:
The preparation of this precursor from commercially available 6-chloro-3-bromo-2-methylpyridine has been described previously in WO2007081569, INTERMEDIATE 9 Step B.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.C1(C)C=CC(S(O)(=O)=[O:15])=CC=1.[CH:19]1[CH:24]=CC=CC=1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:15][CH2:19][CH2:24][O:7]2)=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1ccsc1
Reactant: c1ccccc1
Product: c1cc(C2OCCO2)cs1
Yield: 72 %

Procedure:
In a 100 mL roundbottom flask equipped with a dean stark trap and a reflux condenser, thiophene-3-carboxaldehyde and p-toluenesulfonic acid were dissolved in benzene (50 mL). The mixture was heated to reflux overnight. The reaction was cooled, washed with sat'd sodium bicarbonate, water, dried (MgSO4) and concentrated. Purification by fractional distillation (93°-95° C., 7.5 mm Hg) afforded 45.3 g (72%) of the desired dioxolane as a clear liquid.
Reaction SMILES: C(O)(=O)C.C([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:27]=[CH:26][C:25]3[C:24](=[O:28])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.N1C2C(=CC=CC=2)C=NC=1>C(O)C.[Pd]>[N:15]1([C:18]2[N:27]=[CH:26][C:25]3[C:24](=[O:28])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1
Reactant: O=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Agent: [Pd]
Agent: c1ccc2ncncc2c1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1CCCc2nc(N3CCNCC3)ncc21
Temperature: 25 °C
Yield: 90.4 %

Procedure:
Dissolved in 30 ml of ethanol and 10 ml of acetic acid was 0.64 g (2 mmol, Referential Example 47) of 2-(4-benzylpiperazino)-5-oxo-5,6,7,8-tetrahydroquinazoline, followed by an addition of 64 mg of 10% Pd-C. The quinazoline derivative was hydrogenated at 50° C. for 1 hour under atmospheric pressure. After cooling the reaction mixture to room temperature, the catalyst was filtered off and the solvent was distilled off from the filtrate under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 0.42 g of the intended product as light yellowish crystals (yield: 90%).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: Nc1nnc(-c2cccc(OC(F)(F)F)c2)c(-c2ccccc2)n1
Yield: 25.7 %

Procedure:
6-(3-trifluoromethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (170 mg, 25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-(trifluoromethoxy)phenyl boronic acid (0.44 g, 2.13 mmol) according to the general procedure of Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl-].[NH2:16][C:17]1[CH:39]=[CH:38][C:20]([NH:21][C:22]([C:24]2[CH:37]=[CH:36][C:27]([NH:28][C:29]3[CH:34]=[CH:33][N+:32]([CH3:35])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:19][CH:18]=1.Cl.CO.CCOC(C)=O>CO.CCOC(C)=O>[Cl-:1].[CH3:35][N+:32]1[CH:31]=[CH:30][C:29]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([C:22]([NH:21][C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:39][CH:38]=3)=[O:23])=[CH:37][CH:36]=2)=[CH:34][CH:33]=1
Reactant: O=[N+]([O-])c1ccc2nccc(Cl)c2c1
Reactant: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc(N)cc3)cc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc(Nc4ccnc5ccc([N+](=O)[O-])cc45)cc3)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-chloro-6-nitroquinoline (70 mg, 0.33 mmol) in MeOH (10 mL) was added compound D5 (100 mg, 0.28 mmol), and the mixture was stirred at 20° C. for 1 h (until a clear solution obtained). A drop of c. HCl was then added, and refluxing was continued for a further 20 h. TLC analysis (eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:AcOH) showed some D5 remained, so more 4-chloro-6-nitroquinoline (35 mg, 0.16 mmol) was added and refluxing was continued for a further 4 h. The reaction mixture was then diluted with EtOAc and the resulted precipitate was filtered and washed sequentially with EtOAc, CH2Cl2 and diisopropylether, and finally crystallized from MeOH/EtOAc to give Cpd. N1 (111 mg, 75%), mp (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ 14.50 (br, 1H, N+H); 11, 42, (brs, 1H, NH), 11.10 (s, 1H, NH), 10.58 (s, 1H, NH), 9.82 (d, J=2.1 Hz, 1H, ArH), 8.72 (dd, J=9.3, 2.2 Hz, 1H, ArH), 8.60 (d, J=7.0 Hz, 1H, ArH), 8.42 (d, J=7.4 Hz, 2H, ArH), 8.24 (d, J=8.6 Hz, 1H, ArH), 8.15 (d, J=8.6 Hz, 2 H, ArH), 8.04 (d, J=8.8 Hz, 2H, ArH), 7.51 (t, J=8.3 Hz, 4H, ArH), 7.34 (d, J=7.5 Hz, 2H, ArH), 6.91 (d, J=7.0 Hz, 1H, ArH), 4.01 (s, 3H, N+CH3); LCMS 489+ve.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[S:11])[CH:5]2[CH3:12].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:13][C:5]1([CH3:12])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[NH:7][C:6]1=[S:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2c(c1)C(C)C(=S)N2
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)C(C)(Cl)C(=S)N2

Procedure:
A solution of 5-methyl-3-methylthiooxindole (1.00 g, 0.0052 mol) and N-chlorosuccinimide (700 mg, 0.0053 mol) in carbon tetrachloride (100 ml) was stirred at room temperature for 1 hour. The precipitate was removed by filtration and the filtrate was evaporated to give the crude 3-chloro-5-methyl-3-methylthiooxindole, which was dissolved in tetrahydrofuran (20 ml) and added to a vigorously stirred slurry of red mercuric oxide (1.13 g, 0.0052 mol) and boron trifluoride etherate (745 mg, 0.0052 mol) in 70 ml of 20 percent aqueous tetrahydrofuran. After stirring at room temperature for 2 hours, the reaction mixture was filtered through a Celite pad and the filtrate was extracted with two 100-ml portions of chloroform. The chloroform extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel. Elution with chloroform gave 5-methylisatin (610 mg, 0.0038 mol, 74%), mp 185°-187° (recrystallized from ethanol) as red needles.
Reaction SMILES: CO.[C:3]([O:7][C:8]([N:10]([CH2:38][C:39]1[CH:48]=[CH:47][C:42]2[O:43][CH2:44][CH2:45][O:46][C:41]=2[CH:40]=1)[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]([O:31]CCCC)=[O:30])[CH:27]=3)[C:22]([CH3:36])=[CH:21][C:20]2=[O:37])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O.[OH-].[Li+]>O>[C:3]([O:7][C:8]([N:10]([CH2:38][C:39]1[CH:48]=[CH:47][C:42]2[O:43][CH2:44][CH2:45][O:46][C:41]=2[CH:40]=1)[CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]([OH:31])=[O:30])[CH:27]=3)[C:22]([CH3:36])=[CH:21][C:20]2=[O:37])[CH2:15][CH2:16]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCCCOC(=O)c1ccc2c(C)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(C(=O)O)ccc12
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
To 11 mL of a methanol solution containing 0.65 g of butyl 1-(2-(4-((tert-butoxycarbonyl) (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylate, 55 mg of lithium hydroxide monohydrate was added and stirred for 30 min. Then, 55 mg of lithium hydroxide monohydrate and 1.1 mL of water were added and stirred for 2 hours. The methanol was removed under reduced pressure, water and chloroform were added, and adjusted to pH 5.0 with acetic acid. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.60 g of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylic acid as a white foam.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)=[O:4].[OH-].[Na+].S(=O)(=O)(O)O>C1COCC1.CO>[C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCc1ccc2c(c1)NC(=O)C1CCCC21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc2c(c1)NC(=O)C1CCCC21
Yield: 89.8 %

Procedure:
A solution of 4.0 g (14.6 mmol) of 7-(2-methoxycarbonylethyl)-1,2,3,3a,5,9b-hexahydro-cyclopenta[c]quinolin-4-one in 60 ml of THF and 100 ml of methanol is stirred for 24 hours with 29 ml of 1 M aqueous sodium hydroxide solution. The batch is set at pH 5 with 10% sulfuric acid and extracted with dichloromethane and ethyl acetate. The combined extracts are freeze-dried (Na2SO4) and concentrated by evaporation in a vacuum. After column chromatography on silica gel with dichloromethane-methanol, 3.4 g of 7-(carboxyethyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one is isolated.
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:28][CH2:27][CH2:26][C@H:11]2[C:12]([NH:14][C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:64]([O:66][C:67](=[O:71])[CH2:68][CH2:69][NH2:70])[CH3:65]>CN(C=O)C>[CH2:64]([O:66][C:67](=[O:71])[CH2:68][CH2:69][NH:70][C:23](=[O:24])[CH:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:14][C:12](=[O:13])[C@@H:11]1[CH2:26][CH2:27][CH2:28][N:10]1[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:29])=[CH:2][CH:3]=1)(=[O:8])=[O:9])[CH3:65]
Reactant: CCOC(=O)CCN
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CCNC(=O)C(Cc1ccccc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine (˜2 eq.) in DMF was added BOP (˜2.1 eq.) and NMM (˜4 eq.), and the reaction was stirred at room temperature for about 45 minutes. β-alanine ethyl ester (˜2 eq.) was added and the reaction stirred for about 16 hours at room temperature. The reaction mixture was extracted with water and diethyl ether. The combined organic solution was then washed with 0.2 N HCl, sat. NaHCO3 and sat. NaCl solutions. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (50% EtOAc/Hexane, Rf=0.18) to yield the title compound as a colorless oil, which was determined to be a mixture of diastereomers by NMR.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([O:12]CC)=[O:11])[N:5]=[CH:4][C:3]=1[NH2:15].[H-].[Na+].[C:18]12([C:28](Cl)=[O:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[NH:15][C:28]([C:18]12[CH2:27][CH:22]3[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]3)[CH2:25]1)[CH2:19]2)=[O:29]
Reactant: CCOC(=O)Cn1ncc(N)c(Br)c1=O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)Cn1ncc(NC(=O)C23CC4CC(CC(C4)C2)C3)c(Br)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(5-bromo-4-amino-6-oxopyridazin-1(6H)-yl)acetate (100 mg, 0.362 mmol) in tetrahydrofuran (2 mL) was mixed with sodium hydride (58 mg, 1.46 mmol) and adamantanecarbonyl chloride (144 mg, 0.724 mmol) at room temperature and stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was mixed with water and ethyl acetate and extracted with 1 M aqueous sodium hydroxide. The aqueous layer was acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed by distillation to give the desired product.