Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2=[N:4][CH:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:20]1([NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)=[O:25])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]1([NH:23][C:24](=[O:25])[C:26]2[CH:31]=[CH:30][C:29]([C:2]3[N:6]4[C:7]5[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]4=[N:4][CH:3]=3)=[CH:11][CH:10]=[CH:9][CH:8]=5)=[CH:28][CH:27]=2)[CH2:21][CH2:22]1
Reactant: O=C(NC1CC1)c1ccc(B(O)O)cc1
Reactant: CC(C)CNc1nc2ccccc2n2c(Br)cnc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC(C)CNc1nc2ccccc2n2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 140 °C
Yield: 10.2 %

Procedure:
(1-bromo-imidazo[1,2-a]quinoxalin-4-yl)isobutyl-amine (20 mg, 0.07 mmol), [4-[(cyclopropylamino)carbonyl]phenyl]-boronic acid (21.8 mg, 0.11 mmol), Pd(dppf)Cl2 (1.26 mg, 0.007 mmol) and potassium carbonate (212 μL, 1M in water) were combined in 2 mL NMP in a sealed vial and heated at 140° C. under microwave irradiation for 40 min. After cooling, the solution was filtered and subjected to preparative HPLC to give N-cyclopropyl-4-(4-isobutylamino-imidazo[1,2-a]quinoxalin-1-yl)-benzamide (2.86 mg, 10%): 1H-NMR (300 MHz, d6-DMSO): δ=8.60 (1H, d), 7.97 (2H, d), 7.71 (1H, t), 7.69 (2H, d), 7.54 (1H, d), 7.52 (1H, s), 7.28 (1H, dd), 7.19 (1H, d), 6.91 (1H, dd), 3.39 (2H, dd), 2.86 (1H, m), 2.09 (1H, sept), 0.96 (6H, d), 0.70 (2H, d), 0.55 (2H, d) ppm; UPLC-MS: RT=1.14 min; m/z (ES+) 400.4 [MH+]; required MW=399.5.
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)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:16]([OH:18])=[O:17].[CH2:19](O)[CH2:20][CH3:21].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17]
Reactant: O=C(O)c1ccc2sc3ccccc3c(=O)c2c1
Reactant: CCCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCOC(=O)c1ccc2sc3ccccc3c(=O)c2c1
Reaction time: 72 h

Procedure:
Finally, propyl thioxanthen-9-one-2-carboxylate (S-20) was prepared. Thioxanthen-9-one-2-carboxylic acid (35 g, 137 mmol) was suspended in a mixture of toluene (250 mL), n-propanol (250 mL), and concentrated sulfuric acid (2 mL) and heated at reflux with stirring for 3 d. The reaction mixture was concentrated, and the resulting solid residue was washed with water and dried. The product was purified by recrystallization from heptane to provide 26.6 g (65% of theory) of a pale yellow solid.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11](=[O:49])[C@@H:12]([C@H:39]([CH3:48])[O:40]CC1C=CC=CC=1)[NH:13][C:14](=[O:38])[C@H:15]([CH:27](CC1C=CC=CC=1)[C:28](=[O:30])[OH:29])[NH:16]C(OCC1C=CC=CC=1)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(O)(=O)C>CO.[Pd].[C]>[CH2:1]([C@H:3]([NH:10][C:11](=[O:49])[C@@H:12]([C@H:39]([CH3:48])[OH:40])[NH:13][C:14](=[O:38])[C@H:15]([CH2:27][C:28](=[O:29])[OH:30])[NH2:16])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)[C@H](C)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)CC(=O)O)[C@H](C)O)c1ccccc1
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a solution of 5.30 g (8.0 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-O-benzyl-D-threonine (S)-α-ethylbenzylamide in 150 ml of methanol were added 1.0 ml of acetic acid and 3.0 g of 5% Pd-carbon (water content 50%), and the mixture was reduced under hydrogen overnight at room temperature and then at 50° C. for 3 hours. The catalyst was removed by filtration, the resulting filtrate was concentrated under reduced pressure, and the residue was crystallized from water to obtain 1.60 g (4.6 mmols) of α-L-aspartyl-D-threonine (S)-α-ethylbenzylamide.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[C@@H:15]([CH:16]=[CH:17][C:18]23[O:31][CH2:30][CH2:29][O:28][C:19]2([O:24][CH2:25][CH2:26][O:27]3)[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][CH2:12]1)C.O1CCOCC1.[OH-].[Na+]>O>[CH2:26]1[CH2:25][O:24][C:19]2([O:28][CH2:29][CH2:30][O:31][C:18]2([CH:17]=[CH:16][C@@H:15]2[C@@H:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:32])=[O:3])[CH2:12][CH2:13][CH2:14]2)[O:27]1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC12OCCOC1(C=C[C@H]1CCC[C@@H]1CCCCCCC(=O)OCC)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCC12OCCOC1(C=C[C@H]1CCC[C@@H]1CCCCCCC(=O)O)OCCO2

Procedure:
A mixture of 0.9 g of 9,9;15,15-bis-(ethylenedioxy)-13-prostenoic acid ethyl ester, 60 ml of dioxan, 40 ml of H2O and 0.08 g of NaOH is boiled for 2 hours. The solvent is distilled. After recrystallization of the residue from methanol, the sodium salt of 9,9;15,15-bis-(ethylenedioxy)-13-prostenoic acid is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:37][NH2:38]>C1COCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26]/[C:25](=[N:37]/[NH2:38])/[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N/C(=N/N)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (2 g, 2.05 mmol) in THF (350 mL) was added hydrazine monohydrate (645 μl, 20.51 mmol) to give a yellow solution. The resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered to remove insoluble black particles and concentrated to dryness under reduced pressure. The resulting yellow solid was used directly in the following step as crude without any further purification. LCMS (Method D): RT=1.04 min, M+1=486.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27].[Na]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[NH:9][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccccc1Br
Reactant: Nc1ccc(-c2ccccc2)cc1-c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: Fc1ccccc1Nc1ccc(-c2ccccc2)cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 61.9 %

Procedure:
2,4-diphenylaniline (12 mmol), 1-bromo-2-fluorobenzene (10 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.15 mmol), (±)-2,2′-bis(diphenylphosphine)-1,1′-binaphthalene (0.3 mmol) and sodium tert-butoxie (14 mmol) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 2,4-diphenyl-N-2-fluorophenylbenzenamine (2.1 g) is yielded.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:28]C(OC(C)(C)C)=O)[CH:16]([C:24]([O:26][CH3:27])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+]>C(O)=O>[NH2:28][C@H:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH:16]([C:24]([O:26][CH3:27])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: COC(=O)C(C(=O)OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cccc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)C(C(=O)OC(C)(C)C)[C@H](N)c1cccc(OCc2ccccc2)c1
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To tert-butyl methyl 2-{(1S)-[3-(benzyloxy)phenyl][(tert-butoxycarbonyl)amino]methyl}propanedioate (600 mg, 1.24 mmol) was added 0° C. cold formic acid (13.8 mL) and the solution was stored at 5° C. for 20 hours. Ice was added and pH was adjusted to 8 by addition of aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with ethyl acetate. The combined extracts were washed with aqueous sodium hydrogen carbonate solution and brine and dried over sodium sulfate. Concentration under reduced pressure yields 390 mg of raw tert-butyl methyl 2-{(1S)-amino[3-(benzyloxy)phenyl]methyl}propanedioate. (3R)-1-{3-[1-(Tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidine-3-carboxylic acid (447 mg, 1.21 mmol) were suspended in N,N-dimethylformamide (14 mL) and cooled to 0° C. HATU (646 mg, 1.7 mmol), a solution of the raw tert-butyl methyl 2-{(1S)-amino[3-(benzyloxy)phenyl]methyl}propanedioate (780 mg, 1.21 mmol) in N,N-dimethylformamide (14 mL) and N-ethyl-diisopropylamine (350 μL, 3.64 mmol) were added. The mixture was stirred at 0° C. for 2 hours. Ice water and saturated ammonium chloride solution was added, the mixture extracted with ethyl acetate and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on an amino phase column (Separtis® Flash-NH2, ethyl acetate in hexane 0 to 100%) to yield 700 mg of tert-butyl methyl-[(S)-[3-(benzyloxy)phenyl]({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)methyl]propanedioate.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=O)[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9](OC)=[O:10].CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1cccc(OCC(=O)N(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(CO)c1
Reaction time: 1.5 h
Yield: 68 %

Procedure:
Methyl 3-{[2-(dimethylamino)-2-oxoethyl]oxy}benzoate (for a preparation see Intermediate 16) (2.22 g, 9.36 mmol) was dissolved in THF (15 mL) and cooled in ice. The solution was then treated dropwise with an ether solution of LiAlH4 (1M, 10 mL) under nitrogen, and the mixture was stirred in an ice-bath for 1.5 h. LCMS indicated only completion. The mixture was cooled in ice and aqueous saturated sodium sulfate solution was added until a white precipitate formed. The mixture was stirred for 2 h and then allowed to stand O/W at RT. The mixture was then filtered, the solid was washed with ethyl acetate, and the filtrate and washings concentrated under reduced pressure. The resulting colourless oil was dissolved in methanol and applied to a pre-washed SCX-2 cartridge. The cartridge was washed with methanol and then eluted with 10% aqueous ammonia in methanol. The ammoniacal fractions were combined and evaporated under reduced pressure to give the title compound (1.236 g, 68%). LCMS (System A) RT=0.36 min, ES+ve m/z 196 (M+H)+.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1>C(O)C>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][N:4]=[C:3]2[NH2:1])=[CH:8][CH:9]=1
Reactant: COc1ccc2ccnc(Cl)c2c1
Reactant: N
Solvent: CCO
Product: COc1ccc2ccnc(N)c2c1
Temperature: 170 °C

Procedure:
Liquid ammonia (220 mL) was added to a solution of 32.8 g of 1-chloro-7-methoxy-isoquinoline in 420 mL of ethanol in a steel vessel. Nitrogen was pressed upon until an initial pressure of 20 atm. was obtained. This reaction mixture was heated for 2 days at 170° C. The solvent was removed in vacuo and the residue dissolved in water. The pH value was adjusted to pH 10 by adding aqueous sodium carbonate solution, followed by extraction with ethyl acetate. The organic extract was washed with brine and dried (Na2SO4). Evaporation of the solvent in vacuo gave pure 7-methoxy-isoquinolin-1-ylamine as a white solid. Yield 24.0 g (81%); m.p. 128-130° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:29][CH3:30])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=2)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:29][CH3:30])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCc1cc2cc(C(=O)OC)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCc1cc2cc(C(=O)O)ccc2[nH]1
Temperature: 50 °C

Procedure:
A 200 mL round bottom flask was charged with (S)-methyl 2-(3-(2-(tert-butoxycarbonylamino)butanamido)propyl)-1H-indole-5-carboxylate (1.67 g, 4.00 mmol), tetrahydrofuran (20 mL), and methanol (5.3 mL). 3N Sodium hydroxide (4.0 mL, 12.0 mmol) was added and the resulting mixture stirred and heated to 50° C. for 8 h. The resulting mixture was then cooled to room temperature and acidified with 1N hydrochloric acid. The resulting mixture was extracted two times with ethyl acetate (400 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield (S)-2-(3-(2-(tert-butoxycarbonylamino)butanamido)propyl)-1H-indole-5-carboxylic acid. 1H NMR (300 MHz, CD3OD) δ 8.20 (s, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 6.31 (s, 1H), 3.94-4.10 (m, 1H), 3.22-3.34 (m, 2H), 2.80-2.85 (m, 2H), 1.61-2.08 (m, 4H), 1.46 (s, 9H), and 0.93-1.03 (m, 3H); MS (ES+) 403 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH:24]([N:26]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:25])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][CH:24]([NH2:26])[CH3:25])=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C#Cc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)C#Cc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1

Procedure:
2-{3-[4-(6-Benzyloxypyridin-3-yloxy)phenyl]-1-methylprop-2-ynyl}isoindole-1,3-dione (2.0 g, 2.32 mmol) and hydrazine hydrate (0.57 ml, 11.82 mmol) were stirred in 40 ml of ethanol at 100° C. for 2 h. The reaction mixture was concentrated, heated with ethyl acetate and filtered hot. The filtrate was concentrated. Yield: 800 mg (100%), M+H+: 345.15.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[CH2:19][N:20]([C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]4[OH:29])[C:21](=[O:22])[C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CS(C)=O.[Cu]I>[OH:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:20]1[CH2:19][C:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([N:30]4[CH:34]=[CH:33][CH:32]=[N:31]4)=[CH:3][CH:4]=3)=[N:10][C:11]=2[C:21]1=[O:22]
Reactant: O=C1c2nc(Cc3ccc(Cl)nc3)c3ccccc3c2CN1[C@@H]1CCCC[C@H]1O
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C1c2nc(Cc3ccc(-n4cccn4)nc3)c3ccccc3c2CN1[C@@H]1CCCC[C@H]1O
Temperature: 120 °C

Procedure:
To a solution of (±)-5-[(6-chloropyridin-3-yl)methyl]-2-[trans-2-hydroxycyclohexyl]-1,2-dihydro-3H-pyrrolo[3,4-c]isoquinoline-3-one (Example 16, 0.040 g, 0.098 mmol) and pyrazole (0.020 g, 0.29 mmol) in 1 mL of dimethylsulfoxide under an atmosphere of nitrogen was added cesium carbonate (1.0 M aqeuous, 0.20 mL, 0.20 mmol), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (1.4 mg, 0.0098 mmol), and copper(I) iodide (0.93 mg, 0.0049 mmol). The mixture was heated at 120° C. for 15 hr, cooled to ambient temperature, and purified via preparative reverse phase HPLC to provide the titled compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 440.9 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.51-8.46 (m, 3H), 8.14 (d, J=8.2 Hz, 1H), 7.94-7.80 (m, 5H), 6.54-6.44 (m, 1H), 4.90 (s, 2H), 4.12-4.08 (m, 1H), 3.93-3.86 (m, 1H), 3.49-3.40 (m, 1H), 3.31 (s, 2H), 2.20-2.02 (m, 1H), 1.95-1.90 (m, 1H), 1.89-1.70 (m, 3H), 1.54-1.43 (m, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=O)[C@@H:13]([NH2:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1.B>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C@@H:13]([NH2:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:11]1
Reactant: N[C@H](C(=O)N1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Product: N[C@H](CN1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccccc1
Temperature: 70 °C

Procedure:
The product from Example 20, step b) (0.544 g) was dissolved in THF (5 ml) and borane [10.05 ml (1M in THF)] was added. The reaction was heated at reflux for 2 hours. The reaction was quenched slowly with MeOH and the solvents evaporated. Aqueous HCl (5 ml Concentrated HCl: 5 ml H2O) was added and the reaction heated at 70° C. for 1 hour. NaOH (2M) was added until pH 9 was reached. The product was extracted with CH2Cl2 and the combined organics washed with saturated aqueous NaHCO3, dried with Na2SO4 and solvents evaporated. Purification by flash chromatography (dichloromethane:methanol: 880 NH3 (aq) 89:10:1)gave the sub-title compound as an oil (0.377 g).
Reaction SMILES: [Na+].Cl[Au-:3](Cl)(Cl)Cl.OCCSCC.[SH:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]>O>[SH:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17].[Au:3]
Reactant: Cl[Au-](Cl)(Cl)Cl
Agent: CCSCCO
Agent: O=C(O)CNC(=O)CCS
Agent: [Na+]
Solvent: O
Product: [Au]

Procedure:
A solution of sodium tetrachloroaurate (35g) in distilled water (200 ml) was slowly added to a solution of ethyl 2-hydroxyethyl sulphide (20.5 g) in distilled water (200 ml). Solid addition of mercaptopropionylglycine (5.21 g) followed by vigorous stirring yielded gold mercaptopropionylglycine as a white solid (yield, based on gold, 85%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)[CH:34]=2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(N4CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc(C(=O)N2Cc3ccc(N4CCN(C)CC4)cc3C2)c(O)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-[5-(4-methyl-piperazin-1-yl)-1,3-dihydro-isoindol-2-yl]-methanone (8.61 g, 15.0 mmol) and 10% Pd/C (1.0 g) in methanol (200 mL) was stirred vigorously under a hydrogen atmosphere (˜1 atm) for 18 h at ambient temperature. The mixture was filtered through a plug of Celite and reduced in vacuo to give a purple oil. This residue was purified by column chromatography using an eluant of DMAW120 to give the title compound as its acetate salt. This salt was taken up in MeOH (30 mL) and to the solution was added saturated HCl in EtOAc (20 mL). This mixture was stirred at ambient for 2 h and the solid formed collected by filtration and dried in vacuo to give the title compound as its hydrochloride salt (2.64 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (294 mg, 1.14 mmol), 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (409 mg, 1.22 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (645 mg, 1.38 mmol) in chloroform (10 mL). DIEA (1 mL, 5.73 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (534 mg, 0.92 mmol, 81%): LC-MS (ES) m/z=537 (M+H)+.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[Br:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl.[CH3:24][O:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:31])[CH3:30])[NH2:28]>>[CH3:24][O:25][C:26](=[O:32])[C@@H:27](/[N:28]=[CH:14]/[C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:7])[N:13]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=Cc1cccc(Br)n1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](/N=C/c1cccc(Br)n1)C(C)C
Temperature: 25 °C

Procedure:
Anhydrous magnesium sulfate (5.4 g), 6-bromopyridine-2-carboxaldehyde (5.0 g, 26.9 mmol) and triethylamine (3.75 mL, 26.9 mmol) were each added sequentially in one portion to a cooled (0° C.) solution of (L)-valine methyl ester hydrochloride (4.51 g, 26.9 mmol) and the reaction mixture was allowed to warm slowly to room temperature overnight under a nitrogen atmosphere. The mixture was then filtered and the filter cake washed with diethyl ether (100 mL) before evaporating the filtrate in vacuo. The residue was purified by column chromatography using 5:1 hexane/ethyl acetate as eluent to yield A469.1 (7.1 g, 88%). HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 0.86 min, M+H+=202.08