Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=2)=[CH:5][CH:4]=1.[O:24]1[CH2:30][C:29](=[O:31])[O:28][C:26](=[O:27])[CH2:25]1.C(N(CC)CC)C.ClCCl>C(COC)OC.C(O)C.O>[C:20]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([NH:2][C:29](=[O:31])[CH2:30][O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:4][CH:5]=2)[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]=1[OH:19])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Reactant: O=C1COCC(=O)O1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(-c2ccc(NC(=O)COCC(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 70 °C

Procedure:
To a mixture of 16.7 g (0.050 mole) of 4'-amino-3,-5-di-tertiary-butyl-4-hydroxybiphenyl hydrochloride and 7.0 g (0.060 mole) of oxydiacetic anhydride in 200 ml of glyme was added 0.050 mole of triethylamine and the solution was warmed at 70° C. for one hour. The solution was cooled and a 50:50 mixture of dichloromethane and water was added. The organic layer was separated, washed with water twice and dried over magnesium sulfate. Filtration and evaporation provided a residue which was triturated with hexane and chilled. The solid was separated by filtration. Recrystallization from a mixture of chloroform and hexane gave a grey solid. The solid was dissolved in 23 ml of ethanol, the solution was filtered and 10 ml of water was added to the filtrate. The filtrate was cooled and the resulting precipitate was separated by filtration and dried to provide N-(3',5'-di-tertiary-butyl-4'-hydroxy-4-biphenylyl)diglycolamic acid, m.p. 183°-184° C. Analysis: Calculated for C24H31NO5 : % C, 69.7; % H, 7.5; % N, 3.4; Found: % C, 69.9; % H, 7.6; % N, 3.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](I)[CH:33]([CH3:35])[CH3:34].[Cl-].[Na+]>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CI
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-benzyloxycarbonylamino-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (1.00 g, 2.59 mmol) in dimethylformamide (10 mL) was cooled to 0° C. under argon. Sodium hydride (60 wt %, 156 mg, 3.89 mmol) was added followed by isobutyl iodide. Let warm to room temperature and stirred overnight. The reaction was worked up with methylene chloride and saturated sodium chloride. The organic extracts were dried over sodium sulfate, filtered and concentrated. Chromatography (silica gel, 5 to 50% ethyl acetate in hexane gradient elution), giving the title compound (0.92 g). MS 442 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:14]O>>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:14])=[O:8])=[CH:5][NH:4][N:3]=1
Reactant: CO
Reactant: Cc1n[nH]cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c[nH]nc1C
Reaction time: 12 h
Yield: 57 %

Procedure:
To a solution of 3-methyl-1H-pyrazole-4-carboxylic acid (1.26 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 45 mmol) at 0° C. The mixture was stirred for 12 hours. The solvent was evaporated in vacuo. To the residue, saturated sodium bicarbonate aqueous solution was added and the mixture was extracted with ethyl acetate (100 mL×3), the organic phase was dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 3-methyl-1H-pyrazole-4-carboxylate (0.8 g, 57%). 1H NMR (300 MHz, CDCl1): δ 7.87 (s, 1H), 3.84 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:14]3[C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH:6]=[C:5]2[CH2:20][CH2:21][CH2:22][CH2:23][C:4]=12.[H-].[Na+]>CN(C=O)C>[CH2:23]([N:8]1[C:7]2[CH:6]=[C:5]3[CH2:20][CH2:21][CH2:22][CH2:23][C:4]3=[C:3]([O:2][CH3:1])[C:15]=2[C:14]2[C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:15][CH:3]=1
Reactant: COC(=O)c1cccc2[nH]c3cc4c(c(OC)c3c12)CCCC4
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(OC)c3c(cc1n2Cc1ccccc1)CCCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 132.9 %

Procedure:
A solution of 11-methoxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester, (0.155 g, 0.5 mM) in 5 mL DMF was added to a 60% NaH mineral oil dispersion (0.04 g, 1.0 mM, washed twice with hexane) at room temperature. Following cessation of gas evolution, benzyl bromide (0.067 mL, 0.094 g, 0.55 mM) was added and the mixture stirred at room temperature for 3 h. The mixture was diluted with ethyl acetate and H2O, the solvent layers separated, and the aqueous layer extracted with ethyl acetate (4×25 mL). The combined ethyl acetate extracts were washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, concentrated in vacuo, and triturated with hexanes. The resultant tan solid was dried in vacuo, and purified by column chromatography on silica gel (elution with 9:1 toluene/ethyl acetate) to afford 0.133 g (66%) of the title compound 5-benzyl-11-methoxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazole-1-carboxylic acid, methyl ester as an off-white foam (MP 144–146° C., MW 399.49).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([O:20][CH2:21][CH2:22][OH:23])=[N:16][CH:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:28]([C:27]1[CH:26]=[C:25]([CH:32]=[CH:31][CH:30]=1)[O:23][CH2:22][CH2:21][O:20][C:15]1[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[N:19][CH:18]=[CH:17][N:16]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: O=Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the compound obtained in step 2 above (1.5 g, 4.7 mmol) in dry tetrahydrofuran (THF; 10 mL) was treated with 3-hydroxybenzaldehyde (0.74 g, 6.06 mmol) and triphenylphosphine (1.59 g, 6.06 mmol). This solution was stirred at room temperature then treated with diethyl azodicarboxylate (0.96 mL, 6.06 mmol) in dry THF (5 mL). After 1 hr, TLC indicated some remaining 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol. The reaction was heated at reflux under nitrogen for 5 h, then left to cool to room temperature overnight. TLC again showed unreacted starter. The mixture was treated with further triphenylphosphine (0.80 g, 3.03 mmol), diethyl azodicarboxylate (0.5 mL, 3.03 mmol) and 3-hydroxybenzaldehyde (0.40 g, 3.03 mmol), then stirred at RT for a further 3 hrs (reaction complete by TLC). The volatiles were removed in vacuo and the residue was purified by flash column on silica gel, eluting with petroleum ether/ethyl acetate (2:1). This furnished 0.33 g (16%) of the title product as a colourless oil. 1H NMR (CDCl3) δ 1.5 (s, 9H); 3.5 (bs, 8H), 4.45 (m, 2H); 4.75 (m, 2H); 7.2 (d, 1H); 7.45 (s, 1H); 7.5 (m, 2H); 7.6 (s, 1H); 7.75 (s, 1H).
Reaction SMILES: C(O)CO.[CH3:5][O:6][C:7](=[O:35])[C:8]1[CH:13]=[C:12](Br)[CH:11]=[C:10]([CH3:15])[C:9]=1[N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[CH:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O)=[O:37].C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.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>[CH3:5][O:6][C:7]([C:8]1[CH:13]=[C:12]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH:36]=[O:37])[CH:11]=[C:10]([CH3:15])[C:9]=1[N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:35]
Reactant: O=Cc1ccccc1B(O)O
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
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: OCCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccccc2C=O)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To 5 ml of degassed ethylene glycol dirncthyl ether, was added 505.4 mg (1.0 mmol) of the product of Example 89, 165 mg (1.1 mmol) of 2-formylbenzene boronic acid, 58 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium and 1 ml (2.0 mmol) of 2M aqueous Na2CO3 and the mixture ws heated to reflux under nitrogen for 18 hr. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with EtOAc/Hexane (1:1) as eluant to provide 499 mg (94%) of the desired product as an yellow solid. Electrospray Mass Spec 531 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]2[CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:22][CH2:23][CH3:24].[I-:25].[Na+]>C(C(C)=O)C>[I:25][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]2[CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:22][CH2:23][CH3:24]
Reactant: [I-]
Reactant: CCCc1c(OCCCCl)ccc2c1OC(CCC(=O)OC)CC2
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OC)CC2

Procedure:
The compound of Example 2 (1.6 g, 4.521 mmol) was mixed with sodium iodide (6.8 g, 45.21 mmol) and methyl ethyl ketone (100 ml). The reaction mixture was stirred and refluxed overnight. The solvent was removed under vacuum and 100 ml of water was added to the residue. The solution was extracted three times with ethyl acetate. The extracts were combined, filtered, dried over magnesium sulfate and the solvent was removed under vacuum to give the product as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Yield: 92.5 %

Procedure:
To 1.2 g (4.0 mmol) of codeine in 40 mL of methanol was added 100 mg of 10% Pd—C. The resulting reaction mixture was hydrogenated under pressure of 50 psi. The solution was filtered through CELITE (Celite Corporation), and the filtrate was concentrated to give 1.12 g (3.7 mmol, 93%) of dihydrocodeinone as a white solid. ES (+) m/z 301.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>C(O)(C)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][N:35]([CH2:20][CH:2]([OH:1])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]3[C:14]4[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=4[O:12][N:11]=3)[CH2:6][CH2:5]1)[CH2:34][CH2:33]2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)CN(CC(O)CN1CCC(c3noc4cc(F)ccc34)CC1)CC2
Reaction time: 8 h
Yield: 11 %

Procedure:
A stirred mixture of 1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.2 g, 11.6 mmol), K2CO3 (2 gm, 1.25 eq) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.3 g, 1,25 eq) in isopropyl alcohol (200 ml) was heated at reflux for 6 hours. The mixture was cooled and filtered. The solvent was removed to about 50 ml and the solution was allowed to stand overnight. Crystals (0.6 g) formed and were collected. The mother liquor was concentrated to a white solid. Recrystallization twice from ethanol yielded the product (1.95 g, m.p. 153-154° C.
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.[C:14](=[O:16])=[O:15]>OCC(CO)O>[OH:13][C:1]1[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[C:2]=1[C:14]([OH:16])=[O:15]
Reactant: CCCCCc1cc(O)cc(O)c1
Reactant: O=C=O
Solvent: OCC(O)CO
Product: CCCCCc1cc(O)c(C(=O)O)c(O)c1

Procedure:
A mixture of olivetol (2.1 g, 12 mM), KHCO3 (4.9 g, 39 mM), and solid CO2 (1.95 g, 44.3 mM) in glycerol (5.1 mL) was heated in a stainless steel bomb to 145° C. at 220 psi for 5 hours. The reaction was cooled and removed from the reaction vessel using water to transfer. The aqueous solution was carefully acidified to a pH=3 with 1 N HCl to give a precipitate. The solids were filtered, washed with water and dried to give the desired product. MS (ESI(−)) m/e 223 (M−H)+; 1H NMR (300 MHz, CDCl3) δ 9.40 (bs, 2H), 6.37 (s, 2H), 2.52 (t, 2H), 1.66-1.57 (m, 2H), 1.37-1.29 (m, 4H), 0.93-0.87 (m, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]([NH:17][CH:18]([CH3:23])[CH2:19][S:20]([OH:22])=[O:21])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:24]Br>O>[CH2:7]([O:14][C:15]([NH:17][CH:18]([CH3:23])[CH2:19][S:20]([Br:24])(=[O:22])=[O:21])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(CS(=O)O)NC(=O)OCc1ccccc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(CS(=O)(=O)Br)NC(=O)OCc1ccccc1
Yield: 102.1 %

Procedure:
In water (10 ml) was dissolved 0.52 g (3.8 mmol) of potassium carbonate and 1.73 g (6.7 mmol) of 2-(benzyloxycarbonylamino)propane-1-sulfinic acid was added thereto, after which 1.07 g (6.7 mmol) of bromine was added dropwise thereto (water was properly added because crystals were precipitated during the dropwise addition to make stirring difficult). After stirring at room temperature for 30 minutes, the crystals were filtered and then washed with water to obtain 2.30 g (quantitative) of 2-(benzyloxycarbonylamino)propane-1-sulfonyl bromide.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH2:15][C@H:14]([O:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.NN>C(O)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH2:15][C@H:14]([O:17][NH2:18])[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1O[C@H]1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Agent: NN
Solvent: CCO
Product: NO[C@H]1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Yield: 90.9 %

Procedure:
A solution of (S)-2-(1-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-yloxy)isoindoline-1,3-dione (3.74 g, 8.40 mmol) and hydrazine solution (0.373 g, 9.3 mmol) in ethanol (16 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, the resulting solid was filtered off and washed with diethyl ether (30 ml), and the filtrate was concentrated in vacuo to give (S)—O-(1-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-yl)hydroxylamine (2.37 g, 90%) as greenish oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:14][CH:13]=2)=[N:6][C:7]=1[C:8]([NH:10][NH2:11])=[O:9].[NH2:23][C:24]1[N:29]=[C:28]([C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[CH:21][CH:22]=2)=[N:6][C:7]=1[C:8]([NH:10][NH:11][C:30]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:23])[N:29]=1)=[O:31])=[O:9]
Reactant: Nc1cccc(C(=O)O)n1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3cccc(N)n3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-[5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl]-N,N-dimethyl-benzamide (100 mg, 0.3163 mmol) and 6-aminopyridine-2-carboxylic acid (43.69 mg, 0.3163 mmol) in DMF (1.000 mL) was treated with triethylamine (32.01 mg, 44.09 μL, 0.3163 mmol) then warmed slightly. The mixture was cooled to room temperature and then treated with (benzotriazol-1-yloxy-dimethylamino-methylene)-dimethyl-ammonium tetrafluoroborate (121.9 mg, 0.3796 mmol) and stirred at room temperature overnight. The mixture was poured dropwise onto water (5 ml) with rapid stirring, stirred at room temperature for 1 h then filtered to give a wet paste which was dried under high vacuum at 100° C. overnight. Used directly in the next step without purification.
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH2:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH:20][S:34]([CH3:33])(=[O:36])=[O:35])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1NS(C)(=O)=O)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 25 °C

Procedure:
To a solution of 12.5 mg 20b in 2 mL methylene chloride was added 3.2 μL methanesulphonyl chloride and 9.2 μL N,N-diisopropylethylamine. The mixture was stirred at room temperature. After 1 h the mixture was diluted with methylene chloride and was washed with water. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC on a reversed phase C18 column to give 1.8 mg of compound 29a.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=[O:17])=[CH:11][CH:10]=2)O1.Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[NH:31][N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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]>[O:39]=[C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:26]3)=[O:17])=[CH:13][CH:14]=2)=[N:30][NH:31]1
Reactant: CC1(C)OB(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)OC1(C)C
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2n[nH]c(=O)c3ccccc23)cc1)N1Cc2ccccc2C1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
105 mg N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoindoline-2-carboxamide (0.288 mmol) and 53 mg 4-chloro-1,2-dihydrophthalazin-1-one (0.288 mmol) were dissolved in 2.5 ml dioxane. Cesium carbonate (474 mg, 1.44 mmol) was dissolved in 0.25 ml water and the resulting solution added to the reaction mixture. After the addition of 27.8 mg [1,1′-bis(diphenylphosphino)-ferrocene]dichlorpalladium(II) (0.038 mmol) the reaction mixture was flushed with nitrogen and stirred for 30 minutes in the microwave (Biotage Initiator 2.5) at 110° C. Dioxane was removed under reduced pressure, water and dichloromethane added to the residue and the formed precipitation was filtered. After dissolving the solid matter in a larger amount of dichloromethane/methanol 8:2, silica gel was added and subsequently the solvent was removed under reduced pressure. This residue was was purified by column chromatography using dichloromethane/methanol 95:5. 1H NMR (DMSO-d6, 400 MHz): 6 ppm 12.73 (s, 1H), 8.55 (s, 1H), 8.33 (dd, 1H), 7.85-7.92 (m, 2H), 7.73-7.78 (m, 3H), 7.48 (d, 2H), 7.35-7.38 (m, 2H), 7.30-7.33 (m, 2H), 4.81 (s, 4H). MS (ESI(−)) m/e 383.2 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:10](=[O:11])[O:9][CH:8]1[CH2:12][CH:13]([O:25][C:26]([CH:28]([NH:33][C:34]([CH3:36])=[O:35])[CH2:29][C:30]([NH2:32])=[O:31])=[O:27])[CH2:14][CH:15]=[CH:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[H][H]>[Pt]=O.CO>[CH3:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]([O:25][C:26]([C@@H:28]([NH:33][C:34]([CH3:36])=[O:35])[CH2:29][C:30]([NH2:32])=[O:31])=[O:27])[CH2:12][C@@H:8]1[O:9][C:10](=[O:11])[C@H:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: [H][H]
Reactant: CCCCCC=CCC=CCC(CC1OC(=O)C1CCCCCC)OC(=O)C(CC(N)=O)NC(C)=O
Agent: O=[Pt]
Solvent: CO
Product: CCCCCCCCCCC[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(N)=O)NC(C)=O
Reaction time: 2 h
Yield: 100.3 %

Procedure:
Esterastin (95 mg) was taken up into 10 ml of methanol, and this methanolic solution of esterastin was admixed with 20 mg of platinum oxide as the hydrogenation catalyst. The mixture was subjected to hydrogenation with hydrogen gas at 20 lbs. per square inch at ambient temperature for 2 hours. After the reduction was completed, the reaction mixture was filtered to remove the platinum oxide. The filtrate (the reaction solution) was concentrated to dryness to yield 96 mg of a colorless powder of tetrahydroesterastin which gave a single spot in a silica gel thin layer chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:16][C:17]1[N:18]=[CH:19][C:20]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]3[CH:29]=[C:30]([NH:34]C(=O)OC(C)(C)C)[CH:31]=[CH:32][CH:33]=3)[C:21]=2[N:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C:30]1[CH:29]=[C:28]([N:23]2[C:21]3[N:22]=[C:17]([NH:16][C:4]4[CH:5]=[CH:6][C:7]([N:9]5[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]5)=[CH:8][C:3]=4[O:2][CH3:1])[N:18]=[CH:19][C:20]=3[CH:26]=[CH:25][C:24]2=[O:27])[CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
The crude 1a from above was treated with DCM (20 mL) and TFA (20 mL) and stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure (rotary evaporator) and purified on a silica gel column (1-20% 2M NH3/MeOH in DCM) affording 8-(3-aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b) (470 mg, 1.03 mmol, 79% yield) as a brown amorphous solid. m/z (ESI, +ve ion) 458.0 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.67 (1H, s), 7.88 (1H, d, J=9.4 Hz), 7.63 (1H, d, J=8.2 Hz), 7.32 (1H, t, J=8.0 Hz), 6.91 (1H, dd, J=8.1, 1.5 Hz), 6.59-6.65 (2H, m), 6.53-6.59 (1H, m), 6.46-6.52 (1H, m), 6.24 (1H, br. s.), 3.88 (3H, s), 3.21 (4H, br. s.), 2.84 (4H, br. s.), 2.53 (3H, s).