Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([O:18][CH2:19][CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]12[CH2:7][N:8]([CH2:9][CH2:10]1)[CH2:20][CH2:19][O:18]2
Reactant: Cc1ccc(S(=O)(=O)OCCOC2(c3nccs3)CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: c1csc(C23CCN(CCO2)C3)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To an ambient solution of tert-butyl 3-(thiazol-2-yl)-3-(2-(tosyloxy)ethoxy)pyrrolidine-1-carboxylate (2.3 g, 4.91 mmol) in dichloromethane (24.54 ml) was added trifluoroacetic acid (0.378 mL, 4.91 mmol). The reaction was stirred for 2 hours and was then concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and the solution was added slowly to an ambient mixture of potassium carbonate (6.78 g, 49.1 mmol) in dichloromethane (50 mL). The mixture was heated to 50° C. for 1 hour and then cooled to room temperature. The reaction was diluted with water (100 mL). The layers were separated, and the aqueous layer was extracted with additional dichloromethane (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and dried under reduced pressure, to give the title compound, which was used without further purification. MS ESI(+) m/z 197.1 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([OH:33])[C:25]=1[CH2:34][CH2:35][CH3:36])[C:9]=2[CH2:37][CH2:38][CH3:39])([O:3][CH2:4][CH3:5])=[O:2]>C(O)C.[Ni]>[C:1]([CH:6]1[CH2:15][C:14](=[O:16])[C:13]2[C:8](=[C:9]([CH2:37][CH2:38][CH3:39])[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([OH:33])[C:25]=3[CH2:34][CH2:35][CH3:36])=[CH:11][CH:12]=2)[O:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCc1c(OCCCCCOc2ccc3c(=O)cc(C(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O
Agent: [Ni]
Solvent: CCO
Product: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OCC)CC3=O)ccc(C(C)=O)c1O
Reaction time: 7 h
Yield: 51.2 %

Procedure:
2.45 g (4.55 mmole) of the compound from Example 2 was dissolved in 250 ml of absolute ethanol, 0.5 g W2Raney nickel added, and the mixture hydrogenated at 2 psi and room temperature for 7 hours. After removal of catalyst by filtration and solvent by rotary evaporation, the residue was purified by high pressure liquid chromatography to furnish 1.26 g (51%) of the title compound, mp 80°-81°. Calc: C, 68.87; H, 7.46. Found: C, 68.70; H. 7.43.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[C:27]([O:30][CH2:31][C:32]1[S:36][C:35]2=[CH:37][N:38]=[CH:39][N:34]2[CH:33]=1)(=[O:29])[CH3:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:38]3[CH:37]=[C:35]4[S:36][C:32]([CH2:31][O:30][C:27](=[O:29])[CH3:28])=[CH:33][N+:34]4=[CH:39]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: CC(=O)OCc1cn2cncc2s1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: CC(=O)OCc1c[n+]2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cc2s1
Yield: 13 %

Procedure:
The same procedure as in Example 1 was repeated except that 120 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 97 mg of 2-acetoxymethylimidazo[5,1-b]thiazole were used, thereby obtaining 17.9 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][S:20]([O:19][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[CH:18]=1)(=[O:21])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OS(C)(=O)=O)cc2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Oc1ccc2c(c1)CCNCC2
Yield: 81 %

Procedure:
A solution of 3-(tert-butyloxycarbonyl)-7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (3.8 g, 0.011 mol), trifluoroacetic acid (3.76 g, 0.033 mol) and dichloromethane (50 ml) was heated at 50° C. for 5 h. The solvents were then evaporated in vacuo and the residue partitioned between water (200 ml) and ethyl acetate (150 ml). The aqueous layer was removed and washed with ethyl acetate (100 ml) and then basified to pH 14 with 40% sodium hydroxide. The suspension was then extracted with ethyl acetate (3×150 ml) and the combined organic layers dried (Na2SO4). The solvents were evaporated in vacuo to give the title compound (2.15 g, 80%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4-fluorophenol (5.0 g) was dissolved in DMF (50 ml), ethyl 2-bromo-2-methylpropanoate (13.3 ml) and potassium carbonate (9.25 g) were added thereto, followed by stirring at 100° C. for 2 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1) to obtain ethyl 2-(4-fluorophenoxy)-2-methylpropanoate (5.13 g) as a colorless oily product.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[N:4]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C)C=O>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[O:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)=[CH:18][CH:17]=1
Reactant: OCCOc1ccc(Cn2cccn2)cc1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnc(OCCOc2ccc(Cn3cccn3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
To a mixture of 10 ml of anhydrous N,N-dimethylformamide and 96 mg of sodium hydride (60% oil dispersion) was added dropwise an anhydrous N,N-dimethyl-formamide (5 ml) solution of 500 mg of 2-[4-(1-pyrazolyl)methylphenoxy]ethanol (produced in Reference Production Example 1 described below) under stirring over 10 minutes. After stirring at 60° to 70° C. for 2 hours, the mixture was cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (5 ml) solution of 288 mg of 2-chloropyrimidine was added dropwise over 30 minutes. The mixture was then stirred at room temperature overnight and then at 60° to 70° C. for further 2 hours. The reaction mixture was poured into 50 ml of ice water, which was extracted with twice with 30 ml of toluene. The organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 339 mg of 4-(1-pyrazolyl)methyl-phenyl 2-(2-pyrimidyloxy)ethyl ether (compound 2). Yield, 50%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[CH3:5][O:6][C:7]1[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=1[C:9](Cl)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=1[C:9]([O:4][CH2:3][CH2:2][Cl:1])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCCl
Reactant: COc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccccc1C(OCCCl)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
2-Chloroethanol (4.02 ml, 60 mmol) and monomethoxytrityl chloride (9.2643 g, 30 mmol) were stirred in pyridine (150 ml) at room temperature for 3 hours. Cold water (15 ml) was added to the reaction solution and the mixture was stirred for 30 minutes, and the reaction mixture was extracted with chloroform (500 ml) and washed with water (200 ml ×3 times). The organic layer was dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was distilled under a reduced pressure. n-Hexane (100 ml) was added to the residue to effect crystallization, and thus 9.6307 g (yield=91%) of 2-chloroethyl monomethoxytrityl ether <1> was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[S:10][CH:11]=[CH:12][C:3]=12.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[I:41]I>O1CCCC1.O.ClCCl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[S:10][C:11]([I:41])=[CH:12][C:3]=12
Reactant: N#Cc1cnc2sccc2c1Cl
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cnc2sc(I)cc2c1Cl
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 50.6 %

Procedure:
To a solution of 4-chlorothieno[2,3-b]pyridine-5-carbonitrile (1.2 g, 6.16 mmol) [Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977)] in 72 mL of tetrahydrofuran at −78° C. is added dropwise 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (3.7 mL, 7.40 mmol). After stirring for 35 minutes, a solution of iodine (1.9 g, 7.40 mmol) in 8 mL of tetrahydrofuran is added dropwise over 20 minutes. The reaction mixture is stirred at −78° C. for 4 hours, then 85 mL of dichloromethane and 20 mL of water are added. The mixture is allowed to warm to room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic layer is washed with a solution of sodium thiosulfate, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with dichloromethane to provide 1.0 g of 4-chloro-2-iodothieno[2,3-b]pyridine-5-carbonitrile as colorless crystals, mp 181-182° C.; 1H NMR (DMSO-d6) δ 8.00 (s, 1H), 8.88 (s, 1H); MS 320.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH3:19][C:20]1[O:27][C:23](/[CH:24]=[N:25]\O)=[CH:22][CH:21]=1>N1C=CC=CC=1.CC(C)=O>[F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]/[N:25]=[CH:24]\[C:23]2[O:27][C:20]([CH3:19])=[CH:21][CH:22]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: Cc1ccc(/C=N\O)o1
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1O/N=C\c1ccc(C)o1
Temperature: 25 °C
Reaction time: 96 h
Yield: 18.5 %

Procedure:
In 75 ml of pyridine-acetone (pyridine:acetone=2:1) were dissolved 20 g (76 mmol) of ethyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 11.4 g (91 mol) of (Z)-5-methylfurfuraldoxime, and the solution was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure, and the residue was treated with water. Crystals precipitated were collected by filtration and washed with water. The crystals were dried under reduced pressure and dissolved in acetone, and insoluble matters were filtered off. The filtrate was concentrated, and the residue was chromatographed on silica gel with chloroform-acetone (7:1), followed by recrystallization from ethyl acetate-hexane to yield 4.6 g of ethyl 5-fluoro-6-[(Z)5-methylfurfurylideneaminooxy]-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 163°-164° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[Cl:25][C:26]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[CH3:33]>C(OCCO)C>[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:29]=[CH:28][C:27]=1[CH3:33]
Reactant: Cc1ccc(N)cc1Cl
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(C)c(Cl)c3)c2cc1OC
Yield: 99.2 %

Procedure:
Using an analogous procedure to that described in EXAMPLE 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 170.0 mg (1.2 mmol) of 2-chloro-4-amino-toluene to give 350.9 mg (99.4%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 353.9, 355.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:17]([C@@H:18]([NH2:20])[CH3:19])=[CH:16][C:15]3[C:10](=[C:11]([Cl:21])[CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[C:30](Cl)([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:17]([C@@H:18]([NH:20][C:30](=[O:31])[O:32][CH2:33][CH:34]3[C:46]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:40]4[C:35]3=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH3:19])=[CH:16][C:15]3[C:10](=[C:11]([Cl:21])[CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc(Cn2c([C@H](C)N)cc3cccc(Cl)c3c2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2c([C@H](C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc3cccc(Cl)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(4-methoxybenzyl)-3-(1-aminoethyl)-8-chloroisoquinolin-1(2H)-one (343) (20 g, 58.3 mmol, 1.0 eq) and NaHCO3 (12.7 g, 291.51 mmol, 5.0 eq) in DCM (120 mL) and water (60 mL) at RT, Fmoc-Cl (15.7 g, 61.22 mmol, 1.05 eq) was slowly added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (200 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford (S)-(9H-fluoren-9-yl)methyl 1-(2-(4-methoxybenzyl)-8-chloro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate (344).
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[CH2:17][CH2:16]2)=O)=[CH:7][CH:6]=1.[N+](C1C=CC(C(C2C=CC([N+]([O-])=O)=CC=2)CC(N2CCN(C3C=CC=CC=3OC)CC2)=O)=CC=1)([O-])=O>>[ClH:1].[ClH:1].[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:12][CH2:13][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[CH2:17][CH2:16]2)=[CH:34][CH:33]=1
Reactant: COc1ccc(C(CC(=O)N2CCN(c3ccccc3OC)CC2)c2ccc(OC)cc2)cc1
Agent: COc1ccccc1N1CCN(C(=O)CC(c2ccc([N+](=O)[O-])cc2)c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Product: COc1ccc(C(CCN2CCN(c3ccccc3OC)CC2)c2ccc(OC)cc2)cc1
Reaction time: 3 h

Procedure:
This product was obtained in accordance with the procedure described above, (in Example 3b), with the sole exception that Compound 4A was employed here in place of Compound 3A. In addition, extraction was carried out here with ethyl acetate rather than chloroform. The obtained residue was dissolved in diethyl ether; then, after treatment with charcoal, the resultant solution was acidified with excess hydrochloric acid (3 N solution, in diethyl ether). After 3 h, the precipitate was recovered by filtration; the title product melted at 163-171° C.
Reaction SMILES: [CH3:1][Li].Cl[C:4]1[C:14]2[C:13]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=3[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10][CH2:9][C:8]=2[N:7]=[C:6]([CH3:26])[N:5]=1>CCOCC.O.S>[Cl:19][C:17]1[CH:16]=[CH:15][C:13]2[C:14]3[C:4]([CH3:1])=[N:5][C:6]([CH3:26])=[N:7][C:8]=3[CH2:9][N:10]=[C:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:12]=2[CH:18]=1
Reactant: Cc1nc(Cl)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Reactant: [Li]C
Agent: S
Solvent: CCOCC
Solvent: O
Product: Cc1nc(C)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dropwise 13.2 ml (18.5 mmol) of a 1.4 M ether solution of methyl lithium was added to a suspension of 1.7 g (8.9 mmol) of cuprous iodide in 50 mL of ether which was cooled to 0°. A solution of 0.8 g (2.2 mmol) of 1,9-dichloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepine in 30 mL of ether was added dropwise to the ether solution of lithium dimethylcuprate which was further cooled to -25°. The mixture was stirred at -25° for 1 hr, warmed to room temperature, diluted with water and saturated with hydrogen sulfide. The resulting precipitate was removed by filtration over celite and he filtrate was concentrated at reduced pressure. Purification of the residue by column chromatography (silica gel, 10 g; eluent, 20% ether in methylene chloride) gave an oil which was crystallized from a mixture of ether and petroleum ether to give off-white needles, mp 121°-124°.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:9]2[CH:21]=[CH:22][CH:23]=[C:8]2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[Cl:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[C:7]([OH:24])[C:8]2=[CH:23][CH:22]=[CH:21][N:9]12
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(Cl)c2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2cccc(Cl)c2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(3-chloro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 376 (M+H)+.
Reaction SMILES: N#N.[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[CH:15])[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4].I[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>CCN(CC)CC.C1COCC1>[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Fc1ccc(I)cc1
Reactant: C#Cc1ccnc(NC(C)(C)C)n1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
To a mixture of Pd(PPh3)Cl2 (0.4 g) in Et3N (150 mL) and THF (150 mL) under a stream of N2, was added tert-butylamino-4-ethynylpyrimidine (18.6 g, 0.11 mol). After bubbling N2 into the solution for 15 min, 4-iodo-fluorobenzene (23.6 g, 0.11 mol) and Cul (0.22 g) were added sequentially. The mixture was stirred at rt for 2.5 h. The precipitate was filtered and washed with EtOAc. The filtrate was concentrated and the residue was diluted with EtOAc and loaded directly onto a short pad of silica gel. The product was eluted with 10% EtOAc in hexanes to afford the crude product, which was recrystallized from EtOAc/hexanes to give the title compound as a light yellow solid (25 g, 84%). TLC: Rf=0.30. mp 97-99° C. IR: 3287 (w), 2964 (w), 2222 (w), 1566 (s). 1H NMR: 8.26 (d, J=4.2 Hz, 1H), 7.60-7.55 (m, 2H), 7.10-7.00 (m, 2H), 6.65 (d, J=4.9 Hz, 1H), 5.22 (s, 1H), 1.45 (s, 9H). 13C NMR: 164.19, (162.19, 162.03), 157.77, 150.83, (134.35, 134.29), (117.84, 117.81), (115.94, 115.76), 112.37, 89.91, 87.24, 51.07, 28.86. Anal. Calcd for C16H16FN3: C, 71.36; H, 5.99; N, 15.60. Found: C, 71.25; H, 5.95; N, 15.66.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15](=[O:16])[CH2:14][NH:13][C:12]3[N:17]=[CH:18][C:19]([C:21]4[C:22]([CH3:29])=[CH:23][C:24]([C:27]#[N:28])=[N:25][CH:26]=4)=[N:20][C:11]2=3)[CH2:5][CH2:4]1.CO[C@H]1CC[C@H](C[N:39]2[C:44]3=[N:45]C([Sn](C)(C)C)=CN=C3NCC2=O)CC1.BrC1C(C)=CC(C#N)=NC=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>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].CN(C)C=O>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:11]3=[N:20][C:19]([C:21]4[CH:26]=[N:25][C:24]([C:27]5[N:45]=[CH:44][NH:39][N:28]=5)=[CH:23][C:22]=4[CH3:29])=[CH:18][N:17]=[C:12]3[NH:13][CH2:14][C:15]2=[O:16])[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc([Sn](C)(C)C)nc32)CC1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C#N)cc4C)nc32)CC1
Agent: [Pd]
Agent: Cc1cc(C#N)ncc1Br
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(-c5nc[nH]n5)cc4C)nc32)CC1
Temperature: 100 °C

Procedure:
5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinonitrile. 1-(((trans)-4-Methoxycyclohexyl)methyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.721 g, 1.64 mmol), 5-bromo-4-methylpicolinonitrile (0.323 g, 1.64 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.150 g, 0.164 mmol), triethylamine (0.687 mL, 4.93 mmol), tri-ortho-tolylphosphine (0.100 g, 0.328 mmol) and dimethylformamide (8 mL) were combined in a sealed reaction vessel. Nitrogen was bubbled through the reaction for 5 min and reaction was heated at 100° C. for 3 h. Reaction is filtered, concentrated and purified by silica gel column chromatography (0-80% ethyl acetate in hexanes). Fractions were combined and concentrated to afford the crude title compound used directly for next step (0.607 g, 1.55 mmol, 94% yield). MS (ESI) m/z 393.5 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36]CC)=[O:35]>CN(C=O)C>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([O:17][CH2:33][C:34]([OH:36])=[O:35])([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(OCC(=O)O)c2cccnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.1 %

Procedure:
To a solution of 1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol (200 mg, 0.597 mmol) in DMF (5 mL) was added potassium carbonate (412 mg, 2.98 mmol). After stirring for 5 min at RT, ethyl bromoacetate (200 mg, 1.19 mmol) was added into the reaction mixture, which was stirred at RT for 2 h. The progress of reaction was monitored by LCMS. The reaction was quenched with water and extracted with EtOAc. The aqueous layer was concentrated and residue was purified by reverse HPLC to yield 2-((1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-yl)oxy)acetic acid (80 mg). The resulting racemate was purified and resolved by chiral preparative HPLC. 1H NMR (CD3OD, freebase) δ (ppm): 8.5 (d, 1H), 8.36 (s, 1H), 7.8 (dd, 1H), 7.31 (m, 1H), 7.19 (s, 1H), 7.1 (d, 1H), 6.88 (d, 1H), 4.86 (m, 1H), 4.58 (s, 1H), 4.32 (d, 1H), 4.25 (m, 2H), 3.94 (m, 2H), 3.8 (m, 1H), 3.35 (s, 3H), 3.2 (m, 1H), 3.0 (m, 1H), 2.36 (s, 3H), 1.69 (s, 3H).