Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25](F)[CH:24]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:44][NH2:45]>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:24]=[C:25]3[C:26]([C:29]([NH2:30])=[N:44][NH:45]3)=[CH:27][CH:28]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CC[C@H](C(=O)NC2CCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: C[C@@H]1CC[C@H](C(=O)NC2CCCC2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Yield: 45.8 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-cyclopentyl-6-methyl-3-piperidinecarboxamide (174 mg, 0.412 mmol), 5 mL of EtOH, Hunig's base (0.288 mL, 1.647 mmol), and hydrazine anhydrous (0.078 mL, 2.471 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid and the yellow solution were carefully separated due to the black solid is heavier than yellow solution. Water (20 mL) was added to the yellow solution, and a solid formed. The solid was filtered and washed by water, dried in vacuum, and then treated with EtOAc and CH3OH. The solid in the solvent was filtered, washed by EtOAc, and dried in vacuum to afford the title compound (82 mg) as a light yellow solid. LC-MS (ES) m/z=435 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.14 (m, 3H), 1.65 (m, 12H), 2.14-2.33 (m, 1H), 2.76-3.08 (m, 1H), 3.93-4.12 (m, 1H), 5.38 (s, 2H), 6.07 (s, 2H), 6.57 (s, 1H), 7.57 (m, 1H), 7.69 (m, 1H), 7.87 (m, 1H), 7.94 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].OS(O)(=O)=O.[CH2:10]([O:17][C:18]([CH:20]([CH2:24][CH2:25][NH2:26])[C:21]([OH:23])=[O:22])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[C:2]([O:23][C:21](=[O:22])[CH:20]([C:18]([O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:19])[CH2:24][CH2:25][NH2:26])([CH3:3])([CH3:1])[CH3:4]
Reactant: NCCC(C(=O)O)C(=O)OCc1ccccc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(CCN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
600 ml of liquefied isobutylene and 6 ml of conc. H2SO4 were added to a solution of 172 g of benzyloxycarbonyl-4-aminobutyric acid in 600 ml of methylene chloride. The mixture was shaken for 3 days at room temperature in an autoclave, the isobutylene was distilled off, and the methylene chloride solution was washed twice with 10% sodium carbonate solution and once with water, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in ether and chromatographed over 620 g of basic Al2O3. Elution with ether followed.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[C:11]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:15][CH:14]=3)[CH:12]=2)[CH:9]=1)[CH3:2].CCCCCC.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:52])(=O)=O)=CC=1>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[C:11]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH3:20])=[CH:15][CH:14]=3)[CH:12]=2)[C:9]=1[F:52])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCOc1ccc2cc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3)nn2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOc1ccc2cc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3)nn2c1F
Reaction time: 1.5 h
Yield: 30.9 %

Procedure:
To a solution of tert-butyl {(1S)-2-[4-(6-ethoxypyrazolo[1,5-a]pyridin-2-yl)phenoxy]-1-methylethyl}carbamate (580 mg) in THF (10 mL) was added dropwise a hexane solution (1.6 M, 2.2 mL) of n-butyllithium at −78° C. under an argon atmosphere, and the mixture was stirred for 1.5 hr. To the reaction mixture was added N-fluorobenzenesulfonimide (578 mg) at −78° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow solid (187 mg).
Reaction SMILES: O[C@@H]1CC[C@H](NC(NC23CC4CC(CC(C4)C2)C3)=O)CC1.[CH2:22]([O:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:37]([NH:39][C:40]23[CH2:49][CH:44]4[CH2:45][CH:46]([CH2:48][CH:42]([CH2:43]4)[CH2:41]2)[CH2:47]3)=[O:38])[CH2:32][CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Br)C1C=CC=CC=1.[H-].[Na+]>>[CH2:22]([O:29][C@@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:37]([NH:39][C:40]23[CH2:47][CH:46]4[CH2:48][CH:42]([CH2:43][CH:44]([CH2:45]4)[CH2:49]2)[CH2:41]3)=[O:38])[CH2:32][CH2:31]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)N[C@H]1CC[C@H](OCc2ccccc2)CC1
Agent: BrCc1ccccc1
Agent: O=C(NC12CC3CC(CC(C3)C1)C2)N[C@H]1CC[C@@H](O)CC1
Agent: [H-]
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N[C@H]1CC[C@@H](OCc2ccccc2)CC1

Procedure:
Compound 1078 (2.22 g, 60%) was synthesized from compound 1077 (0.29 g, 1 mmol) by the same method) as that described for compound 1032 with benzyl bromide (0.20 g, 1.2 mmol) and 60% sodium hydride (0.06 g, 1.5 mmol). Yield: 0.35 g (92% of theory). M.P.: 181° C. 1H NMR (300 MHz, CDCl3): δ 7.43-7.24 (m, 5H), 4.49 (s, 2H), 4.11 (d, J=8.3 Hz, 1H), 4.02 (s, 1H), 3.66-3.51 (m, 2H), 2.23-1.07 (m, 23H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[N:5]=1)(=[O:3])[CH3:2].Cl.S(Cl)([Cl:15])(=O)=O>O1CCOCC1>[Cl:10][C:6]1[N:5]=[C:4]([C:1]([CH2:2][Cl:15])=[O:3])[CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1cccc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCl)c1cccc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-acetyl-6-chloropyridine (7.48 g) in 1,4-dioxane (112 ml) was added 4N hydrogen chloride in 1,4-dioxane (12.6 ml). To the solution, sulfuryl chloride (13.51 ml) was added dropwise at 30° C. After stirring for 0.5 hour, ice water (150 ml) was added to the solution and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and toluene (1:1) as an eluent to give chloromethyl 6-chloro-2-pyridyl ketone (7.05 g) as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:16]([CH3:18])[CH3:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[CH:8][CH:7]([CH3:15])[CH2:6]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:14][O:13][C:12]1[C:3]([O:2][CH3:1])=[C:4]([CH:16]([CH3:17])[CH3:18])[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH3:15])[CH:6]=2)[CH:11]=1
Reactant: COc1cc2c(c(C(C)C)c1OC)CC(C)C=C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1cc2ccc(C)cc2c(C(C)C)c1OC
Reaction time: 3 h
Yield: 95.1 %

Procedure:
Compound 12 (3.00 g, 12.2 mmol) was dissolved in 25 mL of benzene and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.80 g, 12.2 mmol) was added slowly with stirring and stirring was continued for 3 h. The reaction mixture was filtered through a short column of alumina which was washed with dichloromethane. The solvent was evaporated from the colorless eluant and the residual product was crystallized from petroleum ether to give 2.83 g (11.6 mmol, 95%) of 18 as colorless microcrystalline plates: mp 62°-63° C.; 1H NMR: δ 1.51 (d, J=7.2 Hz, 6 H), 2.50 (s, 3 H), 3.88 (s, 3 H), 3.90 (sept, J=7.2 Hz, 1 H), 3.94 (s, 3 H), 7.01 (s, 1 H), 7.20 (d, J=8.3 Hz, 1 H), 7.60 (d, J=8.3 Hz, 1 H), 7.88 (s, 1 H). Anal. (C16H20O2) C, H.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>C(O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][S:3][C:2]2[N:4]=[C:5]([OH:6])[CH:7]=[C:8]([OH:9])[N:1]=2)=[CH:16][CH:15]=1
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CSc2nc(O)cc(O)n2)cc1
Temperature: 60 °C
Yield: 54.5 %

Procedure:
To a suspension of thiobarbituric acid (15 g) in 50% ethanol (180 ml) are added a solution of NaOH (5.1 g) in 50% ethanol (75 ml) and p-methoxybenzyl chloride (18.7 g). The mixture is heated under stirring for 60' at 60° C.; then it is cooled and the solid is filtered by suction, washed with water; then dried over CaCl2, yielding 15 g of 2-p-methoxy-benzylthio-4,6-dihydroxypyrimidine.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-])=O)=[O:4].[Sn](Cl)Cl>C(O)C.O.C(=O)(O)[O-].[Na+]>[NH2:15][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:5]=1[C:3]([NH:2][CH3:1])=[O:4])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CNC(=O)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNC(=O)c1ccc(C(=O)OC)cc1N
Temperature: 70 °C
Yield: 56.1 %

Procedure:
A mixture of methyl 4-(methylamino)carbonyl-3-nitrobenzoate (3.84 g, 0.0185 mol) and tin (ii) chloride (15.3 g, 0.08 mol) in ethanol (80 mL) was heated at 70° C. for 1 h. The reaction mixture was diluted with water (150 mL) and sodium bicarbonate solution was added to it to bring the pH close to 8. The mixture was extracted with ethyl acetate and the organic layer washed with water and brine and dried over sodium sulphate. After filtration, the solution was concentrated and the residue was recrystallized from ethyl acetate-hexane to give 2.16 g (64%) of methyl 3-amino-4-(methylamino)carbonylbenzoate as tan needles, mp 167°-168° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:28][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH2:17][CH2:16]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: O=Cc1ccccn1
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(N2CCN(Cc3ccccn3)CC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of pyridine-2-carbaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 8.52 (d, J=6.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.50-7.19 (m, 4H), 6.84 (dd, J=3.6 Hz, 1.0 Hz, 1H), 4.09-4.06 (m, 4H), 3.89 (br s, 2H), 2.51-2.41 (m, 4H) ppm. MS: m/z: 378 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:12])[NH:3]1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.[I-].C([NH3+])(C)(C)C>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:3]2[C:4](=[O:12])[CH2:5][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]2[CH3:1])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1CC(=O)NC1C
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[NH3+]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Ethyl rac-(2R,3S)-2-methyl-5-oxopyrrolidine-3-carboxylate (30 g, 0.18 mol) in DMF (100 mL) was carefully added to a suspension of sodium hydride (7.6 g, 0.19 mol, 60% in mineral oil) in DMF (400 mL) at 0° C. The resulting mixture was stirred for 1 hour before 4-methoxybenzyl chloride (32.8 g, 28.5 mL, 0.21 mol) was added dropwise, followed by tert-butylammonium iodide (13 g, 35 mmol). The reaction mixture was stirred at room temperature for 10 hours and then quenched by adding saturated aqueous ammonium chloride solution (30 mL). The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (500 mL×3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product, which was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to afford ethyl rac-(2R,3S)-1-(4-methoxybenzyl)-2-methyl-5-oxopyrrolidine-3-carboxylate. MS ESI calc'd. for C16H22NO4 [M+H]+ 292. found 292. 1H NMR (CDCl3, 400 MHz) δ: 7.13 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 4.91 (d, J=14.4 Hz, 1H), 4.08-4.15 (m, 2H), 3.89 (d, J=14.4 Hz, 1H), 3.76 (s, 3H), 3.62-3.63 (m, 1H), 2.71 (s, 3H), 1.18-1.26 (m, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][C@@:9]([CH3:19])([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=1.[C:20]1(B(O)O)[CH2:24][CH2:23][CH2:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]1([C:2]2[CH:3]=[N:4][N:5]([CH2:7][CH2:8][C@@:9]([CH3:19])([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=2)[CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: OB(O)C1=CCCC1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(I)cn1)S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOC(=O)[C@@](C)(CCn1cc(C2=CCCC2)cn1)S(C)(=O)=O
Temperature: 100 °C

Procedure:
Ethyl (2R)-4-(4-iodo-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoate (100 mg, 0.25 mmol, 1 eq) was weighed into a 40 mL vial equipped with a septa cap. Cyclopent-1-en-1-ylboronic acid (97 mg, 0.5 mmol, 2 eq) and potassium phosphate (159 mg, 0.75 mmol, 3 eq) was added, followed by PdCl2(PPh3)2 (18 mg, 0.025 mmol, 0.1 eq). The vial was evacuated and backfilled 3 times with nitrogen gas. 2-MeTHF (9 mL) and water (1 mL) were added to the vial and the mixture heated at 100° C. overnight. The reaction mixture was then filtered through celite and eluted with MeOH. The crude product mixture was then purified by flash chromatography on a 25 g silicycle silica gel column eluting with 20% EtOAc/Hpt to give ethyl (2R)-4-[4-(cyclopent-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoate which was used without further purification. LC-MS M+H+341.4.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[O:35]([CH2:42][C:43](Cl)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:43](=[O:44])[CH2:42][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCN(C(=O)COc3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.33 mmol, 55 μL) followed by phenoxyacetyl chloride (0.17 mmol). The reaction was stirred at room temperature for 4 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 2% CH3OH in CH2Cl2), yielding the pure title compound (34 mg) which was characterized by its mass spectrum: MS m/z (%): 493 ([M+H]+, 100).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:14]=[C:13]([C:15]2[C:20]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8].Cl[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=2)[N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[Cl:38][C:32]1[CH:31]=[C:30]2[C:35]([CH:36]=[CH:37][C:28]([N:24]3[CH2:25][CH2:26][CH:21]([C:20]4[C:15]([C:13]5[CH:12]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[C:5]([F:4])[CH:14]=5)=[N:16][CH:17]=[CH:18][N:19]=4)[CH2:22][CH2:23]3)=[N:29]2)=[CH:34][CH:33]=1
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CCNCC2)cc1F
Reactant: Clc1ccc2ccc(Cl)nc2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2nccnc2C2CCN(c3ccc4ccc(Cl)cc4n3)CC2)cc1F
Temperature: 90 °C
Yield: 38.2 %

Procedure:
To a mixture of 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride (315 mg, 0.743 mmol), 2,7-dichloroquinoline (192 mg, 0.969 mmol), cesium carbonate (1211 mg, 3.72 mmol), dioxane (4 mL), and bis(tri-t-butylphosphine)palladium(0) (89 mg, 0.174 mmol). The solution was stirred at 90° C. After stirring for 5 h, the reaction was allowed to cool to room temperature and filtered. The solids were washed with EtOAc. The filtrate was concentrated to ½ it's orginal volume and purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini column (10 micron, C18, 110 Å, Axia, 100×50 mm) eluting at 90 mL/min with a linear gradient of 10-60% MeCN (0.1% TFA) in water (0.1% TFA) over 20 min. The desired fractions were poured into 10% Na2CO3 and extracted with dichloromethane (DCM) (8×10 mL). The combined DCM layers were dried over MgSO4 and concentrated in vacuo to give 4-(3-(1-(7-chloroquinolin-2-yl)piperidin-4-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide (135 mg, 0.284 mmol, 38.2% yield), as an off white solid. m/z=476 (M+1). 1H NMR (300 MHz, CDCl3) δ 8.54 (d, J=2.34 Hz, 1H), 8.49 (d, J=2.34 Hz, 1H), 8.27 (t, J=8.04 Hz, 1H), 7.83 (d, J=9.35 Hz, 1H), 7.67 (d, J=2.05 Hz, 1H), 7.49 (d, J=8.62 Hz, 1H), 7.44 (dd, J=1.46, 8.04 Hz, 1H), 7.35 (dd, J=1.46, 12.42 Hz, 1H), 7.15 (dd, J=2.05, 8.48 Hz, 1H), 6.98 (d, J=9.35 Hz, 1H), 6.79 (d, J=6.28 Hz, 1H), 4.68 (d, J=13.30 Hz, 2H), 3.16-3.31 (m, 1H), 3.09 (dd, J=0.80, 4.75 Hz, 3H), 2.86-3.02 (m, 2H), 2.01-2.19 (m, 2H), 1.82 (d, J=11.55 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][CH:8]=[C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([I:19])[CH:17]=3)[C:12](=[O:20])[NH:11][C:10]2=[O:21])=[CH:4][C:3]=1[OH:24].C(N(CC)CC)C.[CH3:32][N:33]([CH2:35][C:36](O)=[O:37])[CH3:34].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:24][C:3]1[CH:4]=[C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH:22]=[CH:23][C:2]=1[NH:1][C:36](=[O:37])[CH2:35][N:33]([CH3:34])[CH3:32]
Reactant: CN(C)CC(=O)O
Reactant: Nc1ccc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
4-[(4-Amino-3-hydroxy-benzylamino)-methylene]-6-iodo-4H-isoquinoline-1,3-dione (89 mg, 0.20 mmol) is dissolved in N,N-dimethylformamide (3.56 mL), followed by addition of triethylamine (0.236 mL, 1.69 mmol), dimethylamino-acetic acid (30.58 mg, 0.30 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (42.6 mg, 0.22 mmol) and 1-hydroxybenzotriazole (13.8 mg, 0.10 mmol). It is stirred at room temperature overnight. It is then evaporated to dryness, and the residue is washed with ether, and then acetonitrile to yield 21 mg (20%) of the title compound as a solid. MS (ESI) m/z 521 (M+H)+1
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[N+:23]([O-:25])=[O:24])[CH2:4][CH2:5][C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl.[CH3:47][NH:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>ClCCl>[CH:49]1([N:48]([CH3:47])[C:6](=[O:8])[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[CH:12][C:11]=2[N+:23]([O-:25])=[O:24])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: CNC1CCCCC1
Reactant: N#CC(CCC(=O)O)Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CCC(C#N)Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C1CCCCC1
Reaction time: 16 h

Procedure:
4-cyano-5-(2-nitro-5-phenoxy-phenyl)-pentanoic acid (0.230 g, 0.68 mmol) was dissolved in dichloromethane (1.5 mL) followed by addition of HOBt (0.103 g, 0.68 mmol), triethylamine (0.170 mL, 0.68 mmol), EDC (0.194 g, 1.01 mmol) and N-methyl-cyclohexylamine (0.09 mL, 0.68 mmol). The reaction was allowed to proceed for 16 h after which time, the solvent was removed under reduced pressure. The resulting mixture was dissolved in ethyl acetate and washed 3 times with 10% sodium carbonate solution, one time with saturated brine solution, 3 times with 1N HCl and then again one time with brine wash. The organic layer was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield a residue. The residue was purified with flash chromatography using a mixture of 65:35 heptanes:ethyl acetate as the mobile phase to yield a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:14]=[C:15]([CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[S:16][CH:17]=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:14]=[C:15]([CH2:18][CH2:19][NH2:20])[S:16][CH:17]=1
Reactant: COc1ccc2nccc(-c3csc(CCNC(=O)OC(C)(C)C)n3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2nccc(-c3csc(CCN)n3)c2n1
Yield: 315.8 %

Procedure:
The carbamate (c) (0.93 g, 2.4 mmol) was dissolved in trifluoroacetic acid (40 mL). After 1 hour the mixture was evaporated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic extract was washed with brine, dried and evaporated affording a solid (2.17 g, 90%).