Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]2[N:16]=[C:17]([I:22])[C:18]([C:19]([OH:21])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:26](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:19]([C:18]1[C:17]([I:22])=[N:16][N:11]2[CH2:12][C:13]3([CH2:15][CH2:14]3)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]=12)(=[O:21])[NH2:26]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC12CC2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2CC12CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a stirred solution of Intermediate 350E (0.43 g, 1.026 mmol) in DMF (4 mL) was added NH4Cl (0.274 g, 5.13 mmol), HATU (0.780 g, 2.051 mmol) and DIPEA (0.537 mL, 3.08 mmol) and the resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×25 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The residue was triturated with diethyl ether, filtered and dried to afford Intermediate 350F as an off-white solid (0.4 g, 89%). MS(ES): m/z=419 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 6.56 (br. s., 1H), 5.54 (br. s., 1H), 4.96 (br. s., 2H), 4.04 (br. s., 2H), 1.44 (s, 9H), 1.18 (m, 2H), 0.97-0.84 (m, 2H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH3:25]>O1CCOCC1.ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH3:25])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1ccsc1N
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1sccc1C
Yield: 36.4 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (3.6 g, 0.0137 mol) and 2-amino-3-methylthiophene (3.4 g, 0.03 mol) in 1,4 dioxan (30 ml) under a nitrogen atmosphere were stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure to give an oil. The oil was taken up in dichloromethane and extracted with 2N hydrochloric acid (3×100ml). The dichloromethane extracts were then washed with sodium carbonate solution (100 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a solid. The solid was purified by flash chromatography using a gradient elution of dichloromethane/methanol (0-5%, 500 ml). The fractions containing the product were combined and evaporated under reduced pressure to give a solid, (1.94 g), m.p. 130°-132°. Recrystallization from ethyl acetate gave the title compound, (1.7 g), m.p. 132°-133°.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[ClH:16].[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)Cl
Agent: CCCCOC(=O)N1CCNCC1
Solvent: Cc1ccccc1
Product: Cl
Temperature: 2 °C
Reaction time: 1 h

Procedure:
4-Chlorocarbonyl-1-t.-butoxycarbonylpiperazine can be prepared by the simultaneous additions of solutions of 1-t.-butoxycarbonylpiperazine (40.8 g.) in anhydrous toluene (200 cc.) and of phosgene (11.2 g.) in anhydrous toluene (150 cc.) to anhydrous toluene (100 cc.), the temperature being kept at about -5° C. during this operation. After stirring for 1 hour at 2° C., the 1-t.-butoxycarbonylpiperazine hydrochloride formed during the reaction is filtered off and washed twice with anhydrous toluene (total 200 cc.). The filtrate is evaporated to dryness under reduced pressure (20 mm.Hg.). 4-Chlorocarbonyl-1-t.-butoxycarbonylpiperazine (24.8 g.), which melts at 98° C., is obtained. After the product has been purified by recrystallisation from diisopropyl ether, it melts at 99° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([CH3:28])[C:23](=[O:27])OCC)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.ClC1SC(C(NCC2N=NN(C3C=CC(NC)=CC=3)C=2)=O)=CC=1.CCN(C(C)C)C(C)C.[CH3:64][O:65][CH2:66]C(Cl)=O>CS(C)=O.CO>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([CH3:28])[C:23](=[O:27])[CH2:64][O:65][CH3:66])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)N(C)c1ccc(-n2cc(CNC(=O)c3ccc(Cl)s3)nn2)cc1
Agent: CNc1ccc(-n2cc(CNC(=O)c3ccc(Cl)s3)nn2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: COCC(=O)N(C)c1ccc(-n2cc(CNC(=O)c3ccc(Cl)s3)nn2)cc1
Reaction time: 0.5 h

Procedure:
Compound 25 (60 mg, 0.14 mmol) was treated with 2 mL 2N NaOH and 2 mL methanol at 80° C. for 2 hrs and acidified with 2N HCl. The major product in this reaction, 5-chloro-N-((1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide, was isolated with prep HPLC. MS found for C15H14ClN5OS (M+H)+ 348.1, 350.1. This compound (10 mg, 0.023 mmol) was dissolved in 1 mL DMSO. To it were added 20 μL DIEA and CH3OCH2COCl (25 μL, 0.23 mmol). The mixture was stirred for 30 min and directly subjected to prep HPLC to isolate the title compound. MS found for C18H18ClN5O3S (M+H)+ 420.1, 422.1 (Cl pattern).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][OH:2])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCCC1(C(=O)OC)CCCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC1(CO)CCCN1C(=O)OC(C)(C)C
Yield: 100.5 %

Procedure:
To a stirred solution of 2-butyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.842 g, 2.95 mmol) in THF (30 mL) at 0° C. under nitrogen was added LiAlH4 (2.95 mL of a 1.0 M solution in THF, 2.95 mmol) dropwise. After 15 min the reaction mixture was quenched by the addition of sodium sulfate decahydrate (2.5 g) then filtered. The filter cake was washed with DCM (50 mL) then the combined filtrates were concentrated in vacuo to give 2-butyl-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.763 g) as a clear, colourless oil that was used directly without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([CH2:17][OH:18])[CH2:6]1)(=[O:3])[CH3:2].[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@H:7]([CH2:17][O:18][C:25]2[CH:26]=[CH:27][C:22]([C:21]([O:20][CH3:19])=[O:29])=[CH:23][CH:24]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(=O)O[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC(C)=O)CN2C(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
To a stirred mixture of (2S,4S)-4-acetoxy-1tert-butoxycarbonyl-2-pyrrolidinemethanol (9.70 g, 37.4 mmol), p-hydroxybenzoic acid methyl ester (5.69 g, 37.4 mmol) and PPh3 (10.8 g, 41.1 mmol) in THF (200 ml) was added DIAD (8.10 ml, 41.1 mmol) at room temperature. After 1.5 h stirring, the mixture was concentrated in vacuo. The resulting residue was chromatographed on silica gel [700 g, CHCl3/EtOAc (10/1)], to give methyl 4-[(2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-pyrrolidinyl]methoxybenzoate (11.8 g, 81%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.48 (s, 9H), 2.03 (s, 3H), 2.27 (m, 2H), 3.46 (m, 1H), 3.72 (m, 1H), 3.88 (s, 3H), 3.98 (t, J=9.0 Hz, 1H), 4.21-4.47 (m, 2H), 5.31 (br, 1H), 6.96 (br, 2H), 7.98 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=2)[C:9]1=[O:13]
Reactant: CC(=O)Nc1cccc(Br)c1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(N2CCN(c3cnccc3C)C2=O)c1
Yield: 22.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with N-(3-bromo-phenyl)-acetamide (217.6 mg, 1.0169 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (449.7 mg, 0.2542 mmol) and potassium phosphate (29.4 mg, 2.1185 mmol) to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in CHCl3), followed by preparative HPLC afforded 60 mg of the product (23% yield).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@H:7]([OH:18])[C@@H:6]1[OH:19])=[N+]=[N-]>CO>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@H:7]([OH:18])[C@@H:6]1[OH:19]
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Solvent: CO
Product: NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of the 5′-azido-5′-deoxyuridine (2.51 g, 9.33 mmol) obtained as described above in methanol (100 ml) was added palladium-on-carbon Pd/C (10%, about 0.25 g). While bubbling hydrogen (1 atm), the mixture was stirred at room temperature for 2 hours. Then, the reaction mixture obtained was filtered to remove the palladium-on-carbon, the filtrate was evaporated under reduced pressure, and the residue was reprecipitated from methanol-ethanol to give 5′-amino-5′-deoxyuridine (5′-NH2-Urd) (2.22 g, yield 98%) as powders. A white solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24](=[S:26])[NH2:25])[CH2:7]1)(=[O:4])=[O:3].Br[CH2:28][C:29](=O)[C:30]([O:32]CC)=[O:31]>ClCCl.C(O)C>[C:30]([C:29]1[N:25]=[C:24]([C@@H:8]2[CH2:7][C@@H:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][N:9]2[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[S:26][CH:28]=1)([OH:32])=[O:31]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2nc(C(=O)O)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-thiocarbamoylpyrrolidine (2.0 g) in dichloromethane (40 ml) was added a solution of ethyl bromopyruvate (1.04 ml) in absolute ethanol (10 ml) at 0° C. After stirring at room temperature for 2 hours, the mixture was evaporated. The residue was dissolved in ethyl acetate, and washed with saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated and the residue was dissolved in tetrahydrofuran (15 ml) and 1N sodium hydroxide (15 ml). After stirring at 35°-45° C. for 1 hour, the mixture was evaporated and poured into ethyl acetate. To this mixture was added 1N hydrochloric acid (20 ml), and then organic layer was separated, and washed with brine. The dried organic layer was evaporated to give (2S,4R)-2-(4-carboxythiazol-2-yl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.54 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH2:21]3)[CH3:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO.C1COCC1.[Pd]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH3:19])=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCNCC1
Yield: 99.9 %

Procedure:
(±)-Phenylmethyl 4-[1-({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)ethyl]-1-piperidinecarboxylate (Example 139, 0.37 g, 0.75 mmol) was dissolved in MeOH (10 mL) and THF (5 mL). 10% of Pd/C (40 mg, Degussa type) was added, and the mixture was placed under an atmosphere of hydrogen using a H2 balloon at ambient temperature for 4 h. The mixture was filtered through Celite® and the filtrate was concentrated to give 0.27 g (100%) of (±)-2-[4-(methylsulfonyl)phenyl]-5-{[1-(4-piperidinyl)ethyl]oxy}pyridine as a viscous colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=2.9 Hz), 8.12 (d, 2H, J=8.5 Hz), 8.00 (d, 2H, J=8.3 Hz), 7.72 (d, 1H, J=8.8 Hz), 7.30-7.25 (m, 1H), 4.30-4.20 (m, 1H), 3.20-3.10 (m, 2H), 3.08 (s, 3H), 2.70-2.60 (m, 2H), 1.95-1.65 (m, 3H), 1.45-1.25 (m, 5H); LRMS (ESI), m/z 361 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.CN(C=O)C.S(Cl)([Cl:19])=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([Cl:19])=[O:11])=[N:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)nc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5-methoxy-2-pyridylcarboxylic acid (11.9 g, 77.5 mmol) and DMF (5.4 ml, 69 mmol) in 200 ml of tetrahydrofuran (THF) at 5° is added thionyl chloride (8.4 ml, 116 mmol) over 15 minutes. After addition, the slurry is allowed to warm slowly to RT. After 3 hours, the reaction is rotoevaporated to give 5-methoxy-2-pyridylcarboxylic acid chloride. This acid chloride is gradually added, with cooling, to rapidly stirring ammonium hydroxide (40 ml, 340 mmol), and the slurry is stirred for 1 hour. The reaction is filtered and the residue is dried. To this is added dry toluene, with stirring, followed by filtration. More toluene is added, followed by rotoevaporation to give 5-methoxy-2-pyridylcarboxamide.
Reaction SMILES: C([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10]1)(OC(C)(C)C)=O.[ClH:26]>O>[ClH:26].[ClH:26].[NH2:15][O:14][CH2:13][CH:11]1[CH2:12][CH:9]([NH2:8])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CC(CON2C(=O)c3ccccc3C2=O)C1
Agent: Cl
Solvent: O
Product: NOCC1CC(N)C1

Procedure:
Analogously to Example 6, starting from 1.15 g (0.00332 mol) of 2-[3-(N-BOC-amino)cyclobutylmethoxy]-1H-isoindole-1,3(2H)-dione, 6 ml of water and 5 ml of concentrated hydrochloric acid, the title compound is obtained, m.p. 179° C. (decomp.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([F:22])[CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:16]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:3][C:4]=2[F:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(F)c1
Temperature: 140 °C
Yield: 62.3 %

Procedure:
A mixture of 77 (312 mg, 0.864 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), Pd(OAc)2 (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with Et2O (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 220 mg (62%) of compound 78. 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 1.58 (m, 6H), 2.07 (br s, 2H), 2.25 (br s, 2H), 4.78 (s, 1H), 6.30 (d, J=16.0 Hz, 1H), 6.74 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 7.08 (t, J=7.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.49 (d, J=16.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(NC(C)C)(C)C.[Na+].[I-]>CN(C=O)C.O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(C)CC2)nc1
Reaction time: 4 h
Yield: 76.3 %

Procedure:
To a solution of 5.15 g of methyl 6-chloronicotinate, 3.15 g of 1-methylpiperazine and 3.18 g of diisopropylamine in 50 ml of DMF was added a catalytic amount of NaI. The mixture was heated to 120°-130° C. and stirred for 4 hours. The resulting mixture was poured into 250 ml of water followed by extraction with ethyl acetate. The extract was washed twice with water, and once with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. Purification of the concentrate by column chromatography (silica gel; chloroform:methanol=3:1) afforded 5.39 g of methyl 6-(4-methyl-1-piperazinyl)nicotinate (yield 77%).
Reaction SMILES: C(OC([O:6][C@H:7]([C@H:10]([CH3:14])[CH2:11][S:12][CH3:13])[CH:8]=[O:9])C)C.Cl.C(Cl)Cl>C1COCC1>[OH:6][C@H:7]([C@H:10]([CH3:14])[CH2:11][S:12][CH3:13])[CH:8]=[O:9]
Reactant: CCOC(C)O[C@@H](C=O)[C@H](C)CSC
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSC[C@@H](C)[C@@H](O)C=O

Procedure:
A stirred solution of (F) (from above) in fresh THF (75ml.) was treated with lN HCl (15 ml.) The mixture was deaerated under a nitrogen atmosphere and stirred at ambient temperatures until tlc analysis indicated no compound (F) remained. The mixture was transferred to a separatory funnel with methylene chloride (300 ml ). washed lX with water (300 ml.), and the aqueous layer re-extracted 2X with methylene chloride. The organic layers were combined and washed lX with water and concentrated in vacuo to compound (G) as an oil which was used immediately in the following step.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[F:27][C:28]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:39][C:29]=1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)=[O:31]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:41]2[CH:40]=[CH:39][C:29]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[O:31])=[C:28]([F:27])[CH:42]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3ccccn3)c(F)c2)OC1(C)C
Product: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)c(F)c3)c12
Yield: 76 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and 2-Fluoro-N-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 16) to afford the title compound (160 mg, 76%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].Cl.C[O-].[Na+].N[C:10]1[C:15]([C:16]#[N:17])=[CH:14][C:13]([C:18]#[N:19])=[CH:12][N:11]=1.C1CCCCC1.CCOC(C)=O>CCO>[NH2:3][C:2]1[N:4]=[C:16]([NH2:17])[C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[N:11][C:10]=2[N:1]=1
Reactant: N#Cc1cnc(N)c(C#N)c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: N#Cc1cnc2nc(N)nc(N)c2c1
Yield: 34 %

Procedure:
Guanidine·HCl (2.66 g, 27.8 mmol) was added to a solution of NaOMe (sodium methoxide) (1.50 g, 27.8 mmol) in absolute EtOH (180 mL). The mixture was stirred at 20°-23° C. for 15 minutes before 5 (2.00 g, 13.9 mmol) was added. After a 24-hour reflux period with rapid stirring, TLC (cyclohexane-EtOAc, 1:1) showed absence of 5. The solid filtered from the cooled mixture was washed on the funnel with H2O and EtOH; yield 95% (2.45 g). A sample of this material (1.0 g) was stirred with near-boiling Me2SO (dimethyl sulfoxide) (250 mL), and the slightly cloudy solution was filtered (Celite) to give a clear, pale-yellow filtrate which was then concentrated by evaporation in vacuo (to about 60 mL). Addition of EtOH (200 mL) gave 7 as a light yellow solid (880 mg); 1H NMR (Me2SO-d6) δ6.97 (2, NH2), 7.84 (s, NH2), 8.87 and 8.91 (two d, 5-H and 7-H, J=2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([NH:14][CH3:15])=[O:13])[CH:6]=O.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][N:28]2[CH2:29][CH2:30][N:25]([C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=3)[CH2:26][CH2:27]2)[CH:8]=[CH:9][C:10]=1[O:11][C:12]([NH:14][CH3:15])=[O:13]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CNC(=O)Oc1ccc(C=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNC(=O)Oc1ccc(CN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1OC
Temperature: 0 °C
Yield: 85.9 %

Procedure:
To a solution of 3-methoxy-4-(methylaminocarbonyloxy)benzaldehyde (1.01 g) in 1,2-dichloroethane (19.0 ml) was added 1-(4-nitrophenyl)piperazine (1.0 g), and sodium triacetoxyborohydride (1.54 g), with stirring. The reaction mixture was stirred for 3 hrs at ambient temperature, poured into ice/saturated sodium carbonate solution (100 ml) and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was flash chromatographed (silica gel), eluting with dichloromethane, followed by 1% methanol:dichloromethane. The appropriate fractions were collected and concentrated to give 1.66 g (86%) of product. Recrystallization from ethyl acetate gave the analytical sample, mp 155-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:17])[C:13]([O:15]C)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[OH-].[Na+].C(OCC)(=O)C.CCCCCC>CO.O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:17])[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: COC(=O)C(C)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CC(C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of methyl 2-(3-chloro-4-(methylsulfonyl)phenyl)propanoate (3.2 g, crude) in methanol (32 mL, 10 times), a solution of sodium hydroxide (0.46 g, 1 eq) in water (5 mL) was added at 0° C. The contents were warmed to room temperature and allowed to stir for 2 h. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.1). On completion of the reaction, methanol was distilled off completely and the residue obtained was taken in water. The contents were acidified to a pH of 4 and diluted with HCl at 0° C., the precipitate was filtered and dried to yield 2-(3-chloro-4-(methylsulfonyl)phenyl)propanoic acid as a white colored solid (2.7 g, 88%).