Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:9]3[N:31]=[C:12]([CH:13]=[C:14]4[NH:30][C:17](=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.[CH3:38][NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.P.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd].C(OCC)(=O)C>[CH3:38][N:39]([C:2]1[C:3]2[NH:7][C:6]([C:8]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:9]3[N:31]=[C:12]([CH:13]=[C:14]4[NH:30][C:17](=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Brc1c2nc(c(-c3ccccc3)c3ccc(cc4nc(c(-c5ccccc5)c5ccc1[nH]5)C=C4)[nH]3)C=C2
Reactant: CNc1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1c2nc(c(-c3ccccc3)c3ccc(cc4nc(c(-c5ccccc5)c5ccc1[nH]5)C=C4)[nH]3)C=C2

Procedure:
The general procedure was used to couple 5-bromo-10,20-diphenylporphyrin (54 mg, 0.10 mmol) with N-methylaniline (40 μL, 0.36 mmol), using palladium acetate (1.1 mg, 0.005 mmol) as the palladium precursor, DPEphos (4.0 mg, 0.0075 mmol) as the phosphine ligand and cesium carbonate (45.6 mg, 0.014 mmol) as the base. The reaction was conducted in THF (5 mL) at 68° C. for 16 h. The title compound was isolated by flash column chromatography (silica gel, ethyl acetate:hexanes (v)=1:4) as purple solids (53 mg, 94%). 1H NMR (300 MHz, CDCl3): δ 10.18 (s, 1H), 9.30 (d, J=4.8 Hz, 2H), 9.19 (d, J=4.8 Hz, 2H), 9.00 (d, J=4.8 Hz, 2H), 8.90 (d, J=4.8 Hz, 2H), 8.23 (m, 4H), 7.78 (m, 6H), 7.19 (broad, 2H), 6.73 (broad, 3H), 4.26 (s, 3H), −2.82 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 154.9, 141.6, 134.9, 131.9, 131.7, 131.6, 129.6, 129.1, 128.0, 127.2, 124.2, 119.8, 116.9, 113.9, 105.8, 45.5. IR (film, cm−1): 3303, 3055, 3026, 2875, 2810, 1596, 1498, 1351, 1113, 971, 796, 731. UV-vis (CHCl3, λmax, nm): 410, 512, 548, 592. HRMS-EI ([M]+): C39H29N5, 567.2423; found: 567.2419 with an isotope distribution pattern that is same as the calculated one.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH3:11])[C:5]=1[F:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:12][C:5]1[C:6]([CH3:11])=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1ccc(F)c(C)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(F)ccc(CO)c1F
Reaction time: 2 h
Yield: 126.5 %

Procedure:
To a solution of 2,4-difluoro-3-methyl-benzoic acid methyl ester from Step A (1.1 g, 5.5 mmol) in tetrahydrofuran (10 mL), cooled to −78° C. using a dry ice/acetone bath, was added lithium aluminum hydride, 1.0M in tetrahydrofuran (10 mL, 10 mmol), in a dropwise manner. The solution was stirred for two hours. The reaction was quenched by dropwise addition of ice-cold saturated sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the alcohol as a colorless liquid (1.1 g, quantitative yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][CH:3]=1.O=S(Cl)Cl>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(Br)cc1
Yield: 84.1 %

Procedure:
88 g (0.44 mol) of 4-bromobenzoic acid amide and 320 cm3 (4.4 mol) of SOCl2 were refluxed on a warm water bath for 10 hours. The excess SOCl2 was distilled off on warm water bath under reduced pressure using an aspirator and the residue was reorystallized from methanol to yield 67 g (0.37 mol) of 4-bromobenzonitrile.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[C:11]2=[N:10][N:9]=1)=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][CH:14]=3)=[O:5])C.[OH-].[Na+].Cl>O>[C:4]([CH2:6][CH2:7][C:8]1[N:12]2[C:13]3[C:18]([NH:19][C:20](=[O:21])[C:11]2=[N:10][N:9]=1)=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][CH:14]=3)([OH:5])=[O:3]
Reactant: CCOC(=O)CCc1nnc2c(=O)[nH]c3cc([N+](=O)[O-])ccc3n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCc1nnc2c(=O)[nH]c3cc([N+](=O)[O-])ccc3n12
Reaction time: 24 h
Yield: 92.3 %

Procedure:
0.5 g (~1.5 mmol) of 1-(2-ethoxycarbonylethyl)-7-nitro[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one was added to a mixture of 50 ml of water and 1.5 ml of 2N sodium hydroxide. Stirring was continued for 24 h at 25° C. Addition of 4N hydrochloric acid to pH=2-3 gave the title compound (0.42 g; 92%) as a precipitate. M.p.>300° C. decomp.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>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>[CH3:7][O:6][C:4]([C:3]1[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=2)=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(=O)c1ccccc1Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccccc1-c1cccc([N+](=O)[O-])c1

Procedure:
n.m.r. (DMSO-d6) δ values include 3.61 (s, 3 H), 7.51 (d, 1 H), 7.58 (t, 1 H), 7.69 (m, 3 H), 7.88 (d, 1 H), 8.24 (d, 1 H); from methyl 2-bromobenzoate (1.53 g), tetrakis(triphenylphosphine)palladium(0) (270 mg) and 3-nitrophenylboronic acid (1.44 g).
Reaction SMILES: C1(=O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24]([O:36][C:37](=[O:41])[CH:38]([CH3:40])[NH2:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C(O)(C)C>[NH2:39][C@H:38]([C:37]([O:36][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:41])[CH3:40]
Reactant: CCCCCCCCCCCCOC(=O)C(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCCCCCCCCCCOC(=O)[C@H](C)N
Temperature: 60 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
A 100 ml round bottom flask equipped with a condenser, addition funnel, thermometer and mechanical stirrer was charged with D-glucono-1,5-lactone (7.0 g, 0.04 mole) and isopropanol (30 g). The suspension was heated to 60° C. over 15 minutes. A mixture of DL-alanine dodecyl ester p-toluenesulfonate salt (16.9 g, 0.04 mole), triethylamine (4.0 g 0.04 mole) and isopropanol (20 g) were added dropwise over 15 minutes from an addition funnel. The reaction mixture was stirred rapidly for about 6 hrs and then cooled to room temperature. The white product was filtered, washed with chloroform (3×150 ml) and dried under high vacuum at 35° C. giving 12.5 g (73% yield) of N-D-gluconyl dodecyl alaninate with a melting point of 97°-98° C. and 98.8% purity.
Reaction SMILES: C([O:8][C:9]1[CH:40]=[CH:39][C:12]([O:13][CH2:14][CH:15]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:38])[C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[OH:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.N1C=CC=CC=1.FC(F)(F)C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1>CS(C)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:38])[C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:16])=[CH:39][CH:40]=1
Reactant: O=C([C@@H]1CCCN1C(=O)CCc1ccccc1)N1CCCC1C(O)COc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(O)cc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a solution of (2S)-2-{2-(2-[4-(benzyloxy)phenoxy]-1-hydroxyethyl}-1-[N-(3-phenylpropionyl)-L-prolyl]pyrrolidine (1.81 g) in DMSO (30 ml) were added pyridine (0.3 ml), trifluoroacetic acid (0.15 ml) and DCC (1.2 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 1.45 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])/[CH:10]=[C:11](/[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][C:18]=1I)\[C:12]([F:15])([F:14])[F:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH2:1]([O:8][C:9]([C:10]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][OH:25])[CH:21]=2)[NH:16][C:11]=1[C:12]([F:15])([F:14])[F:13])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C(/Nc1ccc(CCO)cc1I)C(F)(F)F)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1c(C(F)(F)F)[nH]c2ccc(CCO)cc12
Reaction time: 8 h
Yield: 6 %

Procedure:
A mixture of (E)-4,4,4-Trifluoro-3-[4-(2-hydroxy-ethyl)-2-iodo-phenylamino]-but-2-enoic acid benzyl ester (9.5 g, 19.3 mmol, 1.0 eq), Pd(OAc)2 (433 mg, 1.93 mmol, 0.1 eq), triethylamine (3.1 mL, 23.2 mmol, 1.2 eq), triphenyphosphinc (1.52 g, 5.79 mmol, 0.3 eq) and DMF (20 mL) was heated under refluxing in a 100-mL round bottom flask under nitrogen. The reaction mixture was stirred overnight. After the stirring was stopped, the mixture was partitioned between dichloromethane (100 mL) and water (100 mL) filtered through celite. The organic layer was washed with water (3×100 mL), dried over MgSO4, and concentrated. The crude residue was purified by flash chromatography (SiO2, hexanes-ethyl acetate) to yield 420 mg of the desired indole as pale yellow gel (6.0% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[CH3:38][O:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]3[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=3)=[CH:4][CH:3]=2)=[CH:30][C:29]=1[F:28])=[O:36]
Reactant: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2Cl)=N/O)ccc1=O
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(C(C/C(=N\O)c3ccc(=O)n(C)c3)c3ccccc3Cl)cc2)cc1F

Procedure:
In analogy to example 166, step 1, 5-{3-(4-bromo-phenyl)-3-(2-chloro-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 203, step 4) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound as a colorless foam, MS (ESI+): m/z=519.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)[O-]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 mg of intermediate x (trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine were dissolved in pyridine (5 mL) and tertbutyl carbonate (200 mg) was then added. The mixture was stirred at room temperature for 12 h, the poured into ice-water. The desired compound was filtered and dried. 1H-NMR (MeOH, 250 MHz, δ): 7.45-7.27 (m, 5H, ArH); 6.96 (d, 8.5 Hz, 2H, ArH); 6.86 (d, J=8.5 Hz, 2H, ArH); 5.03 (s, 2H, CH2); 2.41-2.34 (m, 1H, CH); 1.86-1.76 (m, 10H, CH); 0.98-0.85 (m, 2H, CH2).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([CH2:30][C:31]2[CH:48]=[CH:47][CH:46]=[CH:45][C:32]=2[C:33]([NH:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=2)=[O:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:40]([C:39]3[CH:38]=[CH:37][C:36]([NH:35][C:33](=[O:34])[C:32]4[CH:45]=[CH:46][CH:47]=[CH:48][C:31]=4[CH2:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:44][CH:43]=3)=[O:41])[CH2:6][C:5]=12
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a solution of 0.75 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.57 g of N,N-diisopropylethylamine in 50 ml of methylene chloride is added 1.53 g of 4-[[2-(phenylmethyl)benzoyl]amino]-benzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through hydrous magnesium silicate two additional times to give upon concentration in vacuo to give 1.97 g of the desired product as an amorphous solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[C:5](=[O:19])[NH:4][NH:3]1.[ClH:20].O1CCOCC1>C(Cl)Cl>[ClH:20].[NH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:2](=[O:1])[NH:3][NH:4][C:5]1=[O:19]
Reactant: CC(C)(C)OC(=O)NCCCCn1c(=O)[nH][nH]c1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCCCn1c(=O)[nH][nH]c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)butylcarbamate (I-8b: 590 mg, 2.167 mmol) in CH2Cl2 (10.800 mL) was added HCl in dioxane (5.42 mL, 21.67 mmol) dropwise. The mixture was stirred at room temperature for 4 h, then concentrated and dried on pump, giving 4-(4-aminobutyl)-1,2,4-triazolidine-3,5-dione hydrochloride (I-14a: 461 mg, quantitative) as a beige solid. 1H NMR (400 MHz, dmso-d6) δ ppm 1.41-1.71 (m, 4 H) 2.68-2.87 (m, 2 H) 3.37 (t, J=6.44 Hz, 2 H) 7.86 (br. s., 2 H) 10.13 (s, 2 H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:30])[NH:17][C:18]2[S:26][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+].S([O-])([O-])(=O)=O.[Mg+2].[CH:42]1([C:46](=O)[CH3:47])[CH2:45][CH2:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(=O)(O)[O-].[Na+].CO.C(Cl)Cl.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:30])[NH:17][C:18]2[S:26][C:21]3[CH2:22][N:23]([CH:46]([CH:42]4[CH2:45][CH2:44][CH2:43]4)[CH3:47])[CH2:24][CH2:25][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[CH:13][CH:14]=1
Reactant: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2
Reactant: CC(=O)C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(C1CCC1)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53.4 %

Procedure:
To a slurry of compound A4 (400 mg, 0.860 mmol), sodium acetate (212 mg, 2.58 mmol), and magnesium sulfate (1 g) in anhydrous N,N-dimethylformamide (5 mL) was added 1-cyclobutylethanone (253 mg, 2.57 mmol). After stirring at room temperature for 5 min, sodium triacetoxyborohydride (911 mg, 4.30 mmol) was added. The reaction mixture was then heated at 50° C. for 20 h. After this time, the reaction mixture was cooled to room temperature and diluted with saturated aqueous sodium bicarbonate (10 mL), methanol (5 mL), methylene chloride (20 mL), and water (10 mL). The layers were separated and the aqueous layer back extracted with 20% methanol/methylene chloride (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 2% to 6% methanol/methylene chloride to afford compound (+/−)-C1 as a white solid (199 mg, 53%): MS (M+H) 433.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>CCOCC>[C:26]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: CCCC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)CCC
Yield: 34.2 %

Procedure:
Oleyl alcohol (40 g, Eastman) and anhydrous pyridine (10 ml) were added to a 100 ml round-bottom flask equipped with a magnetic stirrer. The mixture was stirred and cooled in an ice bath for five minutes. Butyryl chloride (15.0 g, 0.14 mol, Eastman) was added dropwise via an addition funnel. The reaction mixture was stirred for 15 minutes at 5° and at room temperature for an hour. It was then diluted with ether and filtered. The filtrate was dried over sodium sulfate. Volatiles were removed under vacuum. Distillation of the residual oil (163°-168°, 0.26-0.28 torr) gave 16.2 g (34%) of 3. NMR: δ 0.9 (m, 6 H, CH3), 1.1-2.4 (m, 32 H, CH2), 3.95 (t, J=6 Hz, CH2O), 5.3 (t, J=4.5 Hz, 2 H vinyl). IR: 3005 (olefinic-CH), 1740 (C=O), 1175 cm-1 (C--O--C)
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH3:11][CH2:12][O:13][C:14]([C@@H:16]1[CH2:20][CH:19]=[CH:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15].[OH-].[Na+]>C(Cl)Cl>[CH3:11][CH2:12][O:13][C:14]([C@@H:16]1[CH2:20][C:19]([CH:9]=[O:10])=[CH:18][N:17]1[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[O:15]
Reactant: CCOC(=O)[C@@H]1CC=CN1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(C=O)=CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
POCl3 (7.59 mL, 83 mmol) was added in 25 min at 0° C. under N2 atmosphere to DMF (6.39 mL, 83 mmol) and the mixture was stirred at RT for 20 min. Dry CH2Cl2 (150 mL) was added at 0° C., followed by a solution of (S)-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (10 g, 41.4 mmol) in CH2Cl2 (50 mL). The mixture was stirred 30 min at RT until completion. The mixture was slowly poured into an ice cold aqueous solution of NaOH 10 N (150 mL) and extracted with CH2Cl2 (×3). The combined organic extracts were washed with brine (×2), with water, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 9:1) to give the desired material as a yellow oil. Rf, TLC (c-hexane/EtOAc 4:1)=0.2; MS (UPLC-MS): 270 [M+H]+, 170 [M−Boc]−; tR (HPLC conditions f): 1.93 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20](I)[N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20]([C:34]3[CH:35]=[CH:36][C:37]([O:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[C:32]([O:31][CH3:30])[CH:33]=3)[N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nc([C@H]3CC[C@H](CNC(=O)OCc4ccccc4)CC3)n3ccnc(N)c23)ccc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of trans-[4-(8-amino-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclohexylmethyl]-carbamic acid benzyl ester (80.0 mg, 0.0002 mol), 2-(3-methoxy-4-phenoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (67.0 mg, 0.0002 mol), potassium carbonate (0.076 g, 0.00055 mol) in DME (3.00 mL) and H2O (0.50 mL) was added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride DCM (9.0 mg, 0.00001 mol). The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. Solvent was removed under reduced pressure and the product was purified by flash chromatography (2% MeOH in DCM). MS (ES+): m/z: 577.95 [MH+]. HPLC: tR=2.72 min (OpenLynx: polar—5 min).
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(SCCl)C=CC=CC=1.I([O-])(=O)(=O)=O.[Na+]>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH2:9]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:1]1=[O:8]
Reactant: O=C1CCCCCO1
Reactant: ClCSc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: C=C1CCCCOC1=O

Procedure:
This synthesis was carried out by reaction of the silyl enol of ε-caprolactone with chloromethyl phenyl sulphide in the presence of a catalytic amount of zinc chloride to give the sulphurized compound, which was oxidized into sulphoxide using sodium metaperiodate. Pyrolysis of the sulphoxide in refluxing toluene gave α-methylene-ε-caprolactone.