Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:16]1.C(O)(=O)C.C(=O)C>CN(C)C=O>[CH2:1]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:16]1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1[nH]ccc2cc(OC3CCCNC3)ccc12
Agent: CC=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCN1CCCC(Oc2ccc3c(=O)[nH]ccc3c2)C1
Reaction time: 17 h

Procedure:
Sodium triacetoxyborohydride (45 mg, 1.8 mol) was added to a solution of 6-(piperidin-3-yloxy)-2H-isoquinolin-1-one (30 mg, 0.12 mmol), acetic acid (100 μl) and acetaldehyde (50 μl or 50 mg) in N, N-dimethylformamide (500 μl) and shaken for 17 hours. The reaction was quenched with water and methanol and passed down an SCX cartridge. The product was purified by preparative HPLC under basic conditions. The clean products were isolated by evaporation under reduced pressure to give 6-(1-ethyl-piperidin-3-yloxy)-2H-isoquinolin-1-one: El-MS: m/z=273.5[M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH:12]=1.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:22][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[CH:12]=[C:7]([CH:25]=[O:26])[CH:8]=[N:9][CH:10]=2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: CN(C)C=O
Reactant: Fc1ccc(C#Cc2cncc(Br)c2)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1cncc(C#Cc2ccc(F)c(F)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
Add a 2.5 M solution of butyllithium in hexanes (3.18 mL, 7.96 mmol) to anhydrous toluene (11 mL) at −78° C. Allow the internal temperature to return to −78° C., then add 3-bromo-5-(3,4-difluorophenylethynyl)-pyridine (1.56 g, 5.30 mmol), (prepared essentially as described in EXAMPLE 100), dissolved in anhydrous toluene (11 mL) at such a rate to maintain the reaction temperature below −60° C. Stir for 5 min, add N,N-dimethylformamide (0.47 g, 6.37 mmol) dropwise at a rate so as to maintain the reaction temperature below 60° C. Stir for 20 min, warm to 0° C. and add an aqueous saturated solution of ammonium chloride and ethyl acetate. Stir for 5 min and separate the layers. Dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes to give the title compound as a white solid (0.780 g, 61%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][N:8]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:4][CH:3]=1
Reactant: COC(=O)NCCCBr
Reactant: Fc1ccc2c(I)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NCCCn1nc(I)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.7 %

Procedure:
to a solution of 6-fluoro-3-iodo-1H-indazole (1.5 g) and methyl (3-bromopropyl)carbamate (1.68 g) in N,N-dimethylformamide (5 mL) was added potassium carbonate (1.58 g), and the mixture was stirred at room temperature for 3 days. To the reaction solution was added ethyl acetate, and the mixture was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/20→3/2) to give methyl [3-(6-fluoro-3-iodo-1H-indazol-1-yl)propyl]carbamate [REx(102-1)] (836 mg) as a red oil.
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=2)=[C:5]([F:24])[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:9][C:8]1[C:3]([Cl:2])=[CH:4][C:5]([F:24])=[C:6]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=2)[CH:7]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 44.8 %

Procedure:
Then, 0.37 g of iron powder was added to a mixture of 5.3 ml of acetic acid and 2.0 ml of water, to which a solution of 0.39 g of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-17) in 1.0 ml of acetic acid was slowly added dropwise, and the mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed twice with water and further with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated, which afforded 0.16 g (yield, 46%) of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-23).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][C:5]2=[C:7]([C:14]([O-:16])=[O:15])[CH:8]=[CH:9][C:10]([N+:11]([O-])=O)=[C:4]2[O:3]1.[C:18](=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Fe]>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:14]([O:16][CH3:18])=[O:15])=[C:5]2[C:4]=1[O:3][C:2]([CH3:17])([CH3:1])[CH2:6]2
Reactant: CC1(C)Cc2c(C(=O)[O-])ccc([N+](=O)[O-])c2O1
Reactant: O=C([O-])[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N)c2c1CC(C)(C)O2
Reaction time: 12 h
Yield: 74.6 %

Procedure:
2,2-Dimethyl-7-nitro-3H-benzofuran-4-carboxylate 4c (1.20 g, 4.77 mmol) and iron powder (0.80 g, 14.32 mmol) were dissolved in 25 mL of acetic acid. The reaction mixture was stirred for 12 hours. The resulting mixture was added with sodium carbonate and solid sodium bicarbonate to adjust pH to 7 to 8, extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 7-amino-2,2-dimethyl-3H-benzofuran-4-carboxylate 4d (789 mg, yield: 74.6%) as a white solid.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:24])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:25]([C:28]([CH3:30])=[CH2:29])[CH2:26]C[C@]1(C(O)=O)[CH2:4][CH2:3]2.C([N:36]([CH2:39]C)[CH2:37][CH3:38])C.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)[O:42]C1C=CC=CC=1>O1CCOCC1>[N:36]([C@:37]12[CH2:38][CH2:26][C@@H:25]([C:28]([CH3:30])=[CH2:29])[C@@H:6]1[C@@H:7]1[C@@:2]([CH3:1])([CH2:3][CH2:4]2)[C@@:19]2([CH3:20])[C@@H:10]([C@:11]3([CH3:24])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:21])([CH3:22])[C:14](=[O:23])[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)=[C:39]=[O:42]
Reactant: CCN(CC)CC
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Yield: 63.2 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (16.41 g, 36.1 mmol) in 1,4-dioxane (200 mL) was added triethylamine (15.09 mL, 108 mmol) and diphenyl phosphorazidate (11.67 mL, 54.2 mmol). The mixture was heated to reflux for 18.5 h, then was cooled to rt and concentrated under reduced pressure. The residue was split into two portions and was purified using a 0-15% ethyl acetate in hexanes gradient and a Thomson 240 g silica gel column to purify each portion. The fractions containing the expected product were combined and concentrated under reduced pressure to give (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)octadecahydro-1H-cyclopenta[a]chrysen-9(5bH)-one (10.3 g, 22.80 mmol, 63.2% yield) as an off-white foam. 1H NMR (400 MHz, chloroform-d) δ=4.75 (d, J=2.0 Hz, 1H), 4.66-4.63 (m, 1H), 2.60-2.36 (m, 4H), 2.17-2.04 (m, 1H), 1.69 (s, 3H), 1.10 (s, 3H), 1.08 (s, 3H), 1.04 (s, 3H), 0.95 (s, 6H), 2.01-0.71 (m, 20H).
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:13]N1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)S1(=O)=O>C(#N)C>[C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]1([OH:25])[CH2:23][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:11][CH2:12][CH2:1][CH2:2][CH2:3]1
Reactant: C1CCCCCCCCCCC1
Reactant: O=C1c2ccccc2S(=O)(=O)N1O
Solvent: CC#N
Product: O=C1CCCCCCCCCCC1
Product: OC1CCCCCCCCCCC1
Yield: 9.5 %
Yield: 4 %

Procedure:
To 7.5 ml of acetonitrile were added 504 mg (3.0 mmol) of cyclododecane, 60 mg (0.3 mmol) of N-hydroxysaccharin and 3.9 mg (0.015 mmol) of acetylacetonatocobalt Co(acac)2. The resultant mixture was stirred under an oxygen atmosphere at a temperature of 85° C. for 22 hours. The products in the reaction mixture were analysed by gas chromatography, with cyclododecane being transformed, with a conversion of 28%, into cyclododecanone (selectivity 34.5%, yield 9.5%) and cyclododecanol (selectivity 14%, yield 4%).
Reaction SMILES: COC1C=CC(C2(C3C=CC(OC)=CC=3)OC3C4C=C(C)C=CC=4C4C5C(=CC(C)=CC=5)C(C)(OCCOCCOCCO)C=4C=3C=C2)=CC=1.[C:51]1(=O)[O:56][CH2:55][CH2:54]C[O:52]1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[N:71](CC[O:76][C:77](=[O:81])[C:78]([CH3:80])=[CH2:79])=C=O>C(Cl)(Cl)Cl>[C:77]([OH:81])(=[O:76])[C:78]([CH3:80])=[CH2:79].[NH2:71][C:51]([O:56][CH2:55][CH3:54])=[O:52]
Reactant: O=C1OCCCO1
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CC(C)[O-]
Agent: COc1ccc(C2(c3ccc(OC)cc3)C=Cc3c4c(c5ccc(C)cc5c3O2)-c2ccc(C)cc2C4(C)OCCOCCOCCO)cc1
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)O
Product: CCOC(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3,3-Di(4-methoxyphenyl)-6,11,13-trimethyl-13-(2-(2-(2-hydroxyethoxy)-ethoxy)ethoxy)-3H,13H-indeno[2′,3′:3,4]naphtho[1,2-b]pyran (53.6 g, 0.08 mole) Photochromic A, trimethylene carbonate (146 g, 1.43 moles), anhydrous chloroform (400 mL) and aluminum isopropoxide (3.3 g, 0.016 mole) were added to a 1 liter 1 neck flask with a magnetic stir bar, purged with dry nitrogen, capped with rubber septum, and then allowed to stir at room temperature for 24 hrs. The resulting dark purple organic solution was washed by adding a solution of conc. HCl (16 g) in H2O (400 g) and stirring vigorously. Upon separation and removal of the aqueous phase, the organic layer was then washed with 10 weight % aqueous sodium bicarbonate solution (400 mL). The recovered organic layer was dried with magnesium sulfate, filtered, and poured into a 1 liter rotary evaporation flask. The molecular weight distribution by GPC was determined to be an Mn of 3,090, a Mw of 3960 and PDI of 1.28. After rotary evaporation for 1 hour at 90° C., the dark purple oil was diluted with anhydrous toluene (200 g), and to this solution was added 4 drops of dibutyltindilaurate and isocyanatoethylmethacrylate (12.6 g, 0.081 mole). The resulting reaction mixture was heated to 76° C., purged with dry nitrogen, capped with a rubber septum, stirred for 3 hrs at 76° C., followed by stirring overnight at room temperature.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#N)=[CH:14][CH:13]=1)([O-:11])=[O:10].Cl.C(OCC)(=[O:23])C>C1COCC1>[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([C:16](=[O:23])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 88 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.48 g (10 mmol) of p-nitrobenzonitrile in 10 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 21 hours. 15 mL of 10% hydrochloric acid was added dropwise at 20° C. or lower, and the mixture was stirred at 20˜25° C. for 2 hours, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 15 mL of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, crystals were loosened with n-hexane, filtered, and washed with n-hexane. After vacuum drying (40° C.), 2.09 g of the desired product was obtained (yield 88%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:20][C:21](=[CH2:24])[CH2:22][NH2:23]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH2:22][C:21]([CH3:24])=[CH2:20])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: C=C(C)CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)CNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In DMF, 700 mg (3.4 mol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine was dissolved, and 759 mg (7.5 mmol) of triethylamine was added thereto, followed by adding 404 mg (3.8 mmol) of 2-methyl-2-propenylamine thereto, under ice cooling. The reaction solution was stirred at 0° C. for 1 hour and allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 687 mg (yield: 79.3%) of the title compound.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]3[C@H:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:27]3[C@H:23]([CH2:24][N:25]([C:8](=[O:10])[C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:11])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: C[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
N,N'-Carbonyldiimidazole (0.66 g) is added to a solution of (R)-2-phenylpropionic acid (0.62 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.35 g) and triethylamine (0.57 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in ethyl acetate (100 cc) and the solution is washed with water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (4 kPa). The residue is chromatographed on a silica gel column (0.2-0.04 mm, diameter 2.8 cm, height 15 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 50 cc fractions. Fractions 4 to 8 are concentrated to dryness under reduced pressure (4 kPa) to give (3aR,7aR)-7,7-diphenyl-2-[(R)-2-phenylpropionyl]-4-perhydroisoindolone (1.4 g) in the form of a white meringue, the infrared spectrum of which is identical to that of the product from Example 68; [α]D20 =-278° (c=1, methanol).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.[OH:12][C@H:13]([C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])[O:26][CH2:27][C:23]=2[C:22]=1[CH3:31])[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CCO>[OH:1][CH:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)[CH2:3][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C@H:13]([OH:12])[C:21]2[CH:30]=[CH:29][C:24]3[C:25](=[O:28])[O:26][CH2:27][C:23]=3[C:22]=2[CH3:31])[CH2:16][CH2:17]1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: N#Cc1ccc(C2CO2)nc1
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(CC(O)c3ccc(C#N)cn3)CC2)ccc2c1COC2=O
Temperature: 140 °C

Procedure:
To a microwave tube were added isomer B of 6-(oxiran-2-yl)pyridine-3-carbonitrile (330 mg, 2.26 mmol), 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one (686 mg, 2.48 mmol, as a free base), and EtOH (7.0 mL). The mixture was heated in the microwave for 60 min at 140° C. The solvent was evaporated and the crude product was purified by silica gel MPLC (0→10% CH2CH2:MeOH) to provide 6-(1-Hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)pyridine-3-carbonitrile as a single isomer. Further, the product was treated with 1 M HCl in diethyl ether to give the final product as an HCl salt. 1H NMR (500 MHz, DMSO-d6), δ 8.92 (s, 1H), 8.28 (dd, J=1.9 Hz, J=2.0 Hz, 1H), 7.68-7.63 (m, 3H), 5.48 (d, J=4.8 Hz, 1H), 5.37 (d, J=2.2 Hz, 2H), 5.20 (d, J=3.9 Hz, 1H), 5.03 (m, 1H), 4.78 (m, 1H), 2.64 (dd, J=4.1, 1H), 2.55-2.41 (m, 8H), 2.33 (dd, J=3.7 Hz, 1H), 2.24 (s, 3H); LC/MS: (IE, m/z) [(M+1)]+=423.04 (57A).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH:3]=1>C(O)C.O.[Pd]>[CH3:12][N:8]([C:4]1[CH:3]=[CH:2][N:7]=[CH:6][N:5]=1)[CH2:9][CH2:10][OH:11]
Reactant: CN(CCO)c1cc(Cl)ncn1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CN(CCO)c1ccncn1
Reaction time: 8 h

Procedure:
To 9.4 g (50 mmol) 2-[(6-chloropyrimidin-4-yl)-methylamino)ethanol in 50 ml ethanol and 10 ml water, 1 g of a 10% Pd/C paste is added and the resulting mixture is subjected to hydrogenation at a pressure of 60 atmospheres and at room temperature for 8 h.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:6][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: BrCc1ccccc1
Reactant: C/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/C=C/C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 104.4 %

Procedure:
Crotonic acid (70 g, 812 mmol) was dissolved in N,N-dimethylformamide (467 ml), which was cooled in an ice bath under nitrogen, and potassium carbonate (61.6 g, 447 mmol) was added. Benzyl bromide (91.7 ml, 772 mmol) was added dropwise to the reaction mixture over 20 minutes. The reaction mixture was stirred at mom temperature for 18 hours. Ethyl acetate was added to the reaction mixture, which was filtered through Celite. The filtered ethyl acetate solution was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (142 g, yield: 99.4%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10]O)=[CH:7][CH:6]=1)[CH3:3].Cl.[NH2:13][CH2:14][CH2:15][SH:16].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:16][CH2:15][CH2:14][NH2:13])=[CH:7][CH:6]=1)[CH3:3]
Reactant: NCCS
Reactant: CN(C)Cc1ccc(CO)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(C)Cc1ccc(CSCCN)o1
Reaction time: 18 h
Yield: 54.2 %

Procedure:
5-(Dimethylamino)methyl-2-furanmethanol (15.5 g) was added dropwise to a stirred, ice-cold solution of cysteamine hydrochloride (11.36 g) in concentrated hydrochloric acid (40 ml). After standing at 0° for 18 hr, excess anhydrous sodium carbonate was added and the resultant solid extracted with diethyl ether. Removal of solvent followed by distillation of the residue gave 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (11.6 g) b.p. 104°-106° (0.1 mm). Picrate salt m.p. 142°-144°.
Reaction SMILES: C1(OC)C=CC=CC=1.COC1C=CC(C[O:16][N:17]([CH2:21][C:22]2[CH:58]=[CH:57][C:25]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34](=[O:56])[C:35]4[CH:40]=[CH:39][C:38]([CH2:41][N:42]([O:46]CC5C=CC(OC)=CC=5)[C:43]([NH2:45])=[O:44])=[CH:37][CH:36]=4)[CH:29]=3)=[O:27])=[CH:24][CH:23]=2)[C:18]([NH2:20])=[O:19])=CC=1>FC(F)(F)C(O)=O>[OH:46][N:42]([CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:26](=[O:27])[C:25]3[CH:57]=[CH:58][C:22]([CH2:21][N:17]([OH:16])[C:18]([NH2:20])=[O:19])=[CH:23][CH:24]=3)[CH:29]=2)=[O:56])=[CH:36][CH:37]=1)[C:43]([NH2:45])=[O:44]
Reactant: COc1ccc(CON(Cc2ccc(C(=O)c3cccc(C(=O)c4ccc(CN(OCc5ccc(OC)cc5)C(N)=O)cc4)c3)cc2)C(N)=O)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N(O)Cc1ccc(C(=O)c2cccc(C(=O)c3ccc(CN(O)C(N)=O)cc3)c2)cc1
Reaction time: 6 h
Yield: 81.7 %

Procedure:
With ice-cooling, 10 ml of anisole and 40 ml of trifluoroacetic acid were added to 1.47 g of 1,3-bis[4-[[1-(4-methoxybenzyloxy)ureido]methyl]benzoyl]benzene. The reaction mixture was stirred with ice-cooling for 30 minutes and then at room temperature for 6 hours. The solvent was evaporated under a reduced pressure and the resulting residue was mixed with diethyl ether. The thus formed crystals were collected by filtration and dried to obtain 0.79 g of 1,3-bis[4-[(1-hydroxyureido)methyl]benzoyl]benzene.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:17]([NH2:19])=[O:18])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.C(OC(=O)[NH:46][C@@H:47]1[C@H:52]([NH2:53])[CH2:51][CH2:50][O:49][CH2:48]1)(C)(C)C>CN1C(=O)CCC1.CCOC(C)=O>[NH2:46][C@@H:47]1[C@H:52]([NH:53][C:3]2[N:4]=[N:5][C:6]([C:17]([NH2:19])=[O:18])=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:8]=2)[CH2:51][CH2:50][O:49][CH2:48]1
Reactant: CSc1nnc(C(N)=O)c(Nc2ccc(C)cc2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
3-(Methylthio)-5-(p-tolylamino)-1,2,4-triazine-6-carboxamide (26 mg, 0.095 mmol) was dissolved in 4 mL NMP. To it was added mCPBA (77%) (86 mg, 0.38 mmol). The mixture was stirred at RT for 1 h. To it was added DIEA (0.17 mL, 0.95 mmol) and tert-butyl((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate (41 mg, 0.19 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was diluted with 100 mL EtOAc, washed with 1N NaOH and brine, dried, concentrated in vacuo. It was then treated with neat TFA for 1 h at RT. The mixture was diluted with water and subjected to reverse phase preparative HPLC to isolate the title compound (27 mg) as HCl salt. MS found for C16H21N7O2 as (M+H)+ 344.4. UV: λ=235, 273 nm. Proton NMR: (CD3OD) δ 7.56 (2H, d, J=6.8 Hz), 7.31 (2H, d, J=7.6 Hz), 4.36 (1H, dt, J=11.6; 5.2 Hz), 4.10 (1H, dd, J=11.6; 4.8 Hz), 3.99 (1H, d, J=13.2 Hz), 3.74 (1H, s), 3.67-3.61 (2H, m), 2.38 (3H, s), 2.16 (1H, m), 1.91 (1H, m) ppm.