Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH2:13][C:14](OCC)=[O:15])=[CH:2]1.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][OH:15])=[CH:2]1
Reactant: CCOC(=O)CNCCc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OCCNCCc1c[nH]c2ccccc12
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
398 g of the product of Step A were dissolved in 4 liters of tetrahydrofuran cooled to +10° C. and while maintaining this temperature, 400 g of 25% sodium diethyl dihydroaluminate in toluene were introduced. The mixture was stirred for 90 minutes while allowing the temperture to rise to 17° C. The medium was cooled to -10° C. and 400 ml of sodium hydroxide solution in 1200 ml of water were introduced over 80 minutes while keeping the temperature at 0° C. during the introduction. The mixture was stirred for 2 hours at +10° C. then allowed to rise to ambient temperature for 16 hours with slower stirring. After decanting, the organic phase was washed with water and the wash water was extracted with ethyl acetate and methylene chloride. The combined organic phases were diluted with methylene chloride and dried, and the solvents were expelled at 40° C. under reduced pressure. The residue was triturated in 1300 ml of ethyl acetate for one hour, separated, washed with ethyl acetate and dried to obtain 240.8 g of the expected product melting at 92° C.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:32])[CH3:31])[N:25]=[C:24]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:32])[CH3:31])[N:25]=[C:24]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCc1nc(C(C)O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(C)O)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
12 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 0.52 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxyethyl)imidazole-5-carbonitrile [prepared as described in step (b) above] in 3 ml of ethanol, and the resulting mixture was heated under reflux for 3 hours. At the end of this time, the reaction mixture was neutralized by the addition of dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of ethyl acetate and hexane, followed by ethyl acetate alone, as the eluent, to afford 0.14 g of the title compound as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:12])[C:8]=1[O:9][CH2:10][CH3:11])[NH2:5].[CH2:13](N(CC)CC)C.ClC1C=C(N[C:30]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[O:31])C=C(Cl)C=1O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:30]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([O:38][CH3:13])=[O:37])=[CH:34][CH:33]=2)=[O:31])[CH:6]=[C:7]([Br:12])[C:8]=1[O:9][CH2:10][CH3:11]
Reactant: CCOc1c(Br)cc(N)cc1Br
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(C(=O)Nc2cc(Cl)c(O)c(Cl)c2)cc1
Solvent: ClCCl
Product: CCOc1c(Br)cc(NC(=O)c2ccc(C(=O)OC)cc2)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
3,5-Dibromo-4-ethoxyaniline (2) (100 mg, 339 μmol) was dissolved in DCM (2.5 mL) and treated with triethylamine (143 μL, 1.02 mmol). 4-(Chlorocarbonyl)benzoic acid methyl ester (3) (135 mg, 678 μmol) was added in one portion and the resultant dark orange mixture was stirred at RT for 3 h then partitioned between EtOAc and aqueous 1M HCl. The organic layer was washed successively with saturated aqueous NaHCO3, water and brine. The organic layer was then dried over MgSO4, filtered and the solvent evaporated in vacuo. The residue was triturated from Et2O and filtered. The filtered solid was washed with methanol and the washings were concentrated in vacuo to provide methyl 4-(3,5-dibromo-4-ethoxyphenylcarbamoyl)benzoate (4) (141 mg, 73%) as a pale brown solid: m/z 456 [M−H]− (ES−).
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:16]([O:18]CC)=O)=[C:13]([CH3:15])[N:14]=2)=[CH:6][CH:5]=1.COC1C=CC(C([NH2:29])=O)=CC=1.ClC(C(C)=O)C(OCC)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>C(O)CCC.C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:16]([NH2:29])=[O:18])=[C:13]([CH3:15])[N:14]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C(N)=O)cc1
Reactant: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: N
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCCCO
Solvent: CCO
Product: COc1ccc(-c2nc(C)c(C(N)=O)s2)cc1
Yield: 69 %

Procedure:
Into a mixed solvent of 50 ml of aqueous 28% ammonia and 450 ml of ethanol, 13.9 g of ethyl 2-(4-methoxyphenyl)-4-methylthiazole-5-carboxylate which had been prepared by heating a mixture of p-methoxybenzamide, ethyl α-chloroacetoacetate, phosphorus pentasulfide and n-butyl alcohol under a reflux for 5 hours was dissolved. Then, in a similar manner as in Example 3 the object was obtained as colourless aciculate melting at 179.5° to 180.5° C. in an amount of 8.6 g corresponding to the yield of 69%.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:12]([NH2:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CCOCC>[O:7]([C:8]([CH2:13][O:12][NH2:14])=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CON
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: NOCC(=O)Oc1ccccc1
Reaction time: 64 h
Yield: 89.9 %

Procedure:
Phenylchloroformate (14.78 g, 94.4 mmol) was dissolved in Et2O (375 mL) and methoxylamine hydrochloride (7.88 g, 94.4 mmol), K2CO3 (15.66 g, 113.3 mmol), and water (18 mL) were added and the solution stirred over 64 hours. Solids were filtered, the phases separated, and the organic component concentrated under reduced pressure. The crude liquid was purified by column chromatography with silica gel (1:4 EtOAc/hexanes) to afford N-(phenoxycarbonyl)methoxylamine as a white solid (14.18 g, 90%).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[H-].[Na+].C([Li])CCC.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:17]1([C:16]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:23][C:1](=[O:6])[CH:2]=[CH:3][CH2:5]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=CCC(c2ccccc2)(c2ccccc2)O1

Procedure:
The title compound was prepared as described in General Method 1 using 20 mmol of methyl acetoacetate, 22 mmol of NaH 60% dispersion in oil, 21 mmol of 1.6M n-butyl lithium in hexane, 20 mmol of benzophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction a solid precipitated out which was triturated with ether and filtered (m.p. 170.5°-173° C.). 1H NMR (CDCl3) δ3.18 (s, 2H), 3.4 (s, 2H), 7.3-7.5 (m, 10H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:11]=2[CH2:12][N:13]([CH2:19][CH3:20])[C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31].C(Cl)Cl.O>C(N(CC)CC)C.[Cu](I)I.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>[CH2:19]([N:13]([CH2:12][C:11]1[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:10]=1[C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:3]=1)[C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15])[CH3:20]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Br)cnc1OC)C(=O)C1CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C#C[Si](C)(C)C)cnc1OC)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropanecarboxylic acid [2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-ethyl-amide (0.215 g, 0.47 mmol), (trimethylsilyl)acetylene (0.07 mL, 0.47 mmol), and copper iodide (0.012 g, 0.05 mmol) were combined in triethylamine (2 mL), and the solution was purged with N2 for 25 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.039 g, 0.05 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was worked-up with CH2Cl2 and H2O, and the combined organic layers were dried, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give cyclopropanecarboxylic acid ethyl-[2-(2-methoxy-5-trimethylsilanylethynyl-pyridin-3-yl)-5-trifluoromethyl-benzyl]-amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:14]Br.CCCCC>CN(C=O)C.C(Cl)Cl>[Br:14][C:11]1[O:10][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(Cc2ccco2)cc1
Reactant: BrBr
Solvent: CCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc(Cc2ccc(Br)o2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a -30° C. solution of 2-(4-fluorophenylmethyl)furan, prepared as in step 1 (32.0 g, 0.18 mol) in anhydrous DMF (60 mL) was added a solution of bromine (28.9 g, 0.18 mol) in CH2Cl2 (250 mL). The mixture was stirred for 0.5 hours at -10° C. and poured into pentane (1600 mL). The penlane was then decanted from the dark colored insoluble layer. Evaporation of the pentane gave the crude product which was purified by flash-chromatography on silica gel eluting with penlane to provide 2-Bromo-5-(4-fluorophenylmethyl)furan as a cream colored solid in a yield of 8.87 g (19.2%).
Reaction SMILES: [SH:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH2:11]([O:15][C:16](=[O:35])[C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:18][C:19]([C:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:12][CH2:13][CH3:14].ON1C2N=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[CH2:11]([O:15][C:16](=[O:35])[C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:18][C:19]([C:21]1([NH:26][C:7]([C:2]2([SH:1])[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:9])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)C1(S)CCCC1
Reactant: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(N)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)C2(S)CCCC2)CCCC1
Reaction time: 14 h

Procedure:
To a stirred solution of 1-mercapto-1-cyclopentanecarboxylic acid (1.74 g, 4.54 mmol) in dichloromethane (50 mL) and triethylamine (0.63 mL) is added [(1-amino-(1-cyclopentyl)carbonyl]-L-tyrosine butyl ester hydrochloride (0.66 g). To this solution is added 1-hydroxy-7-azabenzotriazole (0.68 g, 4.55 mmol) and 1,3-dicyclohexylcarbodiimide (1.03 g, 4.99 mmol). The mixture is stirred for 14 hours and then the solid precipitate is removed by filtration. The organic phase is washed with a saturated solution of sodium bicarbonate (10 mL), brine (10 mL), dried over magnesium sulfate and the solvent is removed to give a clear oil. The oil is purified by flash chromatography (SiO2, hexane/ethyl acetate, 6:4) to give a clear foam. The foam is crystallized from ethyl ether to yield N-[[1-[[(1-mercapto-1-cyclopentyl)carbonyl]amino]-1-cyclopentyl]carbonyl]-L-tyrosine butyl ester, m.p. 106°-107° C.
Reaction SMILES: N#N.[C:3]([C:6]1[S:10][C:9]([CH2:11][C:12]2[O:13][CH:14]=[C:15]([C:17](Cl)=[O:18])[N:16]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH3:20][C:21]1([C:26]2[S:30][C:29]([CH2:31][C:32]3[O:33][CH:34]=[C:35]([C:37](Cl)=[O:38])[N:36]=3)=[CH:28][CH:27]=2)[O:25][CH2:24][CH2:23][O:22]1.[N-:40]=[N+:41]=[N-:42].[Na+]>CC(C)=O.O>[C:3]([C:6]1[S:10][C:9]([CH2:11][C:12]2[O:13][CH:14]=[C:15]([C:17]([N:40]=[N+:41]=[N-:42])=[O:18])[N:16]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH3:20][C:21]1([C:26]2[S:30][C:29]([CH2:31][C:32]3[O:33][CH:34]=[C:35]([C:37]([N:40]=[N+:41]=[N-:42])=[O:38])[N:36]=3)=[CH:28][CH:27]=2)[O:25][CH2:24][CH2:23][O:22]1
Reactant: CC1(c2ccc(Cc3nc(C(=O)Cl)co3)s2)OCCO1
Reactant: CC(=O)c1ccc(Cc2nc(C(=O)Cl)co2)s1
Reactant: [N-]=[N+]=[N-]
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(Cc2nc(C(=O)N=[N+]=[N-])co2)s1
Product: CC1(c2ccc(Cc3nc(C(=O)N=[N+]=[N-])co3)s2)OCCO1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude mixture of 2-(5-acetyl-thiophen-2-ylmethyl)-oxazole-4-carbonyl chloride and 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-oxazole-4-carbonyl chloride in dry acetone (12.0 mL) was cooled to 0° C. and a solution of sodium azide (262 mg, 3.98 mmol) in H2O (1.4 mL) was added over 1 h. The reaction mixture was stirred at 0° C. for 45 min. The mixture was concentrated under reduced pressure (co-evaporation with toluene) then dissolved in CH2Cl2 and filtered. The filtrated was concentrated under reduced pressure to give the title compound (LC-MS-conditions 01: tR=0.85 min, [M+H]+=276.91) along with 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-oxazole-4-carbonyl azide (LC-MS-conditions 01: tR=0.91 min, [M+H]+=320.92) as a brown solid.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=O)[O:10][C@@H:9]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:8]1)(=[O:5])[CH3:4].[O:29]1CCCC1>>[C:17]([O:16][CH2:14][CH2:13][CH2:12][C@H:11]1[O:10][C@@H:9]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:8][C@@H:7]1[O:6][C:3](=[O:5])[CH3:4])(=[O:29])[CH3:18]
Reactant: CCOC(=O)CC[C@H]1O[C@@H](n2cc(CC)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Li+]
Product: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CCCOC(C)=O)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.4 g of lithium borohydride was added to a solution of 5.6 g of 3'-O-acetyl-2',5'-dideoxy-5'-(ethoxycarbonylmethyl)-5-ethyluridine in 100 ml of tetrahydrofuran and the mixture was stirred at room temperature for 4 hours. An additional 0.2 g of lithium borohydride was added and the mixture was stirred at room temperature overnight and then heated under reflux for 1 hour. The solvent was removed by evaporation in vacuo and the residue was dissolved in methanol. After standing at room temperature for a few minutes, the solvent was removed by evaporation and the residue was taken up in 40 ml of pyridine. 5 g of acetic anhydride were added and the mixture was stirred at room temperature overnight. Pyridine was removed by evaporation and the residue was partitioned between water and ethyl acetate. The aqueous solution was evaporated to dryness and the residue was subjected to flash chromatography on a column of silica gel using 10% methanol/dichloromethane for the elution to give 1.3 g of 5'-(2-acetoxyethyl)- 3'-O-acetyl-2',5'-dideoxy-5-ethyluridine in the form of a colorless oil which crystallized upon standing.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1.C(N(C(C)C)C(C)C)C>CS(C)=O.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([N:28]2[CH2:31][CH:30]([OH:32])[CH2:29]2)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1Cl
Reactant: OC1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1N1CC(O)C1
Yield: 66.8 %

Procedure:
A solution of 2-(3-(tert-butylamino)-2-chloroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (345) (28 mg, 0.07 mmol), azetidin-3-ol hydrochloride (41 mg, 0.37 mmol, Matrix Scientific, Columbia, S.C.), and N-ethyl-N-isopropylpropan-2-amine (81 pt, 0.45 mmol) in DMSO (0.75 mL) was stirred at 50° C. for 1 h. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-5% of 2 M NH3 in MeOH/DCM to give 2-(3-(tert-butylamino)-2-(3-hydroxyazetidin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (346) (19 mg, 61% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 9H) 2.85 (t, J=6.94 Hz, 2H) 3.43 (td, J=6.75, 2.35 Hz, 2H) 3.94 (dd, J=9.00, 5.09 Hz, 2H) 4.41 (dd, J=8.80, 6.85 Hz, 2H) 4.57 (sxt, J=5.91 Hz, 1H) 5.64-5.71 (m, 2H) 6.95 (s, 1H) 6.96 (s, 1H) 7.24 (t, J=7.82 Hz, 1H) 7.36 (dd, J=7.92, 1.27 Hz, 1H) 7.61 (dd, J=7.43, 1.37 Hz, 1H) 12.00 (s, 1H). MS (ESI, pos. ion) m/z: 407.1 (M+1).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]([N:14]=[C:15]([NH2:29])[NH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[N:18]=1)[CH2:12][CH3:13]>CCO.C(N(CC)CC)C>[CH2:11]([N:14]=[C:15]([NH2:29])[NH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[N:18]=1)[CH2:12][CH3:13]
Reactant: CCCN=C(N)Nc1ccnc(CCCCCN)n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCN=C(N)Nc1ccnc(CCCCCNC(=O)c2cccnc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.4 %

Procedure:
Nicotinoyl chloride hydrochloride (0.2 g.) was added at 0° to a stirred solution of 4-(2-propyl-guanidino)-2-(5-aminopentyl)pyrimidine (0.2 g.) in EtOH (5 ml.) and triethylamine (2 ml.). The mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was partitioned between 2 N aqueous HCl and EtOAc and the aqueous phase was then basified with 10 N aqueous NaOH and extracted with EtOAc. The extract was dried (MgSO4) and evaporated to dryness. The residual gum was purified twice by preparative thin layer chromatography on Merck 60 F-254 plates using EtOAc/MeOH/aqueous ammonia (s.g. 0.88) 6:1:1 v/v/v as developing solvent. The appropriate zone of the chromatogram was extracted with MeOH/aqueous ammonia (s.g. 0.88) 10:1 v/v and the solvent was evaporated. The residual gum was dissolved in EtOAc, filtered and treated with an excess of a saturated solution of maleic acid in EtOAc. The precipitated gum was washed with EtOAc to give N-[5-(4-[2-propylguanidino]-pyrimid-2-yl)pentyl]nicotinamide (0.015 g.) as a straw coloured gum. The n.m.r. spectrum in d4MeOH using tetramethylsilane as standard included the following resonances (δ):1.0 (3H, triplet), 1.7 (8H, multiplet), 2.9 (2H, triplet), 3.6 (2H, triplet), 6.8 (1H, doublet), 7.6 (1H, multiplet), 8.3 (2H, multiplet) and 8.8 (2H, complex).
Reaction SMILES: [C:1]([CH:3](C(OCC)=O)[C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:23])[C:9]([C:18]([O:20]CC)=[O:19])=[CH:10][N:11]2[CH:15]2[CH2:17][CH2:16]2)=[CH:6][C:5]=1[F:24])#[N:2].C(O)(=O)C.S(=O)(=O)(O)O>O>[C:1]([CH2:3][C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:23])[C:9]([C:18]([OH:20])=[O:19])=[CH:10][N:11]2[CH:15]2[CH2:16][CH2:17]2)=[CH:6][C:5]=1[F:24])#[N:2]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(C(C#N)C(=O)OCC)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Temperature: 25 °C

Procedure:
100 g of the compound from Example 1, 230 ml of acetic acid, 200 ml of water and 20 ml of sulphuric acid are boiled for 5 hours. After cooling to room temperature, water is added. The precipitated solid is isolated, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=2)[O:3]1.O.[NH2:21][NH2:22]>CO>[CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:21][NH2:22])=[O:14])=[CH:11][CH:10]=2)[O:3]1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC1(C)OB(c2ccc(C(=O)NN)cc2)OC1(C)C
Yield: 98.7 %

Procedure:
20 g (76 mmol) of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate are dissolved in 150 ml of methanol, 6 g (120 mmol) of hydrazine hydrate are added, and the mixture is refluxed for 12 hours. Removal of 120 ml of methanol by distillation gives 19.8 g (75 mmol, 98%) of product. The compounds of the formula (III) are obtained analogously using the compounds shown in Table 3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].Cl>C(Cl)Cl>[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7.18 g (54 mmol) of 5-aminoindane and 10.9 g (108 mmol) of triethylamine in 40 mL of CH2Cl2 is cooled to 5° C. Acetic anhydride (7.63 g, 81 mmol) is added carefully dropwise. The reaction is allowed to warm to room temperature and stirred overnight. The reaction is poured into 1 N HCl to acidify it and is then extracted with EtOAc. The organic layer is evaporated in vacuo. Toluene is added to the residue and the mixture is evaporated in vacuo to give 5-acetylaminoindane that was used without purification. 5-Acetylaminoindane (8.8 g) is dissolved in a solution of 26 mL of HOAc and 126 mL of acetic anhydride, and cooled to 0° C. Nitric acid (8.3 mL) is added carefully dropwise to the solution so as to control the temperature of the exothermic reaction. The mixture is stirred for an additional 30 minutes and is poured onto ice and filtered. The solid is washed with water and dried in a vacuum oven overnight to give 5-acetylamino-6-nitroindane that is used without further purification. A mixture of this solid in 230 mL of 6 N HCl is heated to reflux for 4 hours. The mixture is neutralized with Na2CO3 (152 g) in 1000 mL of H2O. The solids are filtered and dried overnight in a vacuum oven to give 5-amino-6-nitroindane.