Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]([C:13]1[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1)#[CH:12].CCN(CC)CC>C1COCC1>[C:11]([C:13]1[CH:14]=[C:15]([NH:19][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[CH:16]=[CH:17][CH:18]=1)#[CH:12]
Reactant: C#Cc1cccc(N)c1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#Cc1cccc(NC(=O)c2ccccc2C)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A dry 25 mL flask was charged with 2-methylbenzoyl chloride (0.155 g, 1.00 mmol) was cooled to room temperature, and THF (10 mL) was added. 3-Ethynyl-phenylamine (0.117 g, 1.00 mmol) was added to the THF solution of the acid chloride followed by NEt3 (0.272 mL, 2.00 mmol), and the mixture was allowed to stir at 55° C. The reaction mixture was then allowed to cool to room temperature and partitioned between EtOAc (10 mL) and H2O (15 mL). The organic layer was washed with then washed once with 1M HCl (˜20 mL) followed by of saturated aqueous NaHCO3 (˜20 mL) and of brine (˜20 mL). The organic extracts were concentrated and the crude residue was purified by chromatography (silica gel, gradient elution EtOAc/hexanes 10 to 70%). The product containing fractions were concentrated to give the title compound as a tan solid (434 mg, 0.88 mmol, 88%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39](=[O:50])[N:40]([CH:47]([CH3:49])[CH3:48])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:19]2=[O:51])=[CH:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39]([N:40]([CH:47]([CH3:48])[CH3:49])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:50])[C:19]2=[O:51])=[CH:9]1
Reactant: CC(C)N(C(=O)CN1C(=O)C(C)(Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(C(=O)CN1C(=O)C(C)(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To a solution of 3-{6-[(isopropyl-phenyl-carbamoyl)-methyl]-4-methyl-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indole-1-carboxylic acid tert-butyl ester in dioxane (1 mL) was added HCl (4.0M in dioxane, 550 μL) and the reaction was stirred at room temperature for 50 hours. The volatiles were concentrated in vacuo and the residue was dissolved in CH2Cl2. The organic solution was washed with aqueous NaHCO3 (1×), dried (Na2SO4), filtered and concentrated. Purification by preparative chromatography eluting with 40% acetone in CH2Cl2 provided 17 mg of 2-[4-(1H-indol-3-ylmethyl)-4-methyl-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD2Cl2) δ 8.37 (s, 1H), 7.78 (m, 1H), 7.53-7.23 (m, 13H), 7.11 (m, 2H), 7.02 (t, 1H), 6.90 (d, 1H), 5.03 (m, 1H), 4.33 (d, 1H), 3.76-3.58 (m, 1H), 2.83 (m, 2H), 1.75 (s, 3H), 1.11 (m, 6H); MS 595.2 (M+1).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:12]([NH2:15])(=[O:14])[CH3:13].C(=O)([O-])O.[Na+]>>[CH3:13][C:12]1[O:14][C:2]([CH3:11])=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:15]=1
Reactant: CC(N)=O
Reactant: CC(Br)C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc(-c2ccccc2)c(C)o1

Procedure:
A mixture of α-bromopropiophenone (9.5 g) and acetamide (26.4 g) was heated on an oil bath at 130°-140° C. for 40 minutes. After cooling, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl ether. The ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was further distilled under reduced pressure to give 2,5-dimethyl-4-phenyloxazole as an oil, yield 6.4 g (82.9%), b.p. 148°-152° C./23 mmHg.
Reaction SMILES: [CH2:1]([O:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:15]=1[F:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])CCC.CCCCCC.[C:35](=[O:37])=[O:36].Cl>C1COCC1>[CH2:1]([O:13][C:14]1[C:15]([F:23])=[C:16]([F:22])[C:17]([C:35]([OH:37])=[O:36])=[C:18]([F:21])[C:19]=1[F:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C=O
Reactant: CCCCCCCCCCCCOc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
40.1 g of the compound (12) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 95 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 37.5 g (99 mmol) of 4-dodecyloxy-2,3,5,6-tetrafluorobenzoic acid (13).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([Br:14])=[CH:20][N:19]=1)=[O:8])=[O:5]
Reactant: Nc1ccc(Br)cn1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,6-Dichlorobenzoyl isocyanate (2.16 grams; 0.01 mole) and 5-bromo-2-aminopyridine (1.73 grams; 0.01 mole) were mixed in 50 ml. of ethyl acetate, at room temperature. The reaction mixture was stirred at room temperature for 4 hours, during which the product precipitated. It was separated by filtration and recrystallized from ethanol, m.p. 228°-230° C., yield 2.0 grams. Elemental analysis showed:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)#[N:11].N1CCCCC1>CO>[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:14][CH:13]=1)#[N:11]
Reactant: COC(=O)CC(=O)OC
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccc(C#N)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dimethyl malonate (5.04 g, 38.13 mmol), 4-cyanobenzaldehyde (5.00 g, 38.13 mmol) and piperidine (0.097 g, 1.1 mmol) are dissolved in methanol (150 ml). The reaction mixture is stirred for two days (48 hours) at room temperature. The solvent is removed in vacuo to afford a viscous oil which is recrystallised from methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[CH:7]2)([O-])=O>CCOC(C)=O.[Pd]>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2C2CCCCO2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred solution of 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.00 g, 4.04 mmol) in EtOAc (10 mL) was degassed for 10 min and then placed under vacuum and filled with nitrogen. The reaction mixture was placed under vacuum again, palladium on carbon (10% wt./wt, 272 mg, 0.256 mmol) was added and the resulting mixture was stirred under an atmosphere of hydrogen at RT for 20 hr. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to yield the title compound, Intermediate D1 as a pale yellow solid (553 mg, 2.47 mmol, 61% yield); Rt 1.38 min, Basic method, m/z 218.3 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.52-1.58 (2H, over-lapping m), 1.71 (1H, m), 1.90 (1H, m), 2.01 (1H, m), 2.36 (1H, m), 3.68 (1H, m), 3.86 (1H, m), 4.85 (2H, s), 5.67 (1H, dd), 6.74 (1H, m), 6.81 (1H, dd), 7.40 (1H, m), 7.75 (1H, d).
Reaction SMILES: [N:1]([C:4](N=[N+]=[N-])=[O:5])=[N+]=[N-].[C:9]([O:13][C:14](OC([O-])=O)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CO.[OH-].[OH-].[Pd+2]>[C:14]([C:4]([NH2:1])=[O:5])([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: [N-]=[N+]=NC(=O)N=[N+]=[N-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C(N)=O
Yield: 82.2 %

Procedure:
A solution of 19b (550 mg, 3.1 mmol)and t-butyldicarbonate (1.36 g, 6.2 mmol) in 50 mL of MeOH was placed in a Parr bottle with 20% Pd(OH)2 (200 mg) and hydrogenated under 50 psi of H2 for 6 hr. The reaction mixture was filtered through Celite in a sintered glass funnel and concentrated on a rotary evaporator. The residue was purified by silica gel chromatography to give 370 mg (55% yield) of Boc-amino ketone 19c.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:15]([O:19][C:20](Cl)=[O:21])[CH:16]([CH3:18])[CH3:17]>O.O1CCOCC1>[CH2:15]([O:19][C:20]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 132 %

Procedure:
L-Valine (5.86 g, 50 mmol) was dissolved in a mixture of water (200 mL) containing sodium carbonate (10.6 g, 100 mmol). The solution was cooled to 0° C., then a solution of isobutylchloroformate (6.76 g, 49.5 mmol) in dioxane (100 mL) was added dropwise over 50 min. The ice-bath was removed and the reaction stirred overnight. Dioxane was evaporated, the aqueous phase was extracted once with diethylether and the brought to pH 2 by addition of hydrochloric acid. Extraction with DCM (3×, 150 mL each), drying of the organic phase (sodium sulfate) and evaporation gave 21 (14.2 g) as a colorless solid. 1H-NMR (DMSO-d6) δ 12.48 (bs, 1 H), 7.24 (d, J=8.2 Hz, 1 H), 3.95 (dd, J=6.2, 8.3 Hz, 1 H), 3.73 (d, J=6.7 Hz, 1 H), 2.01 (m, 1 H), 1.83 (m, 1 H), 0.87 (bs, 12 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4](=[CH2:28])[CH2:5][C@H:6]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH3:28])[CH2:5][CH:6]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)C(C)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid methyl ester (2-a, R1=Boc, R2=H, R3=CO2Me) is added to ethanol (5 ml) at ambient temperature. Triethylamine (176 μl) is then added to the mixture. 50 mg Palladium on carbon (10%, 50% water-wet, Degussa E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is then stirred overnight at ambient temperature and pressure. The mixture is then filtered and concentrated under reduced pressure to afford 2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-a, R1=Boc, R2=H, R3=CO2Me) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-b, R1=Boc, R2=H, R3=CO2Me). Spectroscopic data as in Example 60. Ratio of diastereomers 66:34 (1-a, R1=Boc, R2=H, R3=CO2Me:1-b, R1=Boc, R2=H, R3=CO2Me) by integration of signals at 1.76-1.85 (1-b, R1=Boc, R2=H, R3=CO2Me) and 1.92-1.99 (1-a, R1=Boc, R2=H, R3=CO2Me).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].Cl.[CH:7]1([NH2:11])[CH2:10][CH2:9][CH2:8]1>CC#N>[CH:7]1([NH:11][S:1]([Cl:5])(=[O:3])=[O:2])[CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCC1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: CC#N
Product: O=S(=O)(Cl)NC1CCC1
Temperature: 25 °C

Procedure:
Sulfuryl chloride (104 mmol) was dissolved in dry CH3CN (25 mL), added cyclobutylamine hydrochloride (31 mmol) and stirred at reflux for 16 h. The obtained reaction mixture was cooled to rt and concentrated in vacuo. The obtained residue was trituated with Et2O (2×25 mL). The combined Et2O-phases were concentrated in vacuo affording the title compound as oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C>C(O)(C)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:25])=[O:26])=[CH:21][CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)CBr)cc2)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)CN3CCN(c4ccncc4)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A mixture of 1-(4-pyridyl)piperazine (1.79 g), N-(4-bromoacetylphenyl)-4-methylphenylsulphonamide (3.68 g) and triethylamine (1.39 ml) in isopropanol (50 ml) was stirred for 18 hours. The precipitated solid was collected, triturated with dichloromethane, filtered and dried. This solid was further purified by flash chromatography on neutral alumina eluting successively with dichloromethane, 2.5% v/v methanol/dichloromethane then 5% v/v methanol/dichloromethane. Evaporation of the desired fractions to a small volume followed by addition of dichloromethane gave a crystalline solid. This solid was collected, washed with dichloromethane to give the title compound, 440 mg, as crystals: m.p. 168°-170° C.; NMR (d6DMSO) δ 8.14(2H,d), 7.86(2H,d), 7.71(2H,d), 7.35(2H,d), 7.18(2H,d), 6.80(2H,d), 3.79(2H,s), 3.31(4H,t), 2.59(4H,t), 2.33(3H,s); m/e 451 (M+H)+ ; calculated for C24H26N4O3S: C, 64.0; H, 5.8; N, 12.4. found C, 63.4; H, 5.7; N, 12.2%.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[CH2:23](I)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:23][CH3:24])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:21][CH:22]=1)#[N:2]
Reactant: CCI
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(4-hydroxy-phenyl)-2-methoxy-acetamide was alkylated with ethyl iodide/cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-(4-ethoxy-phenyl)-2-methoxy-acetamide as a colorless solid. MS 325.3 ([M+H]+)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[C:10]([OH:14])(=[O:13])[C:11]#[CH:12].C(N(CC)CC)C>C(OCC)C>[CH2:2]([O:3][C:4]([C:6]1[CH:12]=[C:11]([C:10]([OH:14])=[O:13])[O:8][N:7]=1)=[O:5])[CH3:1]
Reactant: C#CC(=O)O
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C(=O)O)on1
Yield: 60.4 %

Procedure:
Ethyl chlorooximidoacetate (3.30 mmol, 0.5 g) and propiolic acid (33.0 mmol, 2.311 g) were dissolved in diethyl ether (10 ml) with stirring. Triethylamine (3.30 mmol, 0.334 g) dissolved in diethyl ether (5 ml) was added dropwise to the previous mixture. The reaction mixture was stirred for three days at RT during which more triethylamine (2×0.668 g dissolved in 5 ml diethyl ether) was added dropwise. The pH of the reaction mixture was adjusted to 2. The organic phase was washed twice with water. The organic phase was dried, filtered and evaporated. The residue was dried under vacuum. 369 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.44 (t, 3H), 4.49 (q, 2H), 7.41 (s, 1H), 10.59 (bs, 1H).
Reaction SMILES: C([NH:20][C:21]1[NH:22][C:23](=O)[C:24]2[N:25]=[CH:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:28]=2[N:29]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.II.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:71]1[CH:75]=[CH:74][N:73]=[CH:72]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[C:23]([N:71]2[CH:75]=[CH:74][N:73]=[CH:72]2)[N:22]=1
Reactant: O=c1[nH]c(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Nc1nc(-n2ccnc2)c2[nH]cnc2n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A mixture of 2-N,9-bistritylguanine (1.90 g, 3 mmol), I2 (3.88 g, 15 mmol), Ph3P (3.99 g, 15 mmol) and imidazole (1.10 g, 15 mmol) was stirred in toluene (150 mL) at 95° C. for 15 min, and DIPEA (2.9 mL, 2.15 g, 16.6 mmol) was added. The mixture was stirred at 95° C. overnight. After removal of volatiles, the residue was boiled with EtOAc (3×) and filtered hot. The combined EtOAc extracts were evaporated to dryness. The residue was dissolved in TFA/H2O (9:1, 60 mL), and the solution was stirred at 0° C. for 4 h. Volatiles were evaporated in vacuo, and the residue was dissolved in 0.1 N NaOH/H2O//CH2Cl2 (100 mL/100 mL). The organic layer was extracted with 0.1 N NaOH/H2O (50 mL×2), and the aqueous phase was combined, washed [CH2Cl2 (2×50 mL)], and neutralized with CO2. Volatiles were evaporated in vacuo, and the residue was washed (H2O, CH2Cl2) to give 2-amino-6-(imidazol-1-yl)purine (0.40 g, 69%): UV (MeOH) max 222, 320 nm (∈ 29 800, 8700), min 207, 280 nm (∈ 16 100, 1500); 1H NMR (500 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.94 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.18 (s, 1H), 6.67 (s, 2H); 13C NMR (125 MHz, DMSO-d6) δ 160.7, 157.5, 145.4, 141.9, 137.2, 130.5, 117.7, 115.4; HRMS m/z 201.0753 (M+[C8H7N7]=201.0763).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]2[N:7]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:8]([CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]([CH:20]([CH3:22])[CH3:21])[C:12]3=[O:23])=[N:9][C:5]=2[CH:4]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH:20]([N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]([CH2:10][C:8]2[N:7]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:6]3[CH:29]=[CH:30][C:3]([CH2:2][O:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:4][C:5]=3[N:9]=2)[C:12]1=[O:23])([CH3:21])[CH3:22]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CO)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(COS(C)(=O)=O)ccc21
Yield: 33.7 %

Procedure:
To a solution of 1-[5-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (155 mg, 0.38 mmol) and TEA (130 mg, 1.14 mmol) in DCM (5 mL) was added methanesulfonyl chloride (87 mg, 0.76 mmol) at 0° C. The final solution was stirred at ambient temperature for 12 h then washed with sat. NaHCO3 and brine. The organic layer was dried with MgSO4 and evaporated. The residue was purified by flash chromatography (hexanes:EtOAc 2:1 to 1:1) to give 62 mg (33%) of methanesulfonic acid 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl ester as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1.[CH2:13]=[O:14]>CO.CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([CH2:9][CH2:13][OH:14])[CH:8]=1
Reactant: C=O
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Solvent: CS(C)=O
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(CCO)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.7 %

Procedure:
Triton B (2 ml, 35% in MeOH) was added at 80° C. to a mixture of 5-methoxy-2-nitrotoluene (25 g, 150 mmol) and paraformaldehyde (2.3 g, 73 mmol) in DMSO (20 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After being stirred 2.5 h at this temperature, it was cooled to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with H2O (50 ml) and extracted with EtOAc (5×100 ml). The organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a distillation in a high vacuum (p=0.1 torr), whereby a fraction containing starting material (12.1 g) was obtained at 70° C. The residual crude product was purified by column chromatography (240 g SiO2, solvent: toluene/EtOAc 8:1 1400 ml, 7:1 1600 ml, 6:1 400 ml, 5:1 400 ml, 3:1 400 ml, 2:1 600 ml and 1:1 600 ml). 2-(5-methoxy-2-nitrophenyl)ethanol (6.87 g, 48%) was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:36])[C:34]3[CH:41]=[CH:42][CH:43]=[CH:44][C:33]=3[Cl:32])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccccc1Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a magnetically stirred solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-(trifluoromethyl)-benzenesulfonamide (1.5 g, 3.03 mmol) in anhydrous THF (15 mL) was added 2 M isopropylmagnesium chloride in THF (3.3 mL, 6.6 mmol) at −20° C. The temperature was allowed to slowly rise to 10° and then 2-chloro-N-methoxy-N-methylbenzamide (1.2 g, 6.0 mmol) was added and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred for 16 h. It was then quenched with saturated aqueous NH4Cl (50 mL), and extracted with ethyl acetate (3×100 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using ethyl acetate-hexane mixtures (2:98, 5:95) to provide 4-chloro-N-[5-chloro-2-(2-chloro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide mass spectrum m/z 574.8 (M+Na); 521.0 (M−31).