Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[F:8][C:9]([F:24])([F:23])[CH:10]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12](=O)O1.BrC(=[CH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)C#N.O>C(#N)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[NH:14][C:10]([C:9]([F:24])([F:23])[F:8])=[C:29]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:12]=2[C:1]#[N:3])=[CH:16][CH:17]=1
Reactant: N#CC(Br)=Cc1ccc(Cl)cc1
Reactant: CCN(CC)CC
Reactant: O=C1OC(C(F)(F)F)N=C1c1ccc(Cl)cc1
Solvent: O
Solvent: CC#N
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (1.1 g, 0.011 mol) is added dropwise to a mixture of 2-(trifluoromethyl)-4-(4-chlorophenyl)-3-oxazolin-5-one and α-bromo-p-chlorocinnamonitrile in 25 mL of acetonitrile and the mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into 100 mL of water and extracted with two 30 mL portions of ethyl acetate. The combined extracts are washed with 30 mL of water, 30 mL of saturated brine, dried over magnesium sulfate, filtered and the solvent evaporated to leave a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.Cl[C:11]1N=C(Cl)C(F)=CN=1>>[Cl:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([F:9])=[C:6]([CH3:8])[N:7]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1nc(Cl)ncc1F
Product: Cc1nc(Cl)nc(C)c1F

Procedure:
2-Chloro-5-fluoro-4,6-dimethylpyrimidine was prepared in a manner analogous to Intermediate 65, substituting 2,4,6-trichloro-5-fluoropyrimidine for 2,4-dichloro-5-fluoropyrimidine. 1H NMR (500 MHz, CDCl3): 2.50 (d, J=2.7 Hz, 6H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:11]1[S:15][C:14]([C:16]([O-:18])=O)=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:5]([C:11]1[S:15][C:14]([C:16]([Cl:3])=[O:18])=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCc1ccc(C(=O)[O-])s1
Product: CCCCCCc1ccc(C(=O)Cl)s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
10 m of thionyl chloride was added to 1.0 g (4.72×10-3 mol) of 5-hexylthiophene-2-carboxylate and the mixture was stirred for 4 hours at 80° C., followed by removal of excess thionyl chloride, whereby 5-hexylthiophene-2-carboxylic acid chloride was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH2:9])[C:7]#[N:8].C(N(CC)CC)C.[CH2:17]([C:19]1[S:20][C:21]([C:26](Cl)=[O:27])=[C:22]([CH2:24][CH3:25])[N:23]=1)[CH3:18].Cl.C(N(CC)CC)C>C(OCC)(=O)C.O>[C:7]([CH:6]([NH:9][C:26]([C:21]1[S:20][C:19]([CH2:17][CH3:18])=[N:23][C:22]=1[CH2:24][CH3:25])=[O:27])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)#[N:8]
Reactant: N#CC(N)c1ccco1
Reactant: CCc1nc(CC)c(C(=O)Cl)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1nc(CC)c(C(=O)NC(C#N)c2ccco2)s1
Yield: 80.8 %

Procedure:
2.80 g of alpha-(2-furyl)-alpha-aminoacetonitrile and 6.0 g of triethylamine were dissolved in 50 ml of ethyl acetate, and with stirring, 2.1 g of the 2,4-diethylthiazole-5-carboxylic acid chloride was added dropwise, and the mixture was stirred at room temperature for 1 hour. Water (150 ml) was added, and the precipitated triethylamine hydrochloride was dissolved. The ethyl acetate layer was separated, washed with water and dried over sodium sulfate. The dried ethyl acetate layer was evaporated under reduced pressure to remove the solvent. The residue was recrystallized from n-hexane to give 2.41 g (yield 80.0%) of the desired N-(alpha-cyanofurfuryl)-2,4-dimethylthiazole-5-carboxylic acid amide.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[CH3:13][O:14][C:15](=[O:17])[CH3:16].[C:18]1([CH:24]=[N:25][S:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1.O>[CH3:13][O:14][C:15](=[O:17])[CH2:16][CH:24]([NH:25][S:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(C)=O
Reactant: CC(C)(C)S(=O)N=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(NS(=O)C(C)(C)C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under anhydrous conditions a solution of i-Pr2NH (2.2 eq) in 60 mL THF is cooled to 0° C. (J. Org. Chem. 2003, 68, 9948-9957). n-BuLi (2.1 eq, 1.6 M solution in hexane) is added via syringe and the solution is stirred for 30 min. The solution is then cooled to −78° C. A solution of acetic acid methyl ester (2 eq) in 1 mL of THF is added via syringe and the reaction solution is stirred for 30 min. To this solution is added ClTi(Oi-Pr)3 (4.2 eq) in 20 mL THF and the solution is stirred for 30 min. A solution of the tert.-butane-sulfinic acid 1-phenyl-methylidene amide (5.4 mmol, 1 eq) in 5 mL THF is slowly added via syringe and the solution is stirred for 3 h at −78° C. Upon reaction completion as determined by TLC, a saturated aqueous solution of NH4Cl (5 mL) is added and the suspension is warmed to room temperature. The mixture is diluted with H2O and vigorously stirred to dissolve the precipitate. The mixture is then decanted into a separatory funnel, and the remaining solid is diluted with equal parts of H2O and ethyl acetate and vigorously stirred for 15 min. The mixture is then added to the separatory funnel and the organic layer is collected. The aqueous layer is then extracted 3× with ethyl acetate. The combined organic layers are washed with brine, dried with Na2SO4, and concentrated in vacuo. 3-(2-Methyl-propane-2-sulfinylamino)-3-phenyl-propionic acid methyl ester is obtained as a clear colourless solid (102% yield); ES-MS (MH+)=284.1; 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 7.35-7.23 (m, 5H), 5.59 (d, 1H, 6.1 Hz), 4.63 (m, 1H), 3.54 (s, 3H), 3.04-2.99 (m, 1H), 2.80-2.74 (m, 1H), 1.06 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]=[N:4][C:5]1[S:6][CH:7]=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11].[Br:14]Br>C(O)(=O)C>[BrH:14].[CH3:1][N:2]([CH3:13])[CH:3]=[N:4][C:5]1[S:6][C:7]([Br:14])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11]
Reactant: CN(C)C=Nc1scc(Cl)c1C#N
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: CN(C)C=Nc1sc(Br)c(Cl)c1C#N
Temperature: 25 °C
Yield: 72 %

Procedure:
10.7 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-thien-2-yl)-formamidine are dissolved in 100 parts of glacial acetic acid, after which 8 parts of bromine are added dropwise to the solution, and the mixture is then heated at the boil for 3 hours. After the mixture has cooled to room temperature, the resulting precipitate is filtered off under suction, washed with glacial acetic acid, then with aqueous sodium bisulfite solution and then with water and is dried. 13.4 parts (72% of theory) of N,N-dimethyl-N'-(5-bromo-4-chloro-3-cyanothien-2-yl)-formamidine hydrobromide are obtained.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:12][O:11][CH:10]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: C1CCCNCC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(C)N1CCCCCC1
Yield: 72 %

Procedure:
1-Methoxyethylazepane was obtained using procedure 1a, from azepane (10.7 g, 0.107 mol) in methanol (50 cm3), 1-bromo-2-methoxyethane (15.0 g, 0.107 mol) and potassium carbonate (15.0 g). After distillation in vacuo (42-44° C., 1.0 mmHg), 1-methoxyethylazepane was obtained as a colourless liquid in ca. 72% yield. δH (500.13 MHz, CDCl3) 3.6 (6H, m), 3.38 (3H, s), 2.68 (2H, t), 1.59 (8H, br m). ESI-MS: m/z=158 [M+H]+ (100). Calcd. for C9H19NO: 158.1545; found: 158.1535.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:21]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C
Yield: 140.1 %

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 1 g and potassium carbonate 1.95 g were added to dimethylformamide 10 ml, butane 1-iodide 0.70 ml was added, and the mixture was reacted at a temperature of 100° C. for two hours. After the solution was cooled to room temperature, ethyl acetate 200 ml was added. The ethyl acetate solution was washed with water 100 ml twice and a saturated sodium chloride solution 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, and concentrated to 10 ml under reduced pressure. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.84 g.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[Br:17].C([O:22]O)(C)(C)C.O>C1COCC1>[OH:22][C:15]1[C:10]([F:9])=[C:11]([Br:17])[CH:12]=[CH:13][C:14]=1[F:16]
Reactant: CC(C)(C)OO
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Li]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Oc1c(F)ccc(Br)c1F
Temperature: -65 °C
Reaction time: 2 h

Procedure:
A quantity of 40.2 ml of 2.0 M lithium diisopropylamine (LDA) is dissolved in 80 ml of THF at −78° C. and 15.4 g of 2,4-difluorobromobenzene is added keeping the temperature below −65° C. The reaction is stirred at −65° C. for 2 hours and 6.6 ml of 6 M anhydrous t-butyl hydroperoxide is added. After warming to room temperature, 100 ml of water is added and the mixture acidified. The solvent is removed by evaporation and the aqueous layer extracted with ether. The extracts are dried and then concentrated to give the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:21]1[NH:26][C:25](=[O:27])[C:24]([CH:28]([NH:30][C:31](=O)[CH2:32][CH2:33][CH3:34])[CH3:29])=[N:23][N:22]=1)[CH3:2].O=P(Cl)(Cl)Cl>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:6][C:5]=1[C:21]1[NH:22][N:23]2[C:31]([CH2:32][CH2:33][CH3:34])=[N:30][C:28]([CH3:29])=[C:24]2[C:25](=[O:27])[N:26]=1)[CH3:2]
Reactant: CCCC(=O)NC(C)c1nnc(-c2cc(S(=O)(=O)N3CCN(CC)CC3)ccc2OCC)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc(C)c2c(=O)nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)ccc3OCC)[nH]n12
Temperature: 80 °C
Yield: 65.5 %

Procedure:
The compound of formula III (0.51 g, 1 mmol) was added with POCl3 (2 mL), and the mixture was heated for 2 hours at 80° C. The excess phosphorous oxychloride was removed by evaporation under reduced pressure, and the residue was slowly poured into chopped ice. The solution was adjusted to a pH of 8 with sodium carbonate, extracted with dichloromethane (40 mL), washed by saturated saline (15 mL), and dried over anhydrous sodium sulfate. Then, 20 mL of ethanol was added therein, and the solution was decolorized by activated carbon, filtrated, and evaporated to remove the solvent. Ethyl acetate was then added therein to perform a recrystallization, and the crystal was separated to obtain 0.32 g of product with a yield of 65%. 1H NMR (CDCl3, 300 MHz) δ: 1.01 (3H, t), 1.04 (3H, t), 1.62 (3H, t), 1.86 (2H, m), 2.42 (2H, q), 2.54 (4H, t), 2.64 (3H, s), 2.99 (2H, t), 3.07 (4H, m), 4.34 (2H, q), 7.15 (1H, d), 7.88 (1H, dd), 8.48 (1H, d), 9.52 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH2:8])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:61]([N:68]([CH2:70][C:71](O)=[O:72])C)(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:71](=[O:72])[CH2:70][NH:68][CH3:61])[CH3:2]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCNC(=O)CNC
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution of the compound of Example 48 (50 mg, 127 μmol) in THF (2 mL) and DMF (2 mL), EDC hydrochloride (27 mg, 139 μmol), HOBt (19 mg, 139 μmol), DIPEA (25 mg, 190 μmol) and BOC-sarcosine (26 mg, 139 μmol) is added. The mixture is stirred at rt for 1 h before it is concentrated. The residue is dissolved in 4 M HCl in dioxane (2 mL) and the mixture is stirred at rt for 30 min, concentrated and separated by prep. HPLC to give the title compound (23 mg) as a reddish oil; LC-MS: tR=0.89 min, [M+H]+=466.05.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.NC[C:11]1([C:17]#[N:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH2:19]([N:21](CC)CC)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([NH:21][CH2:19][CH:13]2[CH2:12][CH:11]([C:17]#[N:18])[CH2:16][CH2:15][O:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(CN)CCOCC1
Reactant: CCN(CC)CC
Reactant: Fc1cccc(Br)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CC1CCOC(CNc2cccc(Br)n2)C1
Temperature: 110 °C
Yield: 132.2 %

Procedure:
To 2-bromo-6-fluoropyridine (400 mg, 2.273 mmol) in DMSO (4 ml) at ambient temperature was sequentially added 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate R, 382 mg, 2.73 mmol) and triethylamine (0.792 ml, 5.68 mmol). The resulting light brown mixture was heated at 110° C. in a sealed glass bomb for 18 hours. The reaction mixture then was cooled to ambient temperature, reaction mixture diluted with EtOAc, washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 890 mg of a light brown liquid. The crude material was purified by silica gel chromatography using a 12 g column, eluting with 5%-20% ethyl acetate in hexane to afford 410 mg (60.9%) of the desired product “S”. LCMS (m/z): 297.9 [M+H]+; Retention time=0.823 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.67-1.96 (m, 4H), 3.59-3.78 (m, 4H), 3.98 (m, 2H), 4.82 (t, J=6.65 Hz, 1H), 6.39 (d, J=8.22, 1H), 6.72-6.84 (m, 1H), 7.16-7.33 (m, 1H).
Reaction SMILES: [CH2:1](N)[CH2:2]N>CO>[CH2:1]=[CH:2][CH:1]=[CH2:2].[CH2:1]=[CH:2][C:2]1[CH:1]=[CH:1][CH:2]=[CH:1][CH:2]=1
Reactant: NCCN
Solvent: CO
Product: C=CC=C
Product: C=Cc1ccccc1
Reaction time: 6 h

Procedure:
The inside of the system with a 2 lit. capacity autoclave of stainless steel was fully purged with nitrogen gas and 985 cc of toluene, 13 cc of tetrahydrofuran, 135 cc of styrene, 900 cc of butadiene and 10 cc of a butyl lithium solution were put in the autoclave. The mixture solution thus formed was reacted at 70° C. for 3 hr. After sampling of a part of the reaction mixture solution in an amount of 100 cc, 25 g of ethylenediamine was added to the remaining solution to perform a further isomerization reaction. The isomerization reaction was carried out for another 6 hr at the temperature. And after the completion of the reaction, 40 cc of methanol was added thereto to inactivate the catalyst, followed by washing with water. The washing was repeated until the solution was not alkaline. By distilling off the solvents, there was obtained a butadiene-styrene copolymer in a pale color.
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([N:14]2[CH2:23][CH2:22][C:17]3([CH2:21][CH:20]=[CH:19][CH2:18]3)[O:16][C:15]2=[O:24])[CH3:13])=[CH:8][CH:7]=1.C([OH:28])(C)C>O1CCCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([N:14]2[CH2:23][CH2:22][C:17]3([CH2:21][CH:20]([OH:28])[CH2:19][CH2:18]3)[O:16][C:15]2=[O:24])[CH3:13])=[CH:8][CH:7]=1
Reactant: CC(C)O
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC2(CC=CC2)OC1=O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC(O)C2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Borane dimethyl sulfide complex (2 mol/L in diethyl ether, 4.64 mL) is added dropwise to a solution of 8-[(S)-1-(4-bromo-phenyl)-ethyl]-6-oxa-8-aza-spiro[4.5]dec-2-en-7-one (2.60 g) in tetrahydrofuran (30 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature overnight. The solution is then chilled again in an ice bath and 4 M aqueous NaOH solution (2.1 mL) is added followed by the dropwise addition of hydrogen peroxide (35% in water, 6 mL). The cooling bath is removed and the mixture is warmed to 40° C. and stirred at this temperature for 1 h. The mixture is diluted with water and extracted with diethyl ether. The combined extracts are washed with water, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (methanol/ethyl acetate 0:1→4:1) to afford a mixture of the four title compounds which is submitted to SFC (Supercritical Fluid Chromatography) on chiral phase (column: phenomenex LUX 2A, 250×20 mm, 5 μM; eluent: isopropanol containing 0.2% diethylamine/sc carbon dioxide 25:75; flow: 60 mL/min) to give the four isomers in separate fractions.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:14]([NH:16][C:17]1[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3].[N:30]1([C:34]([C:36]2[CH:41]=[N:40][C:39](Cl)=[CH:38][N:37]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[N:30]1([C:34]([C:36]2[N:37]=[CH:38][C:39]([O:27][C:25]3[CH:24]=[C:13]([CH:12]=[C:11]([O:10][C@@H:8]([CH3:9])[CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:4])[CH3:1])([CH3:28])[CH3:29])[CH:26]=3)[C:14]([NH:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][N:18]=3)=[O:15])=[N:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
A mixture of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (0.12 g, 0.29 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (57 mg, 0.29 mmol) and potassium carbonate (80 mg, 0.57 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 1 hour. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give a brown oil which was chromatographed on silica, eluting with 50 to 100% ethyl acetate in isohexane, to give the desired compound as a colourless oil (90 mg). 1H NMR δ (CDCl3): −0.03 (s, 3H), 0.00 (s, 3H), 0.81 (s, 9H), 1.26 (d, 3H), 2.32 (quin, 2H), 2.49 (s, 3H), 3.61-3.76 (m, 2H), 4.20 (t, 2H), 4.46 (sextet, 1H), 4.62 (t, 2H), 6.91 (t, 1H), 7.21 (t, 1H), 7.32 (t, 1H), 8.07 (s, 1H), 8.28 (d, 1H), 8.30 (s, 1H), 8.79 (d, 1H), 9.48 (d, 1H). m/z 579 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][CH:4]=1.OO.[Br:12]Br>C(O)(=O)C>[Br:12][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH3:9]
Reactant: BrBr
Reactant: COc1cccc(C)c1
Agent: OO
Solvent: CC(=O)O
Product: COc1ccc(Br)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
36.65 g (0.3 mol) of m-cresol methyl ether and 39.8 g (0.35 mol) of 30% hydrogen peroxide in 40 ml of acetic acid (98%) are initially introduced into a flask which has a volume of 250 ml and ground-glass joints and is fitted with an internal thermometer, stirrer and dropping funnel. The mixture is stirred vigorously and cooled to 0° C. Subsequently, bromine dissolved in 40 ml of 98% acetic acid is slowly added dropwise over 3 hours. The reaction is highly exothermic. During the period of dropwise addition, the reaction temperature is held constant at about 0° to 5° C. Following the end of dropwise addition, the temperature is raised to 20° C. and stirring is continued for one hour. The stirrer is then switched off and the mixture is left to stand at 20° C. Two phases immediately form. The lower organic, halogenated phase is separated off from the upper acetic acid phase and concentrated, to give 2-bromo-5-methoxytoluene of the formula ##STR11## as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=O)[C:6](=[O:14])[NH:5]2.C(Cl)([Cl:17])=O.C1(C)C=CC=CC=1.O>CN(C)C=O>[Cl:17][C:7]1[C:6](=[O:14])[NH:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]c1=O
Reactant: O=C(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1Cl
Reaction time: 20 h

Procedure:
To a solution of 2.5 g (~10.8 mmol) 6,7-dichloro-quinoxaline-2,3(1H,4H)-dione in 100 ml of dry N,N-dimethylformamide was added at 0° C. 8.5 ml of 1.93 M phosgene in toluene (~16.3 mmol). Stirring was continued at 24° C. for 20 h. Addition of 100 ml H2O gave a precipitate (2.4 g). Purification by column chromatography (silica gel) by using ethyl acetate as eluent gave the title compound (1.5 g; 56%), m.p. >300° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[O:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[N:3]1.C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([O:34][CH3:35])[N:28]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH3:1][N:2]1[C:6](=[O:7])[O:5][C:4]([C:8]2[C:9]([S:14]([NH:17][C:25]([NH:26][C:27]3[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([O:34][CH3:35])[N:28]=3)=[O:24])(=[O:16])=[O:15])=[CH:10][CH2:11][CH2:12][CH:13]=2)=[N:3]1
Reactant: Cn1nc(-c2ccccc2S(N)(=O)=O)oc1=O
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)C2=CCCC=C2c2nn(C)c(=O)o2)n1
Yield: 45.2 %

Procedure:
By the procedure of Example 5, 0.4 g of the product of Example 4 was reacted with 0.41 g of phenyl(4-methyl-6-methoxy-1,3,5-triazin-2-yl)carbamate and 0.24 g of "DBU" in 10 ml of p-dioxane. The isolated crude solid was purified by slurry-washing with 10 ml of warm acetonitrile to yield 0.3 g of the subject compound; m.p. 198°-200° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH-:12].[Na+].[C:14]([CH:17]([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:18][CH2:19][CH2:20][NH2:21])([OH:16])=[O:15]>O>[CH2:5]([O:4][C:2]([NH:25][CH2:24][CH2:23][CH2:22][CH:17]([CH2:18][CH2:19][CH2:20][NH:21][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:12])[C:14]([OH:16])=[O:15])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [OH-]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCC(CCCN)C(=O)O
Agent: [Na+]
Solvent: O
Product: O=C(NCCCC(CCCNC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24.48 g (143.5 mmol) of benzyl chloroformate and 5N aqueous sodium hydroxide solution are simultaneously added in drops at 0° C. to 10 g (57.39 mmol) of 4-carboxy-1,7-diaminoheptane (produced according to: A. Reissert, Chem. Ber. 26, 2137 (1893); 27, 979 (1894)) in 150 ml of water, and the pH is kept at 10. It is stirred overnight at room temperature. It is extracted twice with 150 ml of ethyl acetate each. The aqueous phase is carefully acidified with 4N aqueous hydrochloric acid (pH 2) and extracted three times with 200 ml of ethyl acetate each. The organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum.