Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)=[CH:9][CH:8]=1.[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.Cl>O1CCCC1>[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=C(c1ccc(Br)cc1)c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reaction time: 4 h
Yield: 36.8 %

Procedure:
In a 300 mL three-neck flask, 410 mg (17 mmol) of active magnesium was stirred in 5 mL of dehydrated tetrahydrofuran (THF), and about 0.2 mL of 1,2-dibromoethane was added thereto, so that bubble release and heat generation were confirmed. A solution in which 5.2 g (15 mmol) of 4-bromophenyl-1-phenyl-1H-benzimidazole has been dissolved in 50 mL of dehydrated THF was added thereto. The mixture was heated and stirred for 4 hours, and then cooled to room temperature, so that a Grignard reagent was prepared. Then, in a 500 mL three-neck flask were put 3.7 g (17 mmol) of 4-bromobenzoyl chloride and 150 mL of dehydrated THF, and the mixture was stirred at −40° C. The above Grignard reagent was dropped into the mixture, the mixture was stirred for 1 hour, and then stirred at room temperature for about 15 hours. After reaction, 1N-hydrochloric acid was added to the mixture until the mixed solution became acid. An organic phase of the obtained mixed solution was washed with water, and then magnesium sulfate was added thereto so that moisture was adsorbed. This suspension was filtered, the resulting filtrate was concentrated, and ethyl acetate and toluene were added to perform recrystallization. As a result, 2.5 g of powder was obtained. The reaction scheme is shown in (A-1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 101.9 %

Procedure:
To a solution of tert-butyl-1-piperazinecarboxylate (5.0 g, 26.8 mmol) in DCM (100 mL) triethylamine (5.6 mL, 40.3 mmol) was added, the mixture was cooled down to 0° C. and isobutyryl chloride (4.2 mL, 40.3 mmol) was added. The reaction was allowed to warm up to room temperature and after 3 hours the reaction was complete. The mixture was washed with 50 mL of 0.4M Na2CO3 solution and then with 50 mL of saturated NH4Cl solution. The organic phase was dried over Na2SO4, filtered and the solvent removed under reduced pressure, affording 7.0 g of 4-isobutyryl-piperazine-1-carboxylic acid tert-butyl ester. The product was dissolved in 100 mL of DCM. H2SO4 (2.91 mL, 54.7 mmol) was added and the reaction left stirring for 16 hours. The precipitate formed was filtered affording 6.7 g of the titled compound (96%, yield)
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)=O)(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([NH:30][C:31](OC2C=CC=CC=2)=[O:32])[C:23](=[CH:28][CH:29]=1)[C:24](OC)=[O:25]>>[NH2:8][C:9]1[CH:10]=[C:11]([S:15]([N:18]2[C:24](=[O:25])[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:29][CH:28]=3)[NH:30][C:31]2=[O:32])(=[O:16])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(S(N)(=O)=O)c1
Product: Nc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Yield: 49 %

Procedure:
3.5 g (12.9 mmol) of 3-t-butoxycarbonylamino-benzenesulfonamide and 3.9 g (12.8 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 7 to obtain 2.2 g (yield 49%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 5.72 (2H, s), 6.87 (1H, d), 7.12 (1H, s), 7.23-7.27 (2H, m), 7.33 (1H, S), 7.86 (1H, d), 11.61 (1H, s).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[NH:9])O)=[CH:5][CH:4]=1.[NH3:12]>C(O)C>[ClH:1].[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:12])=[NH:9])=[CH:5][CH:4]=1
Reactant: N
Reactant: N=C(O)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: N=C(N)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
86 g (0.32) of 4-bromobenzimidate hydrogen chloride was added to 240 cm3 of ethanol saturated with gaseous ammonia and stirred at room temperature overnight. Approximately one-half of the volume of the ethanol was distilled off and the residual solution was recrystallized to yield 57 g (0.24 mol) of 4-bromobenzamidine hydrogen chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[C:10]([O:14][C:15]([N:17]1[C@@H:21]([C@H:22]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:19][C@H:18]1[CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Si:30]([O:29][C@H:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:21]1[CH2:20][CH2:19][C@@H:18]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:42](=[O:43])[NH:1][CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:45][CH:46]=2)[N:17]1[C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: NCCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)NCCc3ccccn3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-Aminoethyl)pyridine (0.034 mL, 0.29 mmol) was added to a stirred, room temperature mixture of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (100 mg, 0.190 mmol), HATU (87 mg, 0.228 mmol), and DIPEA (0.166 mL, 0.951 mmol) in DMF (1.9 ml). The resulting mixture was stirred at room temperature overnight. Upon completion, as determined by LC-MS, water was added, and the mixture was partitioned with EtOAc. The aqueous layer was extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give the product that was used directly in the next step. LC-MS=630.3 (M+1)+.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C(=O)(O)[O-].[K+].O>CN(C=O)C>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([NH:11][CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[N:14][CH:15]=1)#[N:18]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNc1ccc(C#N)cn1
Temperature: 90 °C

Procedure:
3.0 g (18.73 mmol) of N-Boc-ethylenediamine, 5.19 g (37.45 mmol) of 6-chloronicotinonitrile and 3.75 g (37.45 mmol) of potassium bicarbonate are suspended in 360 ml of DMF and heated at 90° C. for 16 h. Water is added to the mixture, which is then extracted three times with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution. After drying over magnesium sulphate, the solvent is removed. Drying under high vacuum results in 3.58 g (68% of theory) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1cccs1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1cccs1
Yield: 82.6 %

Procedure:
2.8 g of ethyl 3-(4-chlorobenzoylamino)-3-(2-thienylcarbonyl)propionate, 10 ml of dimethylformamide and 1.4 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 2.2 g of ethyl 2-[2-(4-chlorophenyl)-5-(2-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:28][CH3:29])=O)C1C=CC=CC=1>[Pd].C(O)C>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:28][CH3:29]
Reactant: CCOC(=O)c1coc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)n1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1coc(N2CC[C@H](N)[C@H](OC)C2)n1
Yield: 102.4 %

Procedure:
The same operation as in Example (95b) was performed using ethyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-oxazole-4-carboxylate obtained in Example (103c) (0.7 g, 1.74 mmol), 10% Pd/C (0.25 g) and ethanol (10 mL), to obtain 0.48 g of the title compound as a yellow amorphous solid (100%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:4](Cl)=[O:5])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:20]([OH:22])=[O:21]>>[CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:4]([NH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:20]([OH:22])=[O:21])=[O:5])[CH3:2]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: CCCCCCCCCC(CC)C(=O)Cl
Product: CCCCCCCCCC(CC)C(=O)Nc1cc(C(=O)O)ccc1C
Temperature: 140 °C
Yield: 95.7 %

Procedure:
A mixture of (RS)-2-ethylundecanoyl chloride (1.16 g) and 3-amino-4-methylbenzoic acid (0.75 g) was placed in an oil bath at 90° C. and the temperature was gradually raised to 140° C. for 2 hours. After cooling, the solid was recrystallised from a mixture of ethanol (25 ml) and water (1 ml) to yield (RS)-3-(2-ethylundecanamido)-4-methylbenzoic acid (1.65 g) in the form of a white solid, m.p. 217°-220° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([F:12])[CH:5]=1)([O-:3])=[O:2].C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:14][C:15]([OH:17])=[O:16])=[C:6]([F:12])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1F
Reactant: O=C(O)CC(=O)O
Solvent: CCO
Product: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A suspension of 4-nitro-2-fluorobenzaldehyde (3.16 g, 18.7 mmol), malonic acid (2.14 g, 21 mmol) pyridine (catalytic) and ethanol (10 mL) was heated to reflux for 6 hours. The suspension became a clear solution upon heating. Upon cooling to room temperature solids formed and were isolated by filtration. The solids were washed with cool (15° C.) ethanol and then with 1N HCl and dried, giving 3.32 g 4-nitro-2-fluorocinnamic acid (90% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9]COC)=[CH:4][C:3]=1[N+:13]([O-])=O.[CH3:16][OH:17]>[Fe].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][O:17][CH3:16])=[CH:4][C:3]=1[NH2:13]
Reactant: COCCSc1ccc(N)c([N+](=O)[O-])c1
Reactant: CO
Agent: [Fe]
Solvent: O
Product: COCSc1ccc(N)c(N)c1

Procedure:
1.3 G. of 1-amino-2-nitro-4-methoxyethylthiobenzene is treated in 80 ml. methanol and 20 ml. water at reflux under nitrogen, with 0.7 g. ferrous sulfate and 2.8 g. iron (added in two portions) for 4 hours. The mixture is filtered, stripped under vacuum, and the residue recrystallized from cyclohexane. 1,2-Diamino-4-methoxymethylthiobenzene is thus obtained.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[C:35]([F:43])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:43][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][C:36]=1[C:39]([F:42])([F:41])[F:40]
Reactant: CN(C[C@@H](N)c1ccc(C(F)(F)F)c(F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(C(F)(F)F)c(F)c1

Procedure:
Compound 26 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [409 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.20 (s, 1H), 9.01 (dd, J=4.7, 1.7 Hz, 1H), 8.54 (d, J=1.7 Hz, 1H), 8.45-8.34 (m, 1H), 8.25-8.10 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.61 (d, J=12.1 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 5.53 (t, J=6.5 Hz, 1H), 3.21-3.08 (m, 1H), 3.05-2.88 (m, 1H), 2.30 (s, 3H), 2.01 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=12.[Cu][C:12]#[N:13].O>CN1CCCC1=O>[C:12]([C:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=12)#[N:13]
Reactant: Brc1ccn2ccncc12
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccn2ccncc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
2 g of 8-bromopyrrolo[1,2-a]pyrazine prepared in Preparation Example 7 was added to a mixture of 2 g of copper(I) cyanide dissolved in 20 ml of N-methylpyrrolidone at 160° C. The reaction mixture was stirred for 10 minutes and cooled to room temperature. The reaction mixture was poured into 100 ml of distilled water, extracted with ethyl acetate (50ml×3), and then concentrated to dryness to obtain 1.2 g of yellowish brown title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cccc(CCl)c1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: COc1cccc(COc2ccc(Cl)c([N+](=O)[O-])c2)c1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Chloromethyl-3-methoxy-benzene using the conditions described in Example 10C to provide 1-Chloro-4-(3-methoxy-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1>[Pd].C(O)C>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc2cc(N)ccc21
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A mixture of the nitroindole (D1) (5 g; 28.4 mmol) and 5% palladium on charcoal in ethanol (300 ml) was hydrogenated at 60 p.s.i. (4.14×105Pa) at room temperature for 3 h. Removal of the catalyst by filtration followed by evaporation of the solvent gave the title compound (3.39 g, 95%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22]OS(C)(=O)=O)[O:19][C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O.O>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][N:30]=[N+:31]=[N-:32])[O:19][C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Reaction time: 4 h
Yield: 91.9 %

Procedure:
(5R)-3-(4-(1,4-Dioxa-8-azaspiro[4,5]dec-8-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyl-oxazolidin-2-one (3.03 g, 7.04 mM) was dissolved in N,N-dimethylformamide (50 ml), treated with sodium azide (732 mg, 11.3 mM), and heated with stirring at 50° for 4 hours. After cooling the mixture was diluted with water (250 ml), and extracted into ethyl acetate (3×100 ml). The combined organics were dried (magnesium sulfate), and evaporated to give product (2.44 g), of sufficient quality for use without purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[S:32][C:31]([CH3:36])=[N:30][C:29]=3[C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:20][C:19]=1[CH3:41]>ClCCl>[CH3:41][C:19]1[CH:20]=[C:21]([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[S:32][C:31]([CH3:36])=[N:30][C:29]=3[C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:13]([CH:10]1[CH2:12][CH2:11]1)=[O:14]
Reactant: Cc1nc2c(s1)CCN(C(=O)c1ccc(CN)c(C)c1)c1ccccc1-2
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2c(s1)CCN(C(=O)c1ccc(CNC(=O)C3CC3)c(C)c1)c1ccccc1-2
Temperature: 25 °C
Reaction time: 20 h
Yield: 46 %

Procedure:
DIEA (0.02 ml, 0.115 mmol) and cyclopropanecarbonyl chloride (0.008 ml, 0.088 mmol) were added to a solution of (4-aminomethyl-3-methyl-phenyl)-(2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulen-6-yl)-methanone from E124.2 (20 mg, 0.055 mmol) in dichloromethane (5 ml) at 0° C. The mixture was stirred for 20 h at room temperature then concentrated in vacuo and purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% di-chloromethane) to give a white powder identified as the title compound (11 mg, 46%).
Reaction SMILES: C([O:8][CH:9]([CH2:30][O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35][Br:36])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C1C=CC=CC=1>[Pd].C(O)(=O)C>[Br:36][CH2:35][CH2:34][NH:33][C:32]([O:31][CH2:30][CH:9]([OH:8])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:37]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COC(=O)NCCBr)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOCC(O)COC(=O)NCCBr
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A 40 ml portion of 90% aqueous acetic acid solution was added to 949 mg (1.623 mmole) of 2-benzyl-3-O-(2'-bromoethyl)carbamoyl-1-octadecylglycerol (as synthesized in Example 7) and 250 mg of 10% Pd/C, and hydrogenolysis was carried out at room temperature for 2 hours. After the catalyst was filtered out, the filtrate was concentrated under reduced pressure, and a mixture of n-hexane-ethyl acetate (2:1) was added to the residue. The precipitate was collected by filtration to give 785 mg (97.8 g.) of the alcohol derivative (colorless powder).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:26]=[CH:25][C:11]([CH:12]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:29]=1[NH:36][C:37](=[O:40])[CH2:38]Cl.C(OCC)(=O)C>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]([N:19]2[CH2:20][CH2:21][N:22]([CH2:38][C:37](=[O:40])[NH:36][C:29]3[C:28]([CH3:27])=[CH:33][C:32]([CH3:34])=[CH:31][C:30]=3[CH3:35])[CH2:23][CH2:24]2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:25][CH:26]=1
Reactant: Cc1cc(C)c(NC(=O)CCl)c(C)c1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(NC(=O)CN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)c(C)c1
Temperature: 80 °C
Reaction time: 7.5 h

Procedure:
2 g of anhydrous potassium carbonate were added to a mixture of 192.6 mg of 1-(4-chlorobenzhydryl)piperazine and 142.7 mg of N-(2,4,6-trimethylphenyl)chloroacetamide dissolved in 20 ml of N,N-dimethylformamide, and the reaction mixture was stirred at 80° C. for 7.5 hours. At the end of this time, ethyl acetate was added to the mixture, and the organic layer was separated. The organic layer was washed three times with water, and then the solvent was evaporated off under reduced pressure. The residue was subjected to silica gel thin layer chromatography using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to afford a purified 1-(4-chlorobenzhydryl)-4-(2,4,6-trimethylphenylcarbamoylmethyl)piperazine.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH3:22])=[C:16]([CH3:23])[C:15]=1[CH3:24]>C(Cl)Cl>[CH3:12][O:13][C:14]1[C:15]([CH3:24])=[C:16]([CH3:23])[C:17]([O:21][CH3:22])=[C:18]([CH3:20])[C:19]=1[OH:9]
Reactant: COc1cc(C)c(OC)c(C)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(O)c1C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A solution of 9.4 g of m-chloroperbenzoic acid (70% purity) in 100 ml of methylene chloride was added dropwise, whilst ice-cooling, to a solution of 4.6 g of 1,4-dimethoxy-2,3,5-trimethylbenzene in 20 ml of methylene chloride, and the resulting mixture was stirred at the same temperature for 30 minutes and then at room temperature for 5 hours. At the end of this time, the reaction mixture was washed with a 5% w/v aqueous solution of sodium hydrogensulfite, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with water, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed from the reaction mixture by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using benzene and a 50:1 by volume mixture of benzene and ethyl acetate as the eluents, to give 1.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:43]2[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=2)[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40].O>ClCCl>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:43]2[CH:51]=[CH:50][C:46]([C:47]([N:23]3[CH2:24][CH2:25][N:20]([CH2:19][C:17]4[CH:16]=[CH:15][N:14]=[C:13]([C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH:18]=4)[CH2:21][CH2:22]3)=[O:48])=[CH:45][CH:44]=2)[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40]
Reactant: COc1cc(-c2ccc(C(=O)Cl)cc2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(-c2ccc(C(=O)N3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)cc2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) was dissolved in dichloromethane (0.9 mL), and a saturated aqueous solution (0.9 mL) of sodium hydrogencarbonate was added to the solution. 4-(3,4,5-Trimethoxyphenyl)benzoyl chloride (55 mg) was then added dropwise to the mixture under ice cooling, and the resultant mixture was stirred for 1 hour. After water was added to the reaction mixture to conduct extraction with chloroform, the resultant organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain the title compound as a free base.