Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:18])[NH:5][NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:2].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([NH:3][C:4]1[O:18][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[N:6][N:5]=1)[CH3:2]
Reactant: CCNC(=O)NNC(=O)c1ccccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNc1nnc(-c2ccccc2[N+](=O)[O-])o1
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A mixture of 4-ethyl-1-(2-nitrobenzoyl)semicarbazide (4 g) in DCM (30 mL) was treated with triethyl amine (12 mL), PTS-Cl (4.8 g) and DMAP (100 mg). The reaction mixture was stirred for 4 hours, concentrated, and purified by silica gel chromatography to afford 2.3 g of ethyl-(5-(2-nitro-phenyl)-(1,3,4)oxadiazol-2-yl)-amine: 1H NMR (300 MHz, CDCl3) δ 8.1 (dd, 1H), 8.0 (d, 1H), 7.8 (m, 2H), 4.9 (bs, 1H), 3.6 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=[C:14]1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:18]([C:17]3[S:13][C:14]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][CH:16]=3)=[O:19])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(-c2cccs2)s1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(-c2cccs2)s1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2,2′-bithiophene-5-carboxylic acid (Acros) according to methods A and C; yield 142 mg, 0.37 mmol (93%): 1H NMR (300 MHz, methanol-d4) δ 2.06-2.27 (m, 5H), 2.46 (s, 2H), 3.49 (d, J=13 Hz, 2H), 3.55 (s, 2H), 3.82 (d, J=13 Hz, 2H), 4.24 (s, 1H), 7.08 (dd, J=5, 4 Hz, 1H), 7.24 (d, J=4 Hz, 1H), 7.35 (dd, J=4, 1 Hz, 1H), 7.43 (dd, J=5, 1 Hz, 1H), 7.79 (d, J=4 Hz, 1H); MS (DCI/NH3) m/z 345 (M+H)+; Anal. C18H20N2OS2.HCl: C, H, N.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:10]([CH3:25])([CH3:24])[CH2:9]1)=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:25])[CH3:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 23.0 g (66.1 mmol) 2,2-dimethyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester in 200 mL DCM was treated with 34.5 mL (448 mmol) TFA. The reaction mixture was stirred at RT over night and concentrated in vacuo. The residue was triturated with diethyl ether. The solid was filtered, washed with diethyl ether and dried.
Reaction SMILES: CCO.[O:4]=[C:5]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=2)[NH:9][C@@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)[O:6]1>C1COCC1.Cl[Pd]Cl>[C:19]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[OH:18])[CH2:11][C@@H:10]([C:5]([OH:6])=[O:4])[NH2:9])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cc(C[C@@H]2N[C@@H](c3ccccc3)[C@@H](c3ccccc3)OC2=O)ccc1O
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(C[C@H](N)C(=O)O)ccc1O
Reaction time: 18 h
Yield: 105.9 %

Procedure:
To a 300 mL Parr bottle were added 0.73 g of PdCl2 and 20 mL of 1:1 THF:EtOH. To this was added a solution of 2.43 g of (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-tert-butyl-4-hydroxybenzyl)morpholine in 80 mL of 1:1 THF:EtOH. The mixture was deoxygenated by bubbling nitrogen through for 10 min and was hydrogenated at 45 psi for 18 h. The vessel was purged with nitrogen, catalyst removed by filtration, and the filtrate concentrated in vacuo. The residue was partitioned between water and hexane. The aqueous solution was washed with four additional 50 mL portions of hexane, subjected to brief rotary evaporation to remove residual hexane, frozen and lyophilized to afford 1.47 g (92%) of 3-tert-butyl-L-tyrosine.HCl as a tan hygroscopic solid.
Reaction SMILES: [Na].[CH3:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:15][CH:16]=[C:17]([Cl:19])[CH3:18]>C(O)C>[CH2:12]([O:11][C:9](=[O:10])[C:3]([CH2:15]/[CH:16]=[C:17](\[Cl:19])/[CH3:18])([CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:13]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CC(Cl)=CCCl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C/C=C(/C)Cl)C(=O)OCC
Temperature: 75 °C

Procedure:
11.5 g of sodium cut into small pieces was introduced into a three-necked flask equipped with agitator, reflux condenser, and dropping funnel. To this charge was added dropwise 250 ml of absolute ethanol so quickly that the solution was boiling vigorously. Then 87 g of distilled diethyl methylmalonate was added dropwise to the hot alcoholate solution. After allowing the mixture to cool to about 75° C., the reaction solution was combined with 66 g of 1,3-dichloro-2-butene dropwise; the solution turned yellow during this step. After 2 hours of agitation under heating, the suspension, at this point having pH 5-6 and being almost completely decolorized, was freed of precipitated sodium chloride by filtration. The filtrate was concentrated and combined with the methylene chloride obtained by washing the precipitate. The organic solution was thereafter shaken with saturated sodium chloride solution, dried over magnesium sulfate, concentrated on a forced circulation evaporator, and fractionated under vacuum. Yield: 105 g of the desired diester, bp2.5 110° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].[H-].[Na+].[O:17]=[C:18]1[C:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:22]([CH2:39][CH2:40][CH3:41])[N:21]2[N:42]=[CH:43][N:44]=[C:20]2[N:19]1[CH:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:14])[CH:5]=[C:48]1[CH2:47][CH2:46][CH:45]([N:19]2[C:18](=[O:17])[C:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]#[N:38])=[CH:27][CH:26]=3)=[C:22]([CH2:39][CH2:40][CH3:41])[N:21]3[N:42]=[CH:43][N:44]=[C:20]23)[CH2:50][CH2:49]1)[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=CC(=O)OCC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution (10 mL) of ethyl(diethoxyphosphoryl)acetate (1.2 g) in tetrahydrofuran was added sodium hydride (0.21 g), and the mixture was stirred at room temperature for 1 hr. A solution (10 mL) of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2 g) in tetrahydrofuran was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with 1 N hydrochloric acid and ethyl acetate, and the obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.9 g, 86%). 1H NMR (300 MHz, CHLOROFORM-d) δ1.06 (t, J=7.4 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H), 1.66-1.80 (m, 2H), 1.87-1.98 (m, 2H), 1.99-2.12 (m, 2H), 2.33-2.51 (m, 2H), 2.65-2.89 (m, 2H), 2.98-3.08 (m, 2H), 4.02 (s, 2H), 4.07-4.19 (m, 2H), 5.23-5.38 (m, 1H), 5.71 (s, 1H), 7.35-7.52 (m, 6H), 7.58-7.67 (m, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.90 (s, 1H)
Reaction SMILES: [S:1]=[C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[NH:3]1.[H-].[Na+].[CH3:27]I>O1CCCC1>[CH3:27][S:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1
Reactant: CI
Reactant: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 100 mg of 4,5-dihydro-5-thioxo-8-(3-(trifluoromethyl)phenyl)-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (Example 24) in 10 ml of dry tetrahydrofuran, cooled at 0° C., is added 13 mg of sodium hydride (60 percent dispersion in mineral oil). The reaction mixture is stirred at 0° C. for 15 minutes, then an excess of methyl iodide is added and the mixture is allowed to warm to room temperature and then is stirred for 3 hours. The mixture is quenched with water and extracted with chloroform and evaporation of the extract in vacuo gives 47 mg of the desired product mp 234-237° C. (with decomposition).
Reaction SMILES: [Na+].[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]([O-:13])=O)[N:10]=1)[C:3]([NH2:5])=[NH:4].Cl.[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:16]1>>[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:16]2)=[O:13])[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CCOC(=O)CCNC(=O)C1CCCNC1
Reactant: N=C(N)Nc1nc(C(=O)[O-])cs1
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)CCNC(=O)C1CCCN(C(=O)c2csc(NC(=N)N)n2)C1

Procedure:
In analogy to Example 4, by coupling 2-guanidino-thiazole-4-carboxylic acid sodium salt with ethyl (RS)-3-[(piperidine-3-carbonyl)-amino]-propionate hydrochloride there is obtained ethyl (RS)-3-[[1-(2-guanidino-thiazole-4-carbonyl)-piperidine-3-carbonyl]-amino]-propionate as a white foam. MS: 397 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([NH2:26])[NH:8][C:7]=1[NH2:27])=[O:5])[CH3:2].[CH3:28]C[O-].[Na+].CI>C(O)C>[CH2:24]([O:23][C:21]([C:10]1([CH3:28])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([NH2:27])[N:8]=[C:9]1[NH2:26])=[O:22])[CH3:25]
Reactant: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CCOC(=O)C1=C(N)N=C(N)C(C)(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 37.5 g of 2,6-diamino-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol was treated with 15 g of methyl iodide at the boil. After a further 60 minutes under reflux, the mixture was concentrated by distillation. The residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water, and the organic phase is concentrated. Recrystallization of the residue from ethanol gave 2,6-diamino-3-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 142°C (18 g, 41.5% of theory).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:16]=[N:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:22]3)=[CH:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)NC1CCCCC1

Procedure:
Following the procedure of Example 5, making variations only as required to use cyclohexylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as white powder (34% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.05, 7.82, 7.74, 7.65, 7.55, 7.52, 7.35, 3.69-3.79, 3.44-3.58, 3.35-3.42, 3.20-3.26, 3.11-3.18, 1.75-1.84, 1.58-1.67, 1.47-1.55, 1.10-1.35.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][CH:7]=1.[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[I:1][C:2]1[C:3]2([CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][CH:7]=1)[O:13][CH2:12][CH2:11][O:10]2
Reactant: OCCO
Reactant: CC1(C)CC=C(I)C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CC=C(I)C2(C1)OCCO2
Yield: 46.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 67a by using 2-iodo-5,5-dimethylcyclohex-2-en-1-one (J. Org. Chem., 1994, 59, 5393-5396; 6.10 g, 24.4 mmol), ethylene glycol (3.00 g, 48.3 mmol), p-toluenesulfonic acid hydrate (230 mg, 1.22 mmol) and benzene (70 mL), to yield the title compound (3.33 g, 46%) as a brown oil.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>CS(C)=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][O:3][CH:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]([OH:11])=[O:10])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=C(O)C(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)c1ccccc1
Reaction time: 4 h
Yield: 48.9 %

Procedure:
(+)-Mandelic acid (3.04 g.) was added to a stirred suspension of sodium hydride (1.92 g., 50% w/w dispersion in mineral oil) in dimethyl sulphoxide (50 ml.) at 15°-20° C., and the mixture was then stirred at the same temperature for 4 hours. 4-(4-Chlorophenyl)benzyl chloride (4.74 g.) was then added to the mixture and stirring was continued at room temperature for 1 hour. The resultant mixture was adjusted to pH 1-3 by careful addition of N-hydrochloric acid, and then extracted thoroughly with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated. The solid residue obtained was recrystallised from a mixture of ethyl acetate and hexane to give (+)-2-[4-(4-chlorophenyl)benzyloxy]-2-phenylacetic acid (3.45 g.), m.p. 119°-121° C., [α]D25 +104° (C=1,CHCl3).
Reaction SMILES: [C:1]([N:5]([CH2:9]Cl)[C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[S:14]>C1(C)C=CC=CC=1>[CH3:11][N:12]=[C:13]1[N:15]([CH3:16])[C:6](=[O:7])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][S:14]1
Reactant: CC(C)(C)N(CCl)C(=O)Cl
Reactant: CNC(=S)NC
Solvent: Cc1ccccc1
Product: CN=C1SCN(C(C)(C)C)C(=O)N1C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
In 50 ml of toluene, were dissolved 3.7 g (0.02 mole) of N-t-butyl-N-chloromethylcarbamoyl chloride and 2.0 g (0.02 mole) of 1,3-dimethylthiourea. The solution was heated under reflux with stirring for one hour. After cooling, the precipitated crystals (m.p. >220° C. decomp.) were collected by filtration, washed with a small quantity of acetone, dissolved again in 100 ml of water, admixed with 10 ml of a 20% sodium hydroxide solution, and extracted with 50 ml of benzene. The benzene layer was dried and concentrated under reduced pressure to obtain 3.5 g (83% yield) of crystals melting at 51°-52° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH2:19]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)(=[O:28])=[O:29])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Reactant: O=S(=O)(NCc1ccccc1)c1ccc(B(O)O)cc1
Product: CN(C(=O)Oc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 4-benzylsulfamoylbenzeneboronic acid. The crude product was purified by preparative HPLC (Gilson) (35%, pink crystals).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C[O-].[K+].[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=[O:30])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](=[O:30])[CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Cc1ccccc1C(F)(F)F)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
After dissolving 2.57 g of 2-(trifluoromethyl)benzaldehyde in 15 ml of methanol, 2.75 g of p-toluenesulfonyl hydrazide was added, the mixture was stirred at room temperature for 2 hours, and then 1.09 g of potassium methoxide and a methanol solution (4 ml) of 1.50 g of 1-benzylpiperidine-4-carboxaldehyde was added, and the mixture saws shielded from light and stirred overnight at 55° C. The reaction solution was concentrated under reduced pressure, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue fleas purified by silica gel column chromatography (solvent: toluene/ethyl acetate) to obtain the title compound (1.30 g, 49% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[N:12][N:13](C)[N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1nnc(-c2cccc([N+](=O)[O-])c2)n1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2nnn[nH]2)c1
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
3-Nitro-(2-methyltetrazol-5-yl)benzene (648 mg) was dissolved in 100 ml of ethanol, treated with 0.283 g of 10% palladium/carbon catalyst, and hydrogenated on a Parr apparatus at 30 psi for 15 minutes. The reaction mixture was filtered through Celite and concentrated to give 0.469 g of the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[CH3:21][S:22]([O:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(C#N)=NO)cc1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(C#N)=NOS(C)(=O)=O)cc1C
Yield: 93 %

Procedure:
23.2 g (0.13 mol) of α-hydroxyimino-3,4-dimethylbenzylcyanide are reacted with 27.2 ml (0.20 mol) of triethylamine and 11.1 ml (0.14 mol) of methansulfonyl chloride in tetrahydrofuran, as described under 3.2. After the usual processing, 32.6 g of a crude product are obtained, which is then recrystallised from isopropanol, giving 30.5 g (93%) of α-(methyl-sulfonyloxyimino)-3,4-dimethylbenzylcyanide in the form of a brownish powder having an m.p. of 91-95° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(P(CCCC)(CCCC)=CC#N)CCC.[CH2:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH2:29]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([C:11]#[N:12])=[CH:7]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#Cc1c[nH]c2cc(Br)ccc12
Reactant: OCc1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: N#Cc1cn(Cc2ccccc2)c2cc(Br)ccc12

Procedure:
A solution of 6-bromo-1H-indole-3-carbonitrile (400 mg, 1.81 mmol), 2-(tributylphosphoranylidene)acetonitrile (655 mg, 2.71 mmol) and benzyl alcohol (282 μL, 2.71 mmol) in toluene (5 mL) was heated at 75° C. overnight and concentrated. The residue was purified by flash chromatography on silica (IntelliFlash Varian 971-FP), eluting with 30% heptanes in ethyl acetate to provide the title compound. LCMS: 312.4 (M+H)+.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][C:5]1=O)(=O)[CH3:2].[CH3:12][CH:13]([C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[C:24]([CH:26]=1)[OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[OH:27][C:22]1[C:23]2[CH:1]([CH3:2])[C:4]3[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][C:5]=3[O:25][C:24]=2[CH:26]=[C:20]([CH:13]([CH3:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:21]=1
Reactant: CCCCCCC(C)c1cc(O)cc(O)c1
Reactant: CC(=O)C1CCC(C)CC1=O
Product: CCCCCCC(C)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C

Procedure:
Reaction of 2-acetyl-5-methylcyclohexanone with 5-(1 -methylheptyl)resorcinol according to the procedure of Example 1 gives 5,6,7,8-tetrahydro-1 -hydroxy-6,9-dimethyl-3-(1-methylheptyl)xanthene.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:29])[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][CH3:28].[OH-].[Na+].Cl>O.C(O)(C)C>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:29])[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][CH3:28]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
As in Synthetic Example 1, to 84.7 g of L-arginine were added 706 g of isopropyl alcohol and 302 g of water. Thereto were concurrently added dropwise 147 g of palmitoyl chloride (manufactured by Aldrich) and 27 wt % NaOH aqueous solution over a period of 2 hours with the pH being at 10.5 to 11.5 and the reaction temperature, at 27 to 30° C. After 1 hour of aging, the reaction mixture was warmed to 50° C. and adjusted to below pH 1.8 by adding concentrated hydrochloric acid to dissolve the reaction product completely. Thereafter, the pH was adjusted to 6.0 by adding 27 wt % NaOH aqueous solution to precipitate crystals and the resulting slurry was gradually cooled to 10° C. with stirring. When the slurry was cooled to 10° C., the crystals were collected by filtration and washed with 1,200 g of water and 320 g of isopropyl alcohol, successively. The resulting washed crystals were dried under reduced pressure to obtain 190 g of mono-Nα-palmitoyl-L-arginine as flake-shaped crystals (yield 94.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:16][CH:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:27][C:26]1[CH:28]=[CH:29][C:23]([S:20]([O:19][CH2:18][CH2:17][C@H:15]2[CH2:16][C@@H:14]2[CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=3)[CH2:9][CH2:10]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: OCCC1CC1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was synthesized using 2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol from Example 2b-S (slow) (41.2 mg, 0.146 mmol) was in 1.46 mL dichloromethane. TEA (0.0408 mL, 0.296 mol), DMAP (1.786 mg, 0.015 mmol) and TsCl (33.5 mg, 0.175 mmol) were sequentially added. The mixture was stirred at room temperature for 3 hour. Another 0.02 mL of TEA, 1 mg of DMAP and 14 mg of TsCl were added. Reaction mixture was stirred at room temperature for 30 min. The mixture was poured in to ice water. The aqueous phase was extracted with ethyl acetate for 3 times. The combined organic layers were washed with water and brine, then dried over Na2SO4 and concentrated. The residue was purified by column chromatography using gradient elution (0 to 50% ethyl acetate in hexane) to give the titled compound.