Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[NH:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:19]([C:21]([OH:23])=O)[CH3:20].CCN(C(C)C)C(C)C.Cl.[NH2:41][C@H:42]([C:48]([NH:50][C@H:51]([C:61]([NH:63][CH2:64][C:65]([NH:67][C@H:68]([C:73]([NH:75][CH2:76][C:77]([O:79][CH3:80])=[O:78])=[O:74])[CH2:69][CH:70]([CH3:72])[CH3:71])=[O:66])=[O:62])[CH2:52][O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46]>>[NH:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:19]([C:21]([NH:41][C@H:42]([C:48]([NH:50][C@H:51]([C:61]([NH:63][CH2:64][C:65]([NH:67][C@H:68]([C:73]([NH:75][CH2:76][C:77]([O:79][CH3:80])=[O:78])=[O:74])[CH2:69][CH:70]([CH3:71])[CH3:72])=[O:66])=[O:62])[CH2:52][O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46])=[O:23])[CH3:20]
Reactant: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)CCC(N)=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
The title compound of this example: DPPA (12.38 g, 45 mmol) was added to a cooled solution (0° C.) of Boc-Ala-OH (3.2 g, 45 mmol) and DIEA (7.8 mL, 45 mmol). The mixture was stirred at 0° C. for 15 min. The pentapeptide from paragraph (d), HCl.H-Gln-Ser(Bzl)-Gly-Leu-Gly-OCH3 (9.0 g, 15 mmol), was added to the mixture. The mixture was stirred for 18 h while the temperature of the mixture gradually came to room temperature. The mixture was concentrated to dryness. The resultant solid was triturated with EtOAc, collected on a filter, and washed with Et2O and then with hexane. The collected solid was suspended in Et2O and the suspension stirred vigorously for 1 h. The solid was collected on a filter and dried to give Boc-Ala-Gln-Ser(Bzl)-Gly-Leu-Gly-OCH3 (10.94 g). The latter compound (6.0 g, 8.15 mmol) was suspended in dioxane (150 mL) and H2 0 (200 mL). The suspension was stirred and cooled to 0° C. A solution of NaOH (425 mg, 10.6 mmol) was added dropwise to the cooled suspension. The mixture was stirred at room temperature until it became clear (2 h). The mixture was rendered acidic (pH=4) by the addition of acetic acid and then concentrated under reduced pressure (after addition of isopropanol to prevent foaming). The residue was dissolved in the minimum amount of butanol/H2O/acetic acid (4:5:1). The solution was passed through a column of Sephadex (tradename for a brand of cross linked chains of organic compounds derived from dextran). The pure fractions were combined to give the desired hexapeptide i.e. the title compound of this example, as the HCl addition salt (4.90 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccccc3)nc12
Temperature: 20 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of 2-amino-4-methoxy-7-phenyl-benzothiazole (100 mg, 0.4 mmol) in pyridine (2 ml) was added benzoyl chloride (55 mg, 0.4 mmol) and the mixture stirred overnight at 20 ° C. To this mixture 2N HCl to pH 1 (20 ml) was added then the mixture was extracted twice with EtOAc (20 ml), washed with saturated NaHCO3 solution, dried with Na2SO4 and the solvent evaporated. The crude product was then chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/MeOH (98:2), the product fractions were pooled and the solvent evaporated, to afford the title compound as a white solid (97 mg, 69% yield), MS: m/e=360 (M+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:21]([CH:22]=O)=[CH:20][C:11]3[C:12]([C:15]4[S:16][CH:17]=[CH:18][N:19]=4)=[N:13][O:14][C:10]=3[C:9]=2[F:24])[CH2:5][C@@H:4]([CH3:25])[O:3]1.[NH:26]1[C:31](=[O:32])[CH2:30][C:29](=[O:33])[NH:28][C:27]1=[O:34]>C(O)C>[F:24][C:9]1[C:10]2[O:14][N:13]=[C:12]([C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[C:11]=2[CH:20]=[C:21]2[C:8]=1[N:6]1[CH2:7][C@@H:2]([CH3:1])[O:3][C@@H:4]([CH3:25])[C@@H:5]1[C:30]1([C:29](=[O:33])[NH:28][C:27](=[O:34])[NH:26][C:31]1=[O:32])[CH2:22]2
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-c4nccs4)noc3c2F)C[C@@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CCO
Product: C[C@@H]1CN2c3c(cc4c(-c5nccs5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
A mixture of 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-(thiazol-2-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 430, 1.414 g, 3.91 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (0.501 g, 3.91 mmol) in ethanol (200 ml) was heated at 90° C. for 5 days. Solvent removed. LCMS of crude reaction indicates 9:1 mixture of two diastereomeric products. The major product was purified by reverse phase preparative HPLC to give the title compound (1.320 g, 71.6%).
Reaction SMILES: [BH4-].[K+].[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[C:8]1[N:13]=[C:12]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:10][CH:9]=1>CO>[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[C:8]1[N:13]=[C:12]([CH:14]([OH:16])[CH3:15])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1cccc(C2OCCO2)n1
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CC(O)c1cccc(C2OCCO2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.9 %

Procedure:
0.50 g of potassium borohydride (9.27 mmol) is added in portions to a solution of 0.90 g of 1-(6-[1,3]dioxolan-2-yl-pyridin-2-yl)ethanone (4.66 mmol) in 15 ml of methanol. The mixture is stirred for 12 hours at room temperature and then methanol is evaporated off and the residue is taken up in chloroform. The organic phase is washed with water and then dried over sodium sulfate, filtered, and concentrated under vacuum. 0.70 g of a pale yellow oil is obtained, which oil is used in the next stage without further purification. 1H NMR (CDCl3) δ: 1.47 (d, 3H); 1.84 (s, 1H(exchangeable)); 4.11 (m, 4H); 4.88 (m, 1H); 5.82 (s, 1H); 7.25 (d, 1H); 7.41 (d, 1H); 7.75 (t, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[N:11]1([C@H:14]2[CH:19]3[CH2:18][CH2:17][N:16]([CH2:21][CH2:20]3)[CH2:15]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: c1ccc(CN2CCN([C@@H]3CN4CCC3CC4)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C1CN([C@@H]2CN3CCC2CC3)CCN1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (3S)-3-(4-benzyl-1-piperazinyl)-1-azabicyclo[2.2.2]octane (1.25 g, 4.37 mmol) and 400 mg of Pd(OH)2 (20 wt % on carbon) in MeOH (60 mL) was stirred at room temperature under hydrogen atmosphere (4 atm) for 6 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give a product (850 mg, quant.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][O:32][CH3:33])=[CH:26][C:25]=1[CH2:34][C:35]#[N:36].CN(C)C=O.[H-].[Na+]>O>[CH3:33][O:32][CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:25]([CH2:34][C:35]#[N:36])[CH:26]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COCOc1ccc(O)c(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC#N)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.95 g), 2-(2-hydroxy-5-methoxymethoxyphenyl)acetonitrile (1.0 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60%, oil, 0.23 g) under ice-cooling, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic, layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give crystals (1.40 g, 57%) of 2-[5-methoxymethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 123-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl.[NH2:18][OH:19]>>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:18][OH:19])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2CCC(=O)CC2)cc1
Reactant: NO
Agent: Cl
Product: COc1ccc(CN2CCC(=NO)CC2)cc1

Procedure:
1-(4-Methoxybenzyl)-4-piperidone oxime is prepared from 1-(4-methoxybenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][C:5]([F:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:26][NH2:27]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:27][NH:26][C:13](=[O:14])[C:6]=2[C:5]([F:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NN
Reactant: CCOC(=O)c1c(F)nc(-c2ccccc2)c(N)c1C(=O)OCC
Solvent: CCO
Solvent: O
Product: Nc1c(-c2ccccc2)nc(F)c2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 1 ml of ethanol was dissolved 90 mg of 3-amino-6-fluoro-4,5-diethoxycarbonyl-2-phenylpyridine, followed by addition of 2 ml of hydrazine monohydrate. The mixture was stirred at room temperature for 4 hours. After the solvent was distilled off, the resulting crystals were collected by filtration with ethanol. Water was added to the crystals, and the mixture was neutralized with 1N hydrochloric acid, followed by collection by filtration. A methanol solution of the crystals was mixed with silica gel and purified by silica gel column chromatography (eluent:ethyl acetate→ethyl acetate/methanol 1:1), followed by collection by filtration with water.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([O:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:20]=[CH2:21])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[C:12]([O:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:20]1[CH2:21][O:6]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC1CO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.6 %

Procedure:
m-Chloroperoxybenzoic acid (40.7 g, 236 mmol) was added to a solution of (S)-2-tert-butoxycarbonylaminopent-4-enoic acid tert-butyl ester (Compound 29) (32.0 g, 118 mmol) in dichloromethane (384 ml), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was cooled to 0° C., and the reaction was terminated by adding a solution of sodium bicarbonate (20 g) in water (300 ml) and a saturated aqueous sodium thiosulfate solution (100 ml). The mixture was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol) to afford (S)-2-tert-butoxycarbonylamino-3-oxiranyl-propionic acid tert-butyl ester (Compound 30) (18.53 g, 55%).
Reaction SMILES: Br[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[C:17]([C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)#[CH:18]>N1CCCC1.[Cu]I>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]#[C:18][C:2]#[C:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)CCCCCCCCCC#CBr
Reactant: C#Cc1ccco1
Agent: [Cu]I
Solvent: C1CCNC1
Product: O=C(O)CCCCCCC/C=C\C#CC#Cc1ccco1
Reaction time: 1 h

Procedure:
A mechanically stirred solution of bromoacetylene 5 (35 g, 121 mmol) and ethynylfuran 8 (23% w/w, 16.7 g, 182 mmol) in 400 mL of pyrrolidine under nitrogen was cooled via ice-water bath. Copper (I) iodide (3.69 g, 19 mmol) was added in one portion and after 5 min the cooling bath was removed and the homogeneous mixture was stirred an additional 1 h. The dark red reaction was quenched by addition of 850 mL of water with stirring. The orange-yellow suspension was extracted with 4×300 ml of diethyl ether. The combined organic layers were washed with 3×100 mL of water and 100 mL of brine, dried over sodium sulfate, and concentrated in vacuo to a dark red oil. The residue was resuspended in 100 mL of 10% ethyl acetate in hexanes and passed through a pad of silica gel in a flitted funnel. The pad was washed with an additional 4×50 mL of solvent and concentrated in vacuo to give 21.0 g of crude 9 as a dark red oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:22])[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:35]([N:36]=[C:37]=[O:38])=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:22])[CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:37](=[O:38])[NH:36][C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:27]3[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=3)[CH2:19][CH2:20]2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1ccccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)CN2CCC(O)CC2)C1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)CN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)C1
Temperature: 70 °C

Procedure:
{(R)-1-[2-(4-Hydroxy-piperidin-1-yl)-acetyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Intermediate Z1) (520 mg, 1.6 mmol) and 2-biphenylisocyanate (930 mg, 2.65 mmol) are dissolved in NMP (2 ml) and heated to 70° C. overnight. Purification is carried out by reverse phase column chromatography (Isolute™ C18, 0-100% MeOH in water −0.1% TFA). The fractions containing the product are concentrated in vacuo to remove the acetonitrile and the aqueous is treated with saturated sodium bicarbonate solution. The product is extracted with DCM and the combined organic portions are concentrated in vacuo to afford the title product. [MH+ 523.24].
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([N:19]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[N:28]=1)=[O:26])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([N:19]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:34]=2)[N:28]=1)=[O:26])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C(=O)N(Cc1ccccc1)C(=O)c1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(Cc1ccccc1)C(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 91.7 %

Procedure:
A mixture of methyl thiosalicylate (1.8 g, 10.7 mmol), N-benzyl-N-[(6-cyano-2-pyridyl)carbonyl]-N′,N′-dimethylurea (1.6 g, 5.4 mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxed for 8 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (2.2 g, 93%) as crystals.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[CH2:11]([N:14]([CH2:27][CH2:28][CH3:29])[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([CH2:25][NH2:26])[CH:19]=[CH:20][CH:21]=2)[CH2:16]1)[CH2:12][CH3:13].[OH-].[Na+]>CCOCC.O>[CH2:27]([N:14]([CH2:11][CH2:12][CH3:13])[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([CH2:25][NH:26][CH:5]=[O:7])[CH:19]=[CH:20][CH:21]=2)[CH2:16]1)[CH2:28][CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCCN(CCC)C1CCc2cccc(CN)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: O=CO
Product: CCCN(CCC)C1CCc2cccc(CNC=O)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.04 ml (21.5 mmol) of acetic anhydride and 0.86 ml (22.8 mmol) of formic acid were stirred for 2 h at +60° C. under nitrogen. After cooling to room temperature, 2.6 g (10 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were added dropwise at a maximum of +25° C. After 15 minutes post-reaction, 5 ml of ether were added. The batch was subsequently stirred for a further 18 h at room temperature and then diluted with 20 ml of ether and 20 ml of water. The aqueous phase was adjusted to pH 9 using 1N sodium hydroxide solution and extracted with ether. The organic phase now obtained was washed with water and dried over sodium sulphate, and the solvent was removed by distillation. The residue was recrystallized from petroleum ether 60-80.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[N:2]1.[CH:12]1([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22](Cl)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]2)[CH2:14][CH2:13]1>C(#N)C.N1C=CC=CC=1>[CH:12]1([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22]([N:8]4[CH2:9][CH2:10][CH2:11][CH:6]([N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)[CH2:7]4)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: c1cn(C2CCCNC2)nn1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CCCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 100 °C

Procedure:
3-(1,2,3-triazol-1-yl)piperidine (150 mg, 0.96 mmol) was added to a solution of ethyl 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (150 mg, 0.48 mmol) in a mixture of acetonitrile (10 ml) and pyridine (3 ml). The reaction mixture was heated at 100° C. for 6 hrs and then concentrated to dryness. The residue was diluted with water and thus solid separated was filtered, washed thoroughly with water and dried. Yield 90 mg, m.p. 205°-206° C.; 1H NMR (CDCl3) δ: 8.58 (s, 1H), 8.15 (d, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 4.90 (m, 2H), 4.40 (m, 3H), 3.45 (m, 3H), 1.75-2.50 (m, 4H), 1.40 (t, 3H), 0.95-1.35 (m, 4H).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:22].[OH:23][OH:24]>C(O)(=O)C>[O-:23][OH:24].[OH:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:22]
Reactant: OO
Agent: O=C1CCCCCCCCCCC1CCCO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: [O-]O

Procedure:
These processes are known from EP 0 424 787. EP 0 424 787 describes that an aqueous solution of sulphuric acid is added to a mixture of 2-(3-hydroxypropyl)-1-cyclododecanone and glacial acetic acid. To this mixture hydrogen peroxide (70%) is added, which reacts with 2-(3-hydroxypropyl)-1-cyclododecanone to form a precipitate of a hydroperoxide of 2-(3-hydroxypropyl)-1-cyclododecanone (referred to as DDP-OOH). The precipitate is subsequently filtered, washed with water and then with diluted NaHCO3, after which it is dried.
Reaction SMILES: O1CCCC1.C1([Li])C=CC=CC=1.[Br-].[OH:14][CH2:15][C:16]1[CH:41]=[CH:40][C:19]([CH2:20][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:18][CH:17]=1.[CH2:42]([N:46]([CH2:55][CH2:56][CH2:57][CH3:58])[C:47]1[CH:54]=[CH:53][C:50]([CH:51]=O)=[CH:49][CH:48]=1)[CH2:43][CH2:44][CH3:45]>C1(C)C=CC=CC=1.O>[CH2:42]([N:46]([CH2:55][CH2:56][CH2:57][CH3:58])[C:47]1[CH:48]=[CH:49][C:50]([CH:51]=[CH:20][C:19]2[CH:18]=[CH:17][C:16]([CH2:15][OH:14])=[CH:41][CH:40]=2)=[CH:53][CH:54]=1)[CH2:43][CH2:44][CH3:45]
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Reactant: OCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(CO)cc2)cc1
Reaction time: 1 h
Yield: 85.6 %

Procedure:
In a stream of argon, to 40 ml of tetrahydrofuran was added 8.0 g of phenyllithium (19% solution in dibutylether) (18.1 mmol). To this mixture, 3.81 g (8.2 mmol) of 4-(hydroxymethyl)benzyltriphenylphosphonium bromide was added under cooling. After the mixture was stirred at the same temperature, 2.0 g (8.6 mmol) of 4-(dibutylamino)benzaldehyde was added thereto. The mixture was stirred at the same temperature for 1 hour. After the reaction mixture was added to water, extraction with toluene, washing with a saturated saline solution, and drying over anhydrous sodium sulfate were performed. Toluene was evaporated off. The residue was purified by silica gel column chromatography to give 2.37 g of a yellow liquid (yield: 85.5%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C:5]=1[C:20]1[N:24]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C=O)C>[CH2:37]([O:36][C:34]([N:6]1[C:5]([C:20]2[N:24]([C:25]3[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=3)[N:23]=[CH:22][CH:21]=2)=[C:4]([CH3:3])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]1=[O:19])=[O:35])[CH3:38]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)n1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
Sodium hydride (38 mg of a 60% dispersion in mineral oil, 0.95 mmol) was added to a solution of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (300 mg, 0.73 mmol) in DMF under a nitrogen atmosphere. The mixture was stirred for 5 minutes and the resultant yellow solution was treated with ethyl chloroformate (104 mg, 0.091 mL, 0.95 mmol). The mixture was stirred for 1 h then treated with water and extracted with EtOAc. The organic phase was washed with water and brine then dried (sodium sulfate) and concentrated in vacuo. The residue was purified by chromatography using silica gel eluting with 25%-50% ethyl acetate in cyclohexane. The product thus obtained was freeze-dried from acetonitrile-water to afford the title compound (194 mg) a white solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:20]2[CH2:25][CH2:24][N:23]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: C1CCCC(N2CCNCC2)CC1
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCN(C2CCCCCC2)CC1

Procedure:
This example was prepared according to Example 1 by employing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-cycloheptylpiperazine, which is commercially available from, for example, Sigma-Aldrich. m/z (ES+) M+1=327.2; HPLC tR=1.90 min. 1H NMR (500 MHz, CDCl3) δ 7.26 (m, 2H), 7.22-7.13 (m, 1H), 7.09 (d, J=6.7 Hz, 2H), 3.86-3.50 (m, 4H), 2.60-2.42 (m, 6H), 1.95 (dt, J=5.1, 3.8 Hz, 1H) 1.83-1.73 (m, 2H), 1.71-1.60 (m, 3H), 1.58-1.31 (m, 8H), 1.24 (ddd, J=8.2, 6.1, 4.3 Hz, 1H).