Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[C:1]([C:5]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9]([Cl:29])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)Cl
Reaction time: 2 h

Procedure:
To a stirred slurry of 2-(2,4-di-t-butyl phenoxy) propionic acid (27.8 g, 0.100 mol) in CH2Cl2 (280 mL) with 2 mL of DMF, oxalyl chloride (17.0 g, 0.134 mol) was added dropwise. The solution resulted after several minutes was stirred for 2 hr. TLC indicates no starting material. The solution was filtered through a glass wool plug to remove some debris and the filtrate was concentrated in vacuo, residue was washed with CH2Cl2 (50 mL) and was concentrated once more to give a gelatinous mixture, which was used without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:39][CH2:40][CH2:41]Cl)=[CH:34][CH:33]=1>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:41][CH2:40][CH2:39][CH:38]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=3)[C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
N-Cyclopropyl-N-{1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide (34) was prepared by dissolving N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide (110.6 mg, 0.318 mmol) in 10 mL of DMF and followed by the addition of triethylamine (48.3 mg, 0.477 mmol) and bis(4-fluorophenyl)butyl chloride (98.2 mg, 0.350 mmol). The reaction mixture was stirred overnight at 85° C. The crude compound was purified by column chromatography on silica gel (hexane/EtOAc, 7:3) to give the title compound 34 as a yellow sticky solid. 1H NMR (CDCl3): δ 8.12 (s, 1H), 8.04 (d, 1H), 7.84 (d, 1H), 7.61 (t, 1H), 7.13 (dd, 4H), 6.94 t, 4H), 3.84 t, 2H), 2.85 (d, 2H), 2.30 (t, 2H), 1.92 (m, 7H), 1.48 (m, 2H), 1.37 (m, 2H), 0.96 (m, 2H), 0.75 (m, 2H). LC: 100%. MS (M+H+): 593.
Reaction SMILES: Cl[S:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](Cl)=[O:6].Cl.[CH3:17][NH2:18].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:15][O:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:3]2[S:2][N:18]([CH3:17])[C:5](=[O:6])[C:4]=2[CH:8]=1
Reactant: CN
Reactant: COc1cc(SCl)c(C(=O)Cl)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc2sn(C)c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chlorosulfenyl-4,5-dimethoxybenzoyl chloride (5.0 g) was dissolved in pyridine (30 ml) and methylamine hydrochloride (6.0 g) was added. The mixture was stirred at room temperature for 2 days. Ethyl acetate was added and the mixture was washed with 1 N HCl and water. Ethyl acetate was dried with Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography eluting with heptane-ethyl acetate (1:9).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:10])[CH3:2].C(N(CC)CC)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:10][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CCNC(=O)[C@@H](N)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)[C@H](Cc1ccccc1)NCC(=O)OCC
Temperature: 60 °C
Yield: 80.4 %

Procedure:
Phenylalanyl-β-alanine ethyl ester (10 g, 0.038 mol) and triethylamine (10.3 g, 0.1 mol) were suspended in toluene (45 g), and the suspension was heated to 60° C. To the resultant suspension, ethyl bromoacetate (9.3 g, 0.057 mol) suspended in toluene (5 g) was added dropwise over 0.5 hours, and then the resultant mixture was stirred for three hours. After completion of reaction, the resultant reaction mixture was subjected to extraction with ethyl acetate (20 g). The organic layer was washed with a 2.5% aqueous solution of citric acid. Subsequently, the solvent was removed, to thereby obtain N-(carboethoxymethyl)phenylalanyl-β-alanine ethyl ester (10.7 g, yield: 80.3%). The compound was dissolved in methanol, and a 48% aqueous solution of sodium hydroxide (6.6 g, 0.08 mol) was added to the methanol solution, and the resultant mixture was stirred for three hours. After completion of reaction, the solvent was removed, and the resultant residue was dissolved in water (20 mL), and then washed with ethyl acetate (10 g). Subsequently, hydrochloric acid was added to the aqueous layer, so as to attain a pH of 3.5. After being cooled, the resultant solution was subjected to filtration, to thereby obtain crude crystals. The crystals were recrystallized from a 20% aqueous solution of isopropyl alcohol, to thereby obtain compound 1 (6.0 g, yield: 67%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1
Reaction time: 0.03 h

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and cooled to -10° with stirring. 0.255 G. of butyric acid chloride are added dropwise thereto over a period of 2 minutes. The temperature rises to 0° and pyridine hydrochloride precipitates out. Subsequently, the mixture is stirred overnight at room temperature and the suspension poured on to a mixture of 12 g. of ice and 12 ml. of 20% hydrochloric acid. Thereafter, this mixture is extracted three times with ethyl acetate, washed with water, dried over sodium sulfate and evaporated in vacuum. The 0.552 g. of yellowish crystals obtained as the residue are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.521 g. of yellowish crystals which are recrystallized from acetone-hexene up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl butyrate obtained melts at 77.9°-78.2° and is liquid crystalline (monotrope) upon cooling to 74.7°. UV (EtOH): ε 272 = 26100.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([OH:9])[C:6]([OH:8])=[O:7].C.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([O:9][CH:5]([CH2:4][CH2:3][S:2][CH3:1])[C:6]([OH:8])=[O:7])(=[O:20])[CH3:19]
Reactant: CSCCC(O)C(=O)O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CSCCC(OC(C)=O)C(=O)O
Temperature: 0 °C
Yield: 63.1 %

Procedure:
To a solution of 2-hydroxy-4-(methylthio)butanoic acid (50.74 g, 337.8 mmol, obtained by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap) in dichloromethane (1 L) was added triethylamine (93 mL, 667.3 mmol) and the resulting mixture was cooled to 0° C. To the cooled mixture was added acetyl chloride (26 mL, 365.6 mmol) dropwise. The ice bath was removed and the reaction was allowed to warm to room temperature overnight. The reaction was washed with 1N HCl (2×300 mL), and brine (1×300 mL), dried over magnesium sulfate, filtered and evaporated to give an amber oil (59.82 g, 63.1%). m/z 193 (MH+).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[CH:5]([N:9]=[N:10][C:11](Cl)([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH2:7][CH3:8])[CH3:6].O>CC(C)=O>[CH:5]([N:9]=[N:10][C:11]([N:3]=[C:2]=[O:1])([CH2:13][CH:14]([CH3:15])[CH3:16])[CH3:12])([CH2:7][CH3:8])[CH3:6]
Reactant: N#C[O-]
Reactant: CCC(C)N=NC(C)(Cl)CC(C)C
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCC(C)N=NC(C)(CC(C)C)N=C=O
Temperature: 25 °C

Procedure:
To a stirrred solution of 8.6 grams (0.105 moles) of potassium cyanate in 75 ml of 70% aqueous acetone in a 125 ml erlenmeyer flask was added 19 grams (0.093 moles) of 2-sec.-butylazo-2-chloro-4-methylpentane (from Example 3-23) over 10 minutes while holding the reaction temperature at 15°-20° C. with a cold water bath. After the addition was complete the reaction was stirred an additional hour at room temperature, poured into 200 ml water and the product extracted with 100 mls of pentane. The pentane solution was separated, washed with 50 ml portions of water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 13.1 grams (67% crude yield). The infrared spectrum of the product was in agreement with the structure of 2-sec.-butylazo-2-isocyanato-4-methylpentane (strong broad isocyanate band at 2125-2225 cm- 1).
Reaction SMILES: [OH:1][C:2]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1.CN(C=O)C>O>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:7]3[CH:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[NH:9][N:8]=3)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: CC(C)(O)c1cc(C(=O)O)n[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)[nH]n1
Yield: 20 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylic acid (0.646 mmol, 110 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.539 mmol, 140 mg) using DMF (2 ml) as the solvent. Water was added and the mixture was extracted three times with DCM. The combined organics were washed twice with water. The separated organic phase was evaporated and the residue was purified by flash chromatography and preparative HPLC, respectively. 44.6 mg of the title compound was obtained. 1H-NMR (400 MHz; DMSO-d6): δ 1.11 (d, 3H), 1.45 (s, 6H), 4.22-4.52 (m, 3H), 5.31 (s, 1H), 6.37 (s, 1H), 6.94 (d, 1H), 7.81 (d, 1H), 7.88-8.03 (m, 2H), 8.09 (s, 1H), 8.16 (d, 1H), 12.96 (s, 1H).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][CH:21](C(=O)C)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].ClC1C=CC=[C:34]([C:38]([O:40]O)=[O:39])C=1>ClCCl>[C:38]([O:40][CH:21]1[CH2:20][CH:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:22]1)(=[O:39])[CH3:34]
Reactant: CC(=O)C1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Yield: 45.2 %

Procedure:
To a stirred solution of 1-(3-[tert-butyl(diphenyl)silyl]oxycyclobutyl)ethanone (0.65 g, 0.0018 mol) in dichloromethane (10 mL) at 0° C. was added sodium bicarbonate (0.39 g, 0.0046 mol) and m-chloroperbenzoic acid (1.0 g, 0.0046 mol) with stirring. The reaction was stirred at rt over night. LCMS showed incomplete reaction, another 2.5 eq. of mCPBA and NaHCO3 were added and the reaction was stirred for another day. The reaction was quenched with 20% aq. Na2S2O3 solution (50 mL) and stirred for a further 30 min at rt, then extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, concentrated and purified on silica gel with Combiflash (silica gel, 0-10% EtOAc/Hex) to give the desired product (0.3 g, 40%) as colorless oil. LCMS calculated for C22H29O3Si(M+H)+: 369.2. Found: 369.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][CH3:15])[CH2:9][CH2:10][NH:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:27]>O1CCCC1>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:26](=[O:27])[N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][CH3:15])=[CH:30][CH:31]=1
Reactant: CCNCCN(CC)C(=O)OC(C)(C)C
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCN(CC)C(=O)OC(C)(C)C)C(=O)Oc1ccc(OC)cc1
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A solution of N-tert.-butoxycarbonyl-N,N'-diethylethylenediamine (3.22 g, 15 mmol) and N,N-diisopropylethylamine (2.6 mL, 15 mmol) in tetrahydrofuran (100 mL) was added over 1 hour to a stirred, cooled solution of 4-methoxyphenyl chloroformate (2.78 g, 15 mmol) in tetrahydrofuran (50 mL). After stirring at 20°-25° overnight, solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue over silica gel and elution with 10-20% ethyl acetate-90-80% n-butylchloride gave 3.53 g of the carbamate as an oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][C:9]2[C:18]([NH2:19])=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[S:24](N)(N)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:9]3=[CH:10][CH:11]=[C:12]4[C:17]([N:16]=[CH:15][CH:14]=[CH:13]4)=[C:18]3[NH:19][S:24]2(=[O:26])=[O:25])=[CH:5][CH:4]=1
Reactant: NS(N)(=O)=O
Reactant: Nc1c(NCc2ccc(C(F)(F)F)cc2)ccc2cccnc12
Solvent: c1ccncc1
Product: O=S1(=O)Nc2c(ccc3cccnc23)N1Cc1ccc(C(F)(F)F)cc1
Yield: 12.7 %

Procedure:
In a similar fashion using route 63 general procedure 140, N*7*-(4-trifluoromethyl-benzyl)-quinoline-7,8-diamine 577 (334 mg, 1.0 mmol), sulfamide (154 mg, 1.5 mmol) and pyridine (5 ml) gave the title compound (48 mg, 12%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[CH:11]1([CH2:14][O:15][C:16]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:17]=2[C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)=[O:19])[CH2:13][CH2:12]1>C1COCC1>[CH:11]1([CH2:14][O:15][C:16]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:17]=2[C@:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:21]2)([OH:19])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2OCC2CC2)C1
Reactant: COCCCCCl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(F)c1OCC1CC1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A flame dried 50 mL three-necked flask was charged with magnesium turnings (380 mg, 15.8 mmol) and a small crystal of iodine in THF (5 mL). The flask was evacuated and refilled with N2. Then a solution of 1-chloro-4-methoxybutane (1.6 g, 13.2 mmol) in THF (10 mL) was added dropwise slowly to the mixture. The reaction mixture was stirred under reflux for 2.5 h and most of the magnesium was consumed. The resulting Grignard reagent was used as follows. To another 100 mL three-necked flask was added (R)-tert-butyl 3-(2-(cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-1-carboxylate (0.5 g, 1.32 mmol) and THF (10 mL). The flask was evacuated and refilled with N2. The mixture was cooled with a dry ice-acetone bath and the Grignard reagent (250 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The mixture was quenched with sat'd aq NH4Cl (10 mL), extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4 Evaporation of the solvent and purification by flash column chromatography, eluting with 10% EtOAc/PE afforded (R)-tert-butyl 3-((S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (560 mg, 91%). 1H NMR (400 MHz, CDCl3): 0.35 (m, 2H), 0.63 (m, 2H), 1.05 (m, 1H), 1.43 (s, 9H), 1.55-1.20 (m, 9H), 1.85 (m, 1H), 2.55 (m, 1H), 2.67 (m, 1H), 3.27 (s, 3H), 3.33 (m, 2H), 3.85 (m, 1H), 4.05 (m, 2H), 4.25 (m, 1H), 6.97 (m, 3H). MS (E/Z): 466 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[CH:30]=[N:29][CH:28]=[N:27][CH:26]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(-c3cncnc3)cccc21
Product: CC1c2cccc(-c3cncnc3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyrimidin-5-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:2]1[O:4][CH2:3]1.[OH-:11].[Na+]>C(O)(=O)CCCCC(O)=O.[OH-].[Na+].O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:2]([CH2:3][OH:11])[OH:4]
Reactant: CCCCCOCC1CO1
Reactant: [OH-]
Agent: O=C(O)CCCCC(=O)O
Agent: [Na+]
Solvent: O
Product: CCCCCOCC(O)CO
Temperature: 200 °C
Yield: 277.4 %

Procedure:
In an autoclave, 163 g of the crude pentyl glycidyl ether, 108 g of water, 7.3 g of adipic acid and 10.4 g of sodium hydroxide were charged. The resulting mixture was heated to 200° C. while stirring. After stirring for 2 hours, 1.6 g of sodium hydroxide was added. The resulting reaction mixture was dehydrated at 100° C. under reduced pressure (5.32 kPa), followed by purification by distillation under reduced pressure (133 to 266 Pa, 114 to 115° C.) , whereby 117 g of monopentyl glyceryl ether was obtained. As a result of GLC, it was found that the resulting compound had a purity not less than 99% and the content of organochlorine compounds was not greater than 100 ppm.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.[N:16]1([CH:21]([CH3:26])[C:22]([O:24]C)=O)[CH:20]=[CH:19][CH:18]=[N:17]1.Cl>O1CCCC1.O>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:22]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:11])[F:12])=[CH:9][CH:8]=2)([OH:24])[CH:21]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH3:26])=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: COC(=O)C(C)n1cccn1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(n1cccn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.6 %

Procedure:
A solution of 4-trifluoromethoxybromobenzene (6.3 g.) in dry tetrahydrofuran (40 cm3) was added dropwise to a stirred mixture of magnesium turnings (0.62 g.), dry tetrahydrofuran (10 cm3) and a crystal of iodine under a nitrogen atmosphere. The reaction commenced after about 3 cm3 of the solution had been added and the mixture was warmed gently for a few minutes. When the addition was complete the mixture was stirred for 2 hours after which a solution of methyl 2-(1H-pyrazol-1-yl)propionate (2.0 g) in dry tetrahydrofuran (5.0 cm3) was added dropwise and the mixture then stirred for a further 2 hours at the ambient temperature. Finally the mixture was warmed to 40° C. to complete the reaction. The mixture was poured into water, acidified with dilute hydrochloric acid and extracted with two portions of diethyl ether 2×50 cm3. The extracts were combined, washed with water (3×50 cm3), dried over anhydrous magnesium sulphate and concentrated by removal of the solvent by evaporation under reduced pressure. The residual oil was subjected to purification by repeated chromatographic separation on a silica gel column eluted with a mixture of petroleum ether (boiling range 60°-80° C., 4 parts by volume) and ethyl acetate (1 part by volume) to yield 1,1-bis(4-trifluoromethoxyphenyl)-2-(1H-pyrazol-1-yl) propanol (500 mg.) as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:14](COCC[Si](C)(C)C)[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[CH3:2]>CCOC(C)=O.C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Yield: 91 %

Procedure:
The title compound was prepared by the procedure of Example 15, step (c) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-acetyl-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 40.0 mg, 0.0862 mmol). Silica gel chromatography (10% EtOAc/DCM) afforded the title compound (26.2 mg, 91%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 11.59 (s, 1H), 9.79 (s, 1H), 8.50 (d, 1H, J=8.6 Hz), 7.92 (dd, 1H, J=8.6, 2.0 Hz), 7.82 (d, 1H, J=2.0 Hz), 7.78 (s, 1H), 5.92 (m, 1H), 2.62 (s, 3H), 2.23-2.39 (m, 4H), 1.77-1.94 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C19H18N4O2, 335.1 (M+H), found 335.1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]#[N:13].[NH3:14]>CCO>[NH2:14][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]#[N:13]
Reactant: N
Reactant: N#Cc1c(F)cccc1C(F)(F)F
Solvent: CCO
Product: N#Cc1c(N)cccc1C(F)(F)F

Procedure:
2-Fluoro-6-trifluoromethylbenzenecarbonitrile was heated at 100° C. in a saturated solution of NH3 in EtOH overnight. The reaction mixture was concentrated and the residue was purified by column chromatography on silicagel (EtOAc/Hexanes 1:5), to obtain the title compound as a white solid. GC/MS m/z 186.1 (M+), Rt 10.1 minutes.