Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:26]([O-:28])=[O:27])[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:6]([CH2:20][CH2:21][CH2:22]Br)([C:17]([O-:19])=[O:18])[CH:5]([CH3:24])[NH:4][CH:3]1[CH3:25].[ClH:29].[C:30]1([C:36]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[ClH:29].[CH3:1][C:2]1([C:26]([OH:28])=[O:27])[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:6]([CH2:20][CH2:21][CH2:22][N:39]2[CH2:40][CH2:41][C:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:37][CH2:38]2)([C:17]([OH:19])=[O:18])[CH:5]([CH3:24])[NH:4][CH:3]1[CH3:25]
Reactant: CC1NC(C)C(CCCBr)(C(=O)[O-])C(c2cccc([N+](=O)[O-])c2)C1(C)C(=O)[O-]
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC1NC(C)C(CCCN2CCC(c3ccccc3)(c3ccccc3)CC2)(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C1(C)C(=O)O
Reaction time: 16 h
Yield: 81.7 %

Procedure:
A mixture of 86.6 g of (-)-3-methyl-5-(3-bromopropyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 50 g of 4,4-diphenylpiperidine hydrochloride and 69 g of finely powdered potassium carbonate is heated for 5 h in 300 ml of dimethyl formamide to 100° C. under a nitrogen atmosphere and with vigorous sti rring. After cooling, 500 ml of ethyl acetate and 1 l of water are added with vigorous stirring. The phases are separated; the organic phase is washed four times with water, dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in 1 l of dioxane; then 15.2 ml of concentrated hydrochloric acid solution (12.5 M, d =1.19) are added, and about 200 ml of the solvent mixture are removed by distillation in vacuo. The product crystallizes spontaneously on standing at room temperature or after inoculation or trituration, and is filtered off by suction after 16 h, washed with dioxane and diisopropyl ether, and dried at 80 to 100° C. in vacuo. For further purification the crude product is dissolved in dichloromethane. After addition of 800 ml of dioxane the dichlormethane is distilled off. The product which crystallizes after inoculation on standing at room temperature for 16 h is filtered off by suction, washed with dioxane and diisopropyl ether, and dried at 100° C. in vacuo. 97 g of the title compound {m.p. 158° C. to 160° C. and [α]43622 =-39° (c=1, methanol) or [α]=-14,4 (c =1, methanol)} are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](Cl)([Cl:13])=[O:12]>>[Cl:13][C:11]([O:10][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9])=[O:12]
Reactant: CC(O)c1ccc(Cl)cc1
Reactant: O=C(Cl)Cl
Product: CC(OC(=O)Cl)c1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 1, using the following starting materials: 1-(4-chlorophenyl)ethanol and phosgene (20% in toluene).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([O:12][CH3:13])=[O:11].CCN(CC)CC>CC#N>[CH3:13][O:12][C:10](=[O:11])[CH2:9][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)CBr
Reactant: Sc1ccccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CSc1ccccn1
Yield: 94.3 %

Procedure:
A solution of 2-mercaptopyridine (484 mg, 4.35 mmol), methyl bromoacetate (0.45 ml, 4.8 mmol), and Et3N (0.79 ml, 5.7 mmol) in CH3CN (22 ml) was stirred at room temperature for 20 h to give (pyridin-2-ylsulfanyl)-acetic acid methyl ester as a colorless oil (752 mg, 94%) after aqueous work-up and purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14][S:15][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]#[C:17][CH2:16][S:15][CH2:14][C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][S:37]([CH3:36])(=[O:39])=[O:38])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccccc1CCCCC#CCSCC#CCCCCc1ccccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccccc1CCCCC#CCSCC#CCCCCc1ccccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To a solution of 82 (0.2 g, 0.9 mmol) in 2 mL of anhydrous CH2Cl2 at 0° C. was added anhydrous pyridine (71 mg, 0.9 mmol) and methylsulfonyl chloride (0.1 g, 0.9 mmol) under argon (FIG. 2N). The solution was stirred at room temperature for 6 h. The reaction was carefully quenched with water and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with water, dried (MgSO4), and concentrated in vacuo. Chromatography on silica gel (EtOAc:hexanes, 5:95) gave the desired methylsulfonyloxy derivative 124 as a colorless oil (0.22 g, 84%). 1H NMR (CDCl3) δ7.51-7.53 (dd, 1 H, J=7.6 Hz and 2.6 Hz, ArH), 7.40-7.42 (dd, 1 H, J=7.9 Hz and 2.8 Hz, ArH), 7.26-7.30 (m, 2 H, ArH), 3.66 (t, 2 H, J=1.3 Hz CH2), 3.24 (s, 3 H, CH3), 2.11-2.13 (m, 2 H, CH2), 1.26-1.41 (m, 4 H, CH2), 0.84-0.87 (t, 3 H, J=7.1 Hz, CH3); 13C NMR (CDCl3) δ147.63, 130.77, 129.18, 127.82, 127.59, 123.20, 84.74, 74.54, 38.50, 30.52, 21.97, 21.77, 18.37, 13.53.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1F)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:22][S:23]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:25])=[O:24].O>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:31]1[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][S:23]([CH3:22])(=[O:24])=[O:25])[CH2:33][CH2:32]1)[CH3:2]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCc1cc([N+](=O)[O-])c(OC)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc([N+](=O)[O-])c(OC)cc1N1CCN(CCS(C)(=O)=O)CC1
Temperature: 65 °C

Procedure:
1-Ethyl-2-fluoro-4-(methyloxy)-5-nitrobenzene (1.0 g, 5.0 mmol) was dissolved in DMSO (8 mL). Potassium carbonate (2.1 g, 15 mmol) and 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (Example 148, step B) (1.1 g, 5.0 mmol) were added and the reaction mixture was heated to 65° C. and allowed to stir over the weekend. The mixture was then poured into water and extracted with EtOAc (2×). The combined organics were dried with MgSO4, filtered, and concentrated in vacuo to give the title compound without further purification (1.7 g, 4.7 mmol, 93%). MS (M+H, ES+) 372.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:12]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:13]=1[C:14]#[N:15].NC(N)=[S:24]>>[SH:24][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[SH:24][C:12]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:13]=1[C:14]#[N:15]
Reactant: NC(N)=S
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: Cc1ccc(C#N)c(Cl)n1
Product: Cc1cc(C)c(C#N)c(S)n1
Product: Cc1ccc(C#N)c(S)n1

Procedure:
treating 2-chloro-6-methylnicotinonitrile (or 2-chloro-4,6-dimethylnicotinonitrile) with thiourea to give intermediate compound of 2-mercapto-6-methylnicotinonitrile (or 2-mercapto-4,6-dimethylnicotinonitrile);
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7]([CH3:8])=[CH:6][CH:5]=1)[CH3:3].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[N+:25]([O-:27])=[O:26].C(N(C(C)C)CC)(C)C>C(#N)C>[N+:22]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:25]([O-:27])=[O:26])[C:16]=1[CH:8]=[C:7]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:2][CH3:3])[CH:5]=[CH:6]1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CC[n+]1ccc(C)c2ccccc21
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C=CC(=Cc2c([N+](=O)[O-])cccc2[N+](=O)[O-])c2ccccc21
Reaction time: 8 h
Yield: 25 %

Procedure:
1-Ethyllepidinium iodide (3.0 g., 10 mmole) and 1-chloro-2,6-dinitrobenzene (2.5 g., 12 mmole) are warmed in acetonitrile (50 ml.) and diisopropylethylamine (2.6 g., 20 mmole) is added. The resulting dark mixture is allowed to cool and stand overnight. The precipitate of dye is filtered off and washed with acetonitrile and ether. On recrystallization from acetonitrile, a 25% yield (0.85 g.) of purified dye is obtained with a m.p. of 154°-155° C. dec.
Reaction SMILES: C([O-])(=O)C.[Na+].[SH:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>O.C(#N)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][S:6][C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=2)=[CH:18][CH:19]=1
Reactant: Oc1cc(O)nc(S)n1
Reactant: Fc1ccc(CBr)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Oc1cc(O)nc(SCc2ccc(F)cc2)n1
Reaction time: 20 h
Yield: 89.3 %

Procedure:
Sodium acetate (113 g) was added to a suspension of 2-mercaptopyrimidine-4,6-diol (80 g) in water (900 mL) at room temperature. A solution of 1-(bromomethyl)-4-fluorobenzene (105 g) in acetonitrile (90 mL) was added dropwise over 2 hours. The reaction was allowed to stir for 20 hours before the suspension was filtered and washed with water (3×) and isohexane (3×). The solid was dried in vacuo for 2 hours and azeotroped with toluene (3×) to afford the sub-title product (125 g) as a white solid.
Reaction SMILES: C(O)C.Cl[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([S:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:12]=1.[S-:24][C:25]#[N:26].[K+].[I-].[K+]>C(OCC)(=O)C.CCCCCC>[S:24]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([S:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:12]=1)[C:25]#[N:26]
Reactant: N#C[S-]
Reactant: Cc1ccc(OCCCCCCl)cc1SCC(F)(F)F
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: Cc1ccc(OCCCCCSC#N)cc1SCC(F)(F)F
Temperature: 25 °C
Yield: 84.4 %

Procedure:
To 100 ml of ethanol were added 2.0 g (6.1 mmol) of 5-chloropentyl-{4-methyl-3-(2,2,2-trifluoroethylthio)phenyl}ether, 4.0 g (41 mmol) of potassium thiocyanate and 0.10 g (0.61 mmol) of potassium iodide. The mixture was refluxed for 10 hours under heating and then allowed to cool to room temperature. The solvent was distilled off under reduced pressure. To the residue was added ethyl acetate to conduct extraction. The organic phase obtained was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=10:1), to obtain 1.8 g (yield: 84%) of an intended product.
Reaction SMILES: [NH2:1]N.[Br:3][C:4]1[CH:16]=[CH:15][C:7]([C:8](/[N:10]=[CH:11]/[N:12](C)C)=O)=[C:6]([F:17])[CH:5]=1>C(O)(=O)C>[Br:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]2[NH:1][N:12]=[CH:11][N:10]=2)=[C:6]([F:17])[CH:5]=1
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccc(Br)cc1F
Solvent: CC(=O)O
Product: Fc1cc(Br)ccc1-c1ncn[nH]1
Temperature: 97.5 °C
Reaction time: 2 h
Yield: 114 %

Procedure:
Hydrazine (0.14 mL, 4.4 mmol) was added to a solution of (E)-4-bromo-N-((dimethylamino)methylene)-2-fluorobenzamide (1.105 g, 4.046 mmol) in acetic acid (11 mL). The resulting white suspension was heated to 95-100° C. The resulting solution was stirred at 95-100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and the acetic acid was azeotropically removed in vacuo with multiple additions of heptane. Heptane (10 mL) was added to the residue. The resulting suspension was cooled to 0-5° C. and stirred for 1 hour. The solids were collected by vacuum filtration, rinsed with excess heptane, and dried to afford 5-(4-bromo-2-fluorophenyl)-1H-1,2,4-triazole (1.116 g, 114%) as an off-white solid which was carried on without further purification.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3=[N:24][CH:25]=[N:26][C:27]([O:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[C:22]3[CH:21]=[N:20]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(N(CC)CC)C.CN([CH:45]=[O:46])C>>[CH:1]1([O:7][C:45]([N:32]2[CH2:33][CH2:34][CH:29]([O:28][C:27]3[N:26]=[CH:25][N:24]=[C:23]4[N:19]([C:16]5[CH:17]=[CH:18][C:13]([S:10]([CH3:9])(=[O:11])=[O:12])=[CH:14][CH:15]=5)[N:20]=[CH:21][C:22]=34)[CH2:30][CH2:31]2)=[O:46])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)OC5CCCCC5)CC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Carbonyldiimidizole (0.28 mmol, 46 mg), and cyclohexanol (0.28 mmol, 34 μL) were dissolved in DMF (2 mL) and stirred for 30 minutes at room temperature. Then, 1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride salt (0.16 mmol, 60 mg) and triethylamine (0.84 mmol, 118 μL) were added and continued to stir at 60° C. for 24 hours. The reaction mixture was quenched with water followed by an extraction with ethylacetate. Removal of organic solvents in vacuo and purification by HPLC provided compound A63 as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.67 (s, 1H); 8.61 (d, 2H); 8.26 (s, 1H); 8.11 (d, 2H); 5.62 (h, 1H); 4.71 (h, 1H); 3.91 (m, 2H); 3.38 (m, 2H); 3.10 (s, 3H); 2.10 (m, 2H); 1.87 (m, 4H), 1.65 (m, 6H); 1.28 (m, 2H). LCMS (ESI), m/z 500.4 (MH+, 100%)
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH2:5]([CH:7]1[O:9][CH2:8]1)[Cl:6]>[Ag]>[Cl:6][CH2:5][CH:7]([OH:9])[CH2:8][O:4][CH2:1][CH:2]=[CH2:3]
Reactant: ClCC1CO1
Reactant: C=CCO
Agent: [Ag]
Product: C=CCOCC(O)CCl
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A mixture of 87 grams (1.5 mols) of allyl alcohol and 1 milliliter of boron trifluoride-diethyl etherate is heated to 60° C. in a reaction vessel provided with reflux condenser, thermometer and dropping funnel. Within 45 minutes, 46.25 grams (0.5 mol) of epichlorohydrin are constantly added to said mixture. The reaction is exothermic. Thereafter the reaction mixture is rectified via a 40 centimeter silver-coated column, whereupon at first 55 grams of unreacted allyl alcohol are distilled off at 24° C. and a pressure of 15 millibars. By subsequent distillation at 0.08 millibars there are obtained 59.7 grams (79.3% of the theory) of (3-chloro-2-hydroxy-propyl)-allyl ether with a boiling point of 57° C. and a refractive index nD20 =1.4630.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=5[CH3:28])[NH2:24])[CH:19]=[C:18]([CH3:29])[N:16]4[N:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:46]2[CH:47]=[C:48]([CH:52]=[C:53]([S:55]([F:60])([F:59])([F:58])([F:57])[F:56])[CH:54]=2)[C:49](O)=[O:50])[CH2:42][CH2:41]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([NH:24][C:49](=[O:50])[C:48]6[CH:52]=[C:53]([S:55]([F:60])([F:56])([F:57])([F:58])[F:59])[CH:54]=[C:46]([N:43]7[CH2:42][CH2:41][N:40]([CH3:39])[CH2:45][CH2:44]7)[CH:47]=6)[CH:25]=[CH:26][C:27]=5[CH3:28])[CH:19]=[C:18]([CH3:29])[N:16]4[N:17]=3)[CH:10]=[N:9]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)cc(C)n4n3)cn2)cc1
Reactant: CN1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(N7CCN(C)CC7)cc(S(F)(F)(F)(F)F)c6)ccc5C)cc(C)n4n3)cn2)cc1

Procedure:
70 mg (0.17 mmol) of the compound of Example 9A and 78 mg (0.17 mmol) of the compound of Example 17A were reacted and worked up analogously to the procedure of Example 48A. This gave 125 mg (95% of theory) of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([F:36])[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:33])=[O:34])=[C:28]([F:36])[CH:27]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.09 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.43 g, 4.2 mmol/g loading, 10.2 mmol) followed by 4-bromo-2-fluorobenzenesulfonyl chloride (2.79 g, 10.2 mmol). The resulting solution was stirred at room temperature overnight, the resin was then filtered off, the solvent evaporated in vacuo and the residue was then passed through an SCX column eluting first with methanol and then by 2M ammonia in methanol. The basic fractions were combined and solvent evaporated in vacuo to afford a crude product which was dry loaded onto a column and purified further by chromatography using a Flashmaster and an elution gradient of 0 to 10% methanol in dichloromethane The relevant fractions were collected, combined and solvent evaporated to afford the title compound (E103). MS (ES+) m/e 472/474 [M+H]+.
Reaction SMILES: O.CO.[CH2:4]([OH:6])[CH3:5].[CH:7]([OH:10])([CH3:9])[CH3:8]>>[CH2:4]([O:6][CH2:8][CH2:7][OH:10])[CH3:5].[CH2:4]([O:6][C:7]([OH:10])([CH3:9])[CH3:8])[CH3:5]
Reactant: CCO
Reactant: CC(C)O
Solvent: O
Solvent: CO
Product: CCOC(C)(C)O
Product: CCOCCO
Temperature: 0 °C

Procedure:
The polyhydric alcohol contributes not only for a freezing point depressing agent, as aforementioned, but also for the improvement in mechanical strengths of the coolant gel of the invention. In detail, when compared to the gel obtained from an aqueous solution containing a polyvinyl alcohol only, a gel obtained from a composition containing any of said polyhydric alcohols is further increased in strength. As a result, a coolant gel suited for substitution for an ice pillow and having sufficient mechanical strength can be prepared by allowing one or more of said polyhydric alcohols to co-exist. The concentration of co-existing polyhydric alcohol may be within the range of from 20 to 80 wt %, preferably from 35 to 75 wt %. If the concentration of co-existing polyhydric alcohol is less than 20 wt %, it becomes difficult to lower the freezing or solidification point to a temperature of lower than -10° C. On the contrary, if the concentration of co-existing polyhydric alcohol is higher than 80 wt %, the freezing point is depressed excessively in some cases or conversely the freezing or solidification point is raised, with unnecessary increase in cost. The effect of depressing the freezing or solidification temperature of a gel is provided also by the addition of a water-soluble monohydric alcohol, such as methyl alcohol (Freezing Point: -20° C. at 25 wt % substitution), ethyl alcohol (Freezing point: -20° C. at 30 wt % substitution), isopropyl alcohol (Freezing Point: -19° C. at 40 wt % substitution), ethoxyethyl alcohol (Freezing Point: -21° C. at 40 wt % substitution) and ethoxyisopropyl alcohol (Freezing Point: -30° C. at 62 wt % substitution) or derivatives thereof, and further by the addition of a general water-soluble organic compound, such as acetone (Freezing Point: -20° C. at 36 wt % substitution), dimethyl sulfoxide (Freezing Point: -25° C. at 37 wt % substitution), methyl sulfonic acid (Freezing Point: -28° C. at 32 wt % substitution), ethyl sulfonic acid (Freezing Point: -24° C. at 37 wt % substitution), dimethylamine (Freezing Point: -20° C. at 33 wt % substitution), methylamine (Freezing Point: -20° C. at 20 wt % substitution) and formic acid (Freezing Point: -20° C. at 35 wt % substitution). However, ethylene glycol, propylene glycol and glycerin are particularly preferred for the reasons that they are odorless and poor in volatility, that the object of depressing the freezing point can be attained at relatively low substitution rate by using one or a mixture of them and that the gel obtained by the addition of them is greatly improved in mechanical strengths. Trimethylene glycol (1,3-propylene glycol) and 2,4-pentanediol are inferior to ethylene glycol and propylene glycol in that light almond-like odor is generated therefrom.
Reaction SMILES: [CH3:1][C:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH3:19][I:20]>>[I-:20].[C:14]([O:13][C:12]([NH:11][C:2]([CH3:1])([CH3:10])[CH2:3][N+:4]1([CH3:19])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CI
Reactant: CC(C)(CN1CCOCC1)NC(=O)OC(C)(C)C
Product: CC(C)(C[N+]1(C)CCOCC1)NC(=O)OC(C)(C)C
Product: [I-]
Temperature: 50 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
tert-Butyl 2-methyl-1-morpholinopropan-2-ylcarbamate (640 mg, 2.5 mmol) was dissolved in methyl iodide (20 ml) and placed in a sealed tube. The reaction was stirred at 50° C. for 18 hours. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The water layer was separated and concentrated to give 840 mg (85%) 4-(2-(tert-butoxycarbonylamino)-2-methylpropyl)-4-methylmorpholin-4-ium iodide. 1H NMR (D2O): δ (m, 4 H), 3.83 (s, 2 H), 3.72-3.54 (m, 4 H), 3.37 (s, 3 H), 1.50 (s, 6 H), 1.45 (s, 9 H); MS (ESI+) calculated for C14H29N2O3+: 273.22, Found: 273 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:29][CH2:28][C@@H:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH:25]=3)=[CH:20][CH:19]=2)[C:15](O)=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:41][C:42]1(N)[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[C:44]([CH3:54])[CH2:43]1.CC[N:58](C(C)C)C(C)C>ClCCl.CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:29][CH2:28][C@@H:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH:25]=3)=[CH:20][CH:19]=2)[C:15](=[O:16])[NH:58][C:51]2[CH:52]=[CH:53][C:48]([C:45]3[CH:46]=[CH:47][C:42]([Cl:41])=[CH:43][C:44]=3[CH3:54])=[CH:49][CH:50]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(CC(C(=O)O)c2ccc(C3=CC[C@H](C(C)(C)C)CC3)cc2)cc1
Reactant: CC1=C(c2ccccc2)C=CC(N)(Cl)C1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1-c1ccc(NC(=O)C(Cc2ccc(C(=O)OC(C)(C)C)cc2)c2ccc(C3=CC[C@H](C(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To 4-{2-[4-(4-(R)-tert-Butylcyclohex-1-enyl)-phenyl]-2-carboxy-ethyl}-benzoic acid tert-butyl ester (697 mg, 1.51 mmol) in anhydrous dichloromethane (30 mL) was added oxalyl chloride (650 uL, 7.53 mmol) and 3 drops of DMF. The resulting solution was stirred at rt for 1 hr before being concentrated under vacuum. The residue was co-evaporated with toluene (1×5 mL) then dissolved in toluene again (20 mL). To the mixture was added 4-chloro-2-methylbiphenyl-4-ylamine (361 mg, 1.66 mmol) and DIPEA (1.3 mL, 7.53 mmol). The resulting mixture was refluxed for 90 min, diluted with ethyl acetate and washed with saturated NaHCO3. The organic portion was dried over Na2SO4 and concentrated under vacuum to afford crude material which was crystallized from MeOH to afford a white solid (590 mg). Removing the solvent and purification of the residue by chromatography on silica gel using an ethyl acetate/hexanes gradient afforded an additional 137 mg of product. 1H NMR (500 MHz, DMSO-d6): 10.16 (s, 1H), 7.78 (d, J=8 Hz, 2 H), 7.59 (d, J=8.5 Hz, 2 H), 7.4-7.32 (m, 7 H), 7.21 (d, J=8 Hz, 2 H), 7.15 (d, J=8 Hz, 2 H), 6.14 (m, 1H), 4.03 (dd, J=9, 7 Hz, 1 H), 3.48 (dd, J=13.5, 9.5 Hz, 1 H), 3.41 (dd, J=13.5, 6.5 Hz, 1 H), 2.4-2.3 (m, 1H), 2.2-2.15 (m, 4H), 1.96-1.9 (m, 2H), 1.52 (s, 9 H), 1.32-1.2 (m, 2 H), 0.89 (s, 9H).