Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][Cl:5].[Br-].[Li+].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:20][O:21][CH2:22]OC>>[CH3:20][O:21][CH2:22][O:6][CH:3]([CH2:4][Cl:5])[CH2:2][Cl:1]
Reactant: COCOC
Reactant: OC(CCl)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Br-]
Agent: [Li+]
Product: COCOC(CCl)CCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.5 %

Procedure:
1,3-Dichloro-2-propanol (10.0 g, 77.5 mmol) was dissolved in dimethoxymethane (150 ml), lithium bromide (20.2 g, 232.5 mmol) and p-toluenesulfonic acid (1.33 g, 7.8 mmol) were added, and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the reaction mixture was neutralized and partitioned with 5% aqueous sodium hydrogencarbonate solution (50 ml) and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was filtered off and the filtrate was concentrated to give a crude title compound (12.44 g). The crude title compound was distilled under reduced pressure (15 mmHg, 83° C.) to give a pure title compound (7.7 g, yield 57.5%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[C:4]([Cl:18])[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[C:4]([Cl:18])[CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1ccc(O)cc1)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of 70 (2.00 g, 6.14 mmol) and AlCl3 (3.50 g, 26.2 mmol) were refluxed in benzene (50 mL) for 3 h and then cooled to RT. Water (100 mL) was cautiously added dropwise, and the mixture was extracted with Et2O (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 1.42 g (74%) of 71. 1H NMR (400 MHz, CDCl3): δ 5.97 (br s, 1H), 6.89 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.1 Hz, 1H), 7.50 (dd, J=8.1 Hz, 1.7 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]([Cl:19])([P:11](=[O:18])([O:15]CC)[O:12]CC)[P:3](=[O:10])([O:7]CC)[O:4][CH2:5][CH3:6].[Na+:20].[I-].C[Si](Cl)(C)C.ClC(Cl)(P(=O)(O[Si](C)(C)C)OCC)P(=O)(O[Si](C)(C)C)O[Si](C)(C)C.[OH-].[Na+]>CC#N.CO.O>[Na+:20].[Na+:20].[Na+:20].[CH2:5]([O:4][P:3]([C:2]([Cl:1])([Cl:19])[P:11](=[O:12])([O-:18])[O-:15])(=[O:7])[O-:10])[CH3:6]
Reactant: CCOP(=O)(OCC)C(Cl)(Cl)P(=O)(OCC)OCC
Agent: CCOP(=O)(O[Si](C)(C)C)C(Cl)(Cl)P(=O)(O[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CCOP(=O)([O-])C(Cl)(Cl)P(=O)([O-])[O-]
Reaction time: 2 h

Procedure:
5.0 g (0.014 moles) of tetraethyl (dichloromethylene)bisphosphonate and 6.7 g (0.045 moles) of NaI are dissolved in 50 ml of anhydrous CH3CN and while stirring 12.2 g (0.112 moles) of trimethylsilyl chloride are added. After the addition stirring is continued at room temperature, protected from moisture, for appr. 4 days and is evaporated under a vacuum. To the mixture obtained as a residue (contains as the major component monoethyl tris(trimethylsilyl) (dichloromethylene)bisphosphonate) 10 ml of water are added and the mixture is made alkaline with a 10% NaOH solution. The mixture is diluted with 50 ml of CH3OH and is left standing at +4° C. for 2 h and is filtered (the precipitate is (dichloromethylene)bisphosphonic acid sodium salt). To the filtrate 25 ml of ethanol are added and it is left standing for 1 day at +4° C. and is filtered. The filtrate is evaporated under a vacuum and the residue is washed with acetone and filtered. The precipitate is dried to constant weight whereby appr. 2.0 g (50% of the theor.) of colourless crystalline (dichloromethylene)bisphosphonic acid monoethyl ester trisodium salt are obtained (31P-NMR (D2O): δ 6 11.86 (P), 9.40 (P') 2JPP =15.4 Hz) at a concentration of >90% and wherefrom the corresponding acid may be liberated with acid treatment.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14](=[O:33])[CH:15]([NH:22]C(OCC1C=CC=CC=1)=O)P(OC)(OC)=O.[Cl:34][C:35]1[CH:36]=[C:37]([CH:43]=O)[C:38](=[CH:41][CH:42]=1)[CH:39]=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:34][C:35]1[CH:36]=[C:37]2[C:38](=[CH:41][CH:42]=1)[CH:39]=[N:22][C:15]([C:14]([O:13][CH3:12])=[O:33])=[CH:43]2
Reactant: O=Cc1ccc(Cl)cc1C=O
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc2cc(Cl)ccc2cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
DBU (2.36 mL, 15.2 mmol) and methyl{[(benzyloxy)carbonyl]amino}(dimethoxyphosphoryl)acetate (5.02 g, 15.2 mmol) are dissolved in CH2Cl2 (75 mL). The resulting solution is added drop-wise to a solution of 4-chlorophthalaldehyde (2.31 g, 13.8 mmol) in CH2Cl2 (100 mL) at 0° C. The reaction is stirred for 1 hour at 0° C. and then for 18 hours at rt. The volatiles are evaporated to yield a yellow oil, which is dissolved in CHCl3 (10 mL). DBU (2.36 mL, 15.2 mmol) and TFAA (2.15 mL, 15.2 mmol) are added. The reaction is stirred under N2 for 3 hours and is quenched with 150 mL of saturated NaHCO3 solution. The organic layer is separated, and the aqueous layer is extracted with 2×150 mL of CHCl3. The combined organic layers are dried (MgSO4), filtered, and concentrated to a yellow oil. This mixture is purified by column chromatography using a step gradient of 25% to 45% EtOAc in hexanes in 5% increments. Product containing fractions are concentrated, dissolved in MeOH and loaded onto a column of AGW-×2 resin (H+ form). The column is rinsed with MeOH, and the product is eluted with a solution of 5% TEA in MeOH. The product is concentrated from MeOH/MeCN several times to yield methyl 6-chloroisoquinoline-3-carboxylate as a white solid in 67% purity by HPLC (0.810 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1.[NH2:36][NH2:37]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:36][NH:37]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: NN
Reactant: COc1ccc(-c2c[nH]c(C3CN(c4cc(-c5ccc(C#N)c(F)c5)nc(N)n4)CCO3)n2)cc1
Solvent: CCO
Product: COc1ccc(-c2c[nH]c(C3CN(c4cc(-c5ccc6c(N)n[nH]c6c5)nc(N)n4)CCO3)n2)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
A mixture of 4-[2-amino-6-(2-{4-[4-(methyloxy)phenyl]-1H-imidazol-2-yl}-4-morpholinyl)-4-pyrimidinyl]-2-fluorobenzonitrile (350 mg, 0.742 mmol) and hydrazine (1.18 mL, 37.1 mmol) in ethanol (4 mL) was heated under microwave conditions with stirring for 1 hour. The mixture was concentrated. Ethanol (15 mL) was added to the resulting residue, and the resulting mixture was heated to 85° C. for 20 minutes, and then filtered while hot and dried in vacuo to afford the title compound (115 mg) as a pale yellow solid. LC-MS (ES) m/z=484 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.09-3.15 (m, 1H), 3.19-3.25 (m, 1H), 3.69-3.77 (m, 4H), 4.02-4.05 (m, 1H), 4.29-4.36 (m, 1H), 4.56-4.62 (m, 1H), 4.72 (s, 1H), 5.39 (s, 2H), 6.21 (s, 2H), 6.71 (s, 1H), 6.89-6.98 (m, 2H), 7.21-7.68 (m, 1H), 7.60-7.65 (m, 1H), 7.68-7.72 (m, 3H), 7.99 (s, 1H), 11.52 (s, 1H), 12.22-12.48 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28]COC)=[N:11][C:12]([O:16][CH3:17])=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1.Cl>CO.[OH-].[OH-].[Pd+2]>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:10]1[C:9]([OH:8])=[C:14]([CH3:15])[N:13]=[C:12]([O:16][CH3:17])[N:11]=1
Reactant: COCOCCCCCCCCCCc1nc(OC)nc(C)c1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1nc(C)c(O)c(CCCCCCCCCCO)n1

Procedure:
To a stirred solution containing 30.0 mg (0.07 mmol) of 5-(Benzyloxy)-2-methoxy-4-(10-(methoxymethoxy)decyl)-6-methylpyrimidine in 3 mL of methanol was added a drop of concentrated HCl. The mixture was stirred at reflux for 16 h. Then, were added 2 mg of 20% palladium hydroxide on carbon (Degussa type E101 NE/N) and the mixture was stirred at 23° C. for 20 min. The mixture was filtered through celite and concentrated under diminished pressure to afford the expected product as a yellowish oil: yield 20 mg (97%); silica gel TLC Rf 0.45 (4:1 hexanes-ethyl acetate); 1H NMR (methanol) δ 1.30 (br m, 12H), 1.50 (br m, 2H), 1.74 (br m, 2H), 2.56 (s, 3H), 2.89 (dd, 2H, J=7.6, 7.6 Hz), 3.51 (t, 2H, J=6.4 Hz) and 4.15 (s, 3H); 13C NMR (methanol) δ 16.16, 25.49, 26.83, 28.94, 29.04, 29.11, 29.18, 29.22, 30.82, 32.20, 56.14, 61.56, 143.11, 143.11, 152.95 and 152.95; mass spectrum (APCI), m/z (M+H)+ 297.2180 (C16H29N2O3 requires 297.2178).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[C:19]([C:21]1([OH:30])[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH2:23][CH2:22]1)#[CH:20]>>[OH:30][C:21]1([C:19]#[C:20][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH2:23][CH2:22]1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC1(O)CCc2cccnc21
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CCc4cccnc43)ccc1OCC2

Procedure:
The title compound was prepared similarly according to Procedure E by reacting 10-bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide with 7-ethynyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol. 1H NMR (500 MHz, DMSO) δ 2.30-2.43 (1H, m), 2.54-2.61 (1H, m), 2.83-2.95 (1H, m), 2.96-3.07 (1H, m), 4.49 (4H, s), 6.21 (1H, br. s.), 7.03 (1H, d, J=8.51 Hz), 7.14 (1H, br. s.), 7.24-7.36 (2H, m), 7.57 (1H, br. s.), 7.73 (1H, d, J=7.41 Hz), 7.80 (1H, s), 8.46 (1H, d, J=4.26 Hz), 8.53 (1H, d, J=2.05 Hz); LC-MS: m/z=387.10 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]([C:19]1[O:23][N:22]=[C:21]([OH:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:15]([C:19]1[O:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[C:21](=[O:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(O)no1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(=O)n(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)o1
Reaction time: 5 h
Yield: 40.1 %

Procedure:
After mixing 15 g of 2-chloro-5-nitrobenzotrifluoride, 11.3 g of 5-t-butyl-3-hydroxyisoxazole, 11.0 g of potassium carbonate, and 80 ml of dimethyl sulfoxide, the reaction was performed for 5 hours at 80° C. After the reaction was over, the reaction mixture was cooled and extracted with ethyl acetate and water. The organic phase thus formed was recovered and applied to silica gel column chromatography. The main product thus obtained was recrystallized from a mixture of methanol and water to provide 8.8 g of the desired product with a yield of 40.1%. The melting point thereof was 59° C. to 60° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([O:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[N:13]=3)=[C:10](C3C=CC(F)=CC=3)[N:9]=[CH:8]2)[CH2:3][CH2:2]1.[C:35](O)([C:37]([F:40])(F)F)=O>>[NH:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([O:18][C:19]4[CH:20]=[CH:21][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=4)[N:13]=3)=[C:10]([O:18][C:19]3[CH:24]=[CH:35][C:37]([F:40])=[CH:21][CH:20]=3)[N:9]=[CH:8]2)[CH2:5][CH2:6]1
Reactant: CC(C)c1ccc(Oc2nccc(-c3c(-c4ccc(F)cc4)ncn3C3CCNCC3)n2)cc1
Reactant: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(Oc2nccc(-c3c(Oc4ccc(F)cc4)ncn3C3CCNCC3)n2)cc1
Reaction time: 0.5 h

Procedure:
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-isopropylphenoxy)pyrimidin-4-yl]imidazole. The product of the preceding example was combined with TFA, stirred 30 min and the TFA was removed in vacuo. The residue was dissolved in EtOAc (75 mL) and washed with 10% aq NaOH, H2O, satd aq NaCl, dried (Na2SO4) and concentrated. The resulting residue was crystallized from EtOAc/hexane to afford 44 mg of the title compound as a white solid. ES+MS m/z=458 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:12](=[O:14])[CH3:13])[CH:3]=2)[NH:7]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Yield: 46 %

Procedure:
A mixture of 200 mg (1.35 mmol) of 5-amino 1,3-dihydro-indol-2-one in 6 ml of acetic anhydride was refluxed for 30 minutes. The reaction mixture was poured onto 50 g of crushed ice. The mixture was stirred well and the solid was collected by vacuum filtration. The solid was washed with 200 ml of H2O and air dried to yield N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (119 mg, 46%): 1H NMR (DMSO-d6): δ1.97 (s, 3H), 3.41 (s, 2H), 6.68 (d, J=8.4 Hz, 1H), ), 7.26 (dd, J1=2 Hz, J2=8.4 Hz, 1H), 7.46 (d, J=2 Hz, 1H), 9.73 (s, 1H). 10.23 (s, 1H),
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]=[C:4]([CH3:7])[O:3]1.S(=O)(=O)(O)O.[CH2:13]=[O:14].[OH-].[Na+]>O>[OH:14][CH2:13][C:5]1[CH2:6][N:2]([CH3:1])[O:3][C:4]=1[CH3:7]
Reactant: CC1=CCN(C)O1
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1=C(CO)CN(C)O1
Temperature: 70 °C
Yield: 19.5 %

Procedure:
2,5-dimethylisooxazole (10.0 g) was dissolved in water (100 ml). To the solution were added concentrated sulfuric acid (35.3 g) and 40% aqueous formaldehyde solution (46.4 g) at 0° C., and the mixture was heated at 70° C. overnight. The mixture was neutralized with 1N sodium hydroxide solution at 0° C. and extracted with chloroform three times. The extract was dried with magnesium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was distilled under reduced pressure to give 4-hydroxymethyl-2,5-dimethylisooxazole (2.54 g) as colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[C:12](=O)([O-])[O-].[K+].[K+].CO>CC(C)=O>[CH3:12][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: O=C1CCc2c(O)cccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: COc1cccc2c1CCC2=O
Reaction time: 10 h
Yield: 79.4 %

Procedure:
To a mixture of 4-hydroxy-indan-1-one (14.5 g, 0.0979 mol) and 27.08 g (0.195 mol) of potassium carbonate was added 500 ml of acetone and 48.7 ml (0.78 mol) of methanol with stirring and the resulting mixture was heated to reflux for 4 h, cooled, and allowed to stand at room temperature for 10 h. The above mixture was filtered concentrated under vacuo, the solid residue was dissolved in methanol, heated and filtered. The filtrate was concentrated to a volume of 100 ml, cooled and filtered to afford 12.6 g (79 %) of 4-methoxy-indan-1-one.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCNCc1ccccc1

Procedure:
This compound is prepared according to the method of Klioze and Ehrgott (U.S. Pat. No. 4,216,218) from ethyl acrylate and benzylamine
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH2:6].CO[CH:9]1[CH2:13][CH2:12][CH:11](OC)O1.[OH-].[Na+]>C(O)(=O)C>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:9]=[CH:13][CH:12]=[CH:11]1
Reactant: COC1CCC(OC)O1
Reactant: CSCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSCCCn1cccc1

Procedure:
A mixture of 25 g (0.36 mole) 3-(methylthio)-propylamine and 43 g (0.36 mole) 2,5-dimethoxytetrahydrofuran is placed in a 1-liter 3-neck flask equipped with a stirrer, addition funnel, thermometer and condenser, and 200 ml glacial acetic acid is added dropwise with stirring while maintaining the temperature below 20°C. The reaction mixture is refluxed for 30 minutes and, after cooling, it is made basic (pH 9-10) by the addition of 375 ml 30% aqueous sodium hydroxide and steam-distilled for 3 hours.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:23](=[O:24])[C:22]2[CH:26]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])[N:7]([CH2:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(C[C@@H]2CCCO2)n1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)Nc1cc(C(C)(C)C)nn1C[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To the mixture of the product from Example 12C (447 mg, 2.0 mmol) and the product from Step A of Example 11C (410 mg, 2.0 mmol) in CH2Cl2 (8 mL) at about 0° C. was added triethylamine (0.34 mL, 2.4 mmol) dropwise. After stirring for 1 hour at room temperature, water (10 mL) was added to quench the reaction, and CH2Cl2 (20 mL) was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography using an Analogix® IT280™ eluting with ethyl acetate/Hexanes in 0-50% gradient to yield the title compound (330 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.26 (s, 1H), 7.81 (d, J=2.71 Hz, 1H), 7.62 (dd, J=8.98, 2.88 Hz, 1H), 7.28 (d, J=9.15 Hz, 1H), 6.31 (s, 1H), 4.05-4.23 (m, 3H), 3.97 (s, 3H), 3.54-3.72 (m, 2H), 1.83-2.01 (m, 1H), 1.62-1.82 (m, 2H), 1.43-1.60 (m, 1H), 1.24 (s, 9H). MS (ESI) m/z 392 (M+H)+.
Reaction SMILES: [SH2:1].[C:2](O)([CH3:5])([CH3:4])[CH3:3]>>[C:2]([S:1][C:2]([CH3:5])([CH3:4])[CH3:3])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)O
Reactant: S
Product: CC(C)(C)SC(C)(C)C

Procedure:
In a similar manner, ethanol and H2S may be reacted to produce diethyl sulfide, isopropanol and H2S may be reacted to produce di-isopropyl sulfide; tertiary-butanol may be reacted with H2S to produce di-tertiary-butyl sulfide; and octanol-1 may be reacted with H2S to produce di-n-octyl sulfide.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])[N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23]=2[CH2:24][CH3:25])=[O:18])=[CH:5][CH:4]=1.Cl.Cl.[NH2:45][CH2:46][CH2:47][O:48][NH2:49].N1C=CC=CC=1>C(O)C>[NH2:45][CH2:46][CH2:47][O:48][N:49]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:41])([F:1])[F:42])=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]1[N:20]=[C:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[N:22]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[C:23]=1[CH2:24][CH3:25])=[O:18]
Reactant: CCc1c(C(=O)NCCCCCCC(=O)c2ccc(C(F)(F)F)cc2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCc1c(C(=O)NCCCCCCC(=NOCCN)c2ccc(C(F)(F)F)cc2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Yield: 106.8 %

Procedure:
Part C: 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid {7-[4-(trifluoromethyl)phenyl]-7-oxo-heptyl}amide (1.15 g, 1.86 mmol) was dissolved in absolute ethanol (10 ml), and O-(2-aminoethyl)hydroxylamine dihydrochloride (0.276 mg, 1.865 mol) and pyridine (0.18 ml) were successively added. The resulting mixture was stirred at reflux temperature for 20 hours. The mixture was allowed to attain room temperature. After removal of the solvent in vacuo, the residue was dissolved in dichloromethane and washed successively with an aqueous KHSO4 solution and brine. The organic layer was subsequently dried over Na2SO4, filtered and concentrated in vacuo to give 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid [7-(2-amino-ethoxyimino)-7-[4-(trifluoromethyl)phenyl] heptyl]-amide (Compound 2) (1.34 g) as a mixture of E/Z stereoisomers. Melting point: 90-95° C. 1H-NMR (400 MHz, CDCl3) δ 1.05 (t, J=7, 3H), 1.34-1.62 (m, 8H), 2.81 (br t, J=7, 2H), 2.93 (q, J=7, 2H), 3.32-3.42 (m, 4H), 4.44-4.50 (m, 2H), 7.11 (d, J=8, 2H), 7.21-7.34 (m, 5H), 7.37 (d, J=8, 1H), 7.49 (br s, 1H), 7.59 (d, J=8, 2H), 7.71 (d, J=8, 2H), 8.65 (br s, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[CH2:20]([O:22][P:23]([O:27]CC)[O:24][CH2:25][CH3:26])[CH3:21]>>[CH2:20]([O:22][P:23]([CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[CH:4]=1)(=[O:27])[O:24][CH2:25][CH3:26])[CH3:21]
Reactant: FC(F)(F)c1ccc(Oc2cccc(CCl)c2)nc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cccc(Oc2ccc(C(F)(F)F)cn2)c1)OCC
Temperature: 150 °C
Reaction time: 6 h
Yield: 90.5 %

Procedure:
2-(3-Chloromethyl-phenoxy)-5-trifluoromethyl-pyridine (4.88 g, 17.0 mmol) from Step 2 was treated neat with triethylphosphite (4.36 mL, 25.4 mmol) and heated to 150° C. After 6 h, the reaction mixture was cooled, treated with an additional 0.5 mL triethylphosphite (2.9 mmol) and reheated to 150° C. After 6 h, the reaction mixture was removed from the heat and slowly treated with heptane (about 60 mL) while stirring to afford a white solid. The solid was collected by filtration, washed with heptane and dried in a vacuum oven for 16 h at 45° C. to afford a white powder (5.99 g, 91% yield). MS (APCI) M+1=390.1; 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=7.02 Hz, 6H) 3.18 (d, J=21.83 Hz, 2H) 3.99-4.10 (m, 4H) 7.01 (d, J=8.58 Hz, 1H) 7.03-7.08 (m, 1H) 7.12 (q, J=2.21 Hz, 1H) 7.19-7.24 (m, 1H) 7.38 (t, J=7.90 Hz, 1H) 7.90 (dd, J=8.58, 2.53 Hz, 1H) 8.43 (dd, J=1.66, 0.88 Hz, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[C:5]1=[O:14].Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[Cl:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:14]
Reactant: O=C1C(=O)N(CCCl)c2ccccc21
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: O=C1Cc2ccccc2N1CCCl

Procedure:
1-(2-Chloroethyl)-lH-indol-2,3-dione (5.24 g) [C.A. Reg no. 77218-99-6] was suspended in acetic acid (50 ml) and hydrogenated at 60 p.s.i., at room temperature, in the presence of 70% perchloric acid (0.2 ml) and 5% palladium on charcoal (1 g) for 24 hours. The clear solution was filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluent chloroform, to give 1-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one as a white solid.