Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.IC1C=CC=CC=1.C(O)(=O)C.C(O)(=O)C>ClCCl>[CH:2]([CH2:3][C:4]1([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:1]
Reactant: COC(=O)c1ccccc1OCCC1(CCO)CCCCC1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1OCCC1(CC=O)CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.6 %

Procedure:
To a solution of methyl 2-[2-[1-(2-hydroxyethyl)cyclohexyl]ethoxy]benzoate (synthesized in Example 36) (226 mg) and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (23 mg) in dichloromethane (4 mL) was added diacetic acid iodobenzene (261 mg) at room temperature. The solution was stirred at room temperature for 48 hours. Silica gel was added to the reaction solution and it was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, hexane-ethyl acetate (5:1)] to give the title compound (118 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: Nc1ccc(-c2ccc(F)cc2)cc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccc(-c2ccc(F)cc2)cc1

Procedure:
Using the same method as in Example 1-(ii), 4′-fluorobiphenyl-4-yl amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[(4′-fluorobiphenyl-4-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 86%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=1[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C[N:22](C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[NH2:22][C:12]([C:11]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:10]=1[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(N)=O
Reaction time: 0.5 h

Procedure:
2-{[(Tert-butoxycarbonyl)amino]methyl}-5-fluorobenzoic acid (800 mg, 2.97 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (854 mg, 4.46 mmol), and 1-hydroxy-7-azabenzotriazole (607 mg, 4.46 mmol) were added to dry DMF (10 mL) and stirred for 30 minutes to preform the activated ester. Ammonia gas was bubbled through the solution for 30 seconds and the reaction was allowed to stir for 5 minutes. The solvent was removed in vacuo and the residue was purified by flash column chromatography (ISCO column, 120 g silica) running a gradient of 0-40% acetone/hexane over 35 min. The product fractions were concentrated to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1.[CH3:31][NH2:32]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:32][CH3:31])[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1
Reactant: COc1cc2c(c(-c3ccccc3F)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3ccccc3F)c2O1

Procedure:
The title compound was prepared (0.039 g, 51%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.102 g, 0.24 mmol) and methylamine (0.074 g, 2.4 mmol). mp 110-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][CH2:11][CH:10]([CH2:13][O:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][CH:3]=1.[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])([O:20][CH3:21])=[O:19].[OH-].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([C:24](=[O:25])[CH2:23][CH2:22][C:18]([O:20][CH3:21])=[O:19])[CH2:11][CH:10]([CH2:13][O:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: CCCOCC1CNC(c2ccc(Cl)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCOCC1CN(C(=O)CCC(=O)OC)C(c2ccc(Cl)cc2)O1

Procedure:
To 25.6 milliliters of 25 percent w/v, 2-p-chlorophenyl-5-propoxymethyl oxazolidine solution in 50 milliliters of benzene was added 3.8 grams of 3-carbomethoxypropionyl chloride. To this reaction mixture was added 2 grams of 50% sodium hydroxide. Upon completion of the reaction solvent, benzene, was removed in vacuo. There was obtained 6.0 grams of the title compound, nD30 1.4975. Analytical data supports the structure.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([C:12]1[CH:24]=[CH:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:25])[CH:20]=3)[NH:15][C:14]=2[CH:13]=1)(C)[C:6](OCC)=O)C.Cl>C(O)(=O)C>[Cl:25][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH:13]=[C:12]([CH:5]([CH3:6])[C:4]([OH:26])=[O:3])[CH:24]=[CH:23][C:22]2=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc2c(c1)[nH]c1ccc(Cl)cc12
Agent: Cl
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(c1)[nH]c1ccc(Cl)cc12
Temperature: 25 °C

Procedure:
A mixture of 247 g. of (6-chloro-2-carbazolyl)-methyl-malonic acid diethyl ester, 1.9 liters of glacial acetic acid and 1.9 liters of 6 N hydrochloric acid is heated under reflux overnight with stirring and the resulting black solution is cooled to room temperature. The solid formed is removed by filtration, washed with acetic acid/water (1:1) and water and then dried. The 192 g. of crude 6-chloro-α-methyl-carbazole-2-acetic acid obtained are dissolved in 1.2 liters of 1 N potassium hydroxide, the solution is extracted with four 300 ml. portions of diethyl ether and acidified by the addition of 100 ml. of concentrated hydrochloric acid while cooling in an ice-bath under nitrogen. The mixture is stirred for 15 minutes, the precipitated solid is removed by filtration, washed with water and dried. 167.7 G. of product are obtained. The last purification is carried out by crystallization from 4.7 liters of boiling 1,2-dichloroethane with 8.0 g. of active carbon. The solution is cooled overnight, the crystals are removed by filtration, washed with dichloroethane and dried. There are obtained 103.8 g. (57.3% of theory) of almost white 6-chloro-α-methyl-carbazole-2-acetic acid having a melting point of 198.5°-201° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: COC1(c2cc(F)cc(Cl)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COC1(c2cc(F)cc(Cl)c2)CCNC1
Yield: 27.7 %

Procedure:
Preparation according to Example 1: (+)-1-benzyl-3-(3-chloro-5-fluorophenyl)-3-methoxypyrrolidine (0.212 g, 0.66 mmol), 1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (0.38 g, 2.65 mmol). Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound 0.042 g (27%). [a]D=+2.7° (methanol). MS m/z (relative intensity, 70 eV) 229 (M+, 1), 214 (58), 199 (bp), 187 (75), 157 (37).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH:3]2[CH2:7][CH2:8][CH:9]=[CH:10][CH:2]12.C1(=O)OC(=O)C2CCCCC12>>[C:4]1([CH:3]2[CH:2]([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:1][O:6]1)=[O:5]
Reactant: O=C1OC(=O)C2CCC=CC12
Agent: O=C1OC(=O)C2CCCCC12
Product: O=C1OCC2CCCCC12

Procedure:
Undiluted tetrahydrophthalic acid anhydride was continuously hydrogenated in the trickle phase over 3 liters of catalyst No. 3 at a pressure of 120 bar and a temperature of 95° C. A volume/time yield of 800 g per liter of catalyst an hour was achieved. 400 Nl of exhaust gas per hour were released from the separator. The yield of hexahydrophthalic acid anhydride was 99.2%. A small amount of hexahydrophthalide was formed as by-product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[C:20]([N+:37]([O-])=O)=[C:21]([CH:34]=[CH:35][CH:36]=2)[O:22][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1>O1CCCC1.[Ni]>[NH2:37][C:20]1[C:19]([NH:18][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:36][CH:35]=[CH:34][C:21]=1[O:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 403B (2.76 g) in tetrahydrofuran (125 mL) in a stainless steel pressure bottle was added nickel catalyst (2.76 g). The mixture was stirred for 1 hour under hydrogen at 30 psi and ambient temperature. The mixture was filtered though a nylon membrane to remove the catalyst, and concentrated to give the product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl>ClCCl>[CH3:27][O:28][CH2:29][O:1][CH:2]1[CH2:3][CH2:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(O)CC1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)CCC(OCOC)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
12.3 g of diethyl 4-hydroxycyclohexane-1,1-dicarboxylate was dissolved in 160 ml of dichloromethane and 26.3 ml of diisopropylethylamine was added thereto followed by ice-cooling. Next, 9.6 ml of chloromethyl methyl ether was added thereto and the reaction mixture was stirred at room temperature for 15 hours. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 11.10 g of the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH2:28])[C:19]2=[O:29])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.CO.O>CCOCC.CCCCCC.C(O)C>[CH:30]1([C:33]([NH:28][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[C:26](=[O:27])[N:18]([CH:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:19]3=[O:29])=[O:34])[CH2:32][CH2:31]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Solvent: O
Solvent: CO
Solvent: CCO
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
A mixture of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminoisoindoline-1,3-dione (570 mg, 1.4 mmol) and cyclopropane carbonyl chloride (2 mL) was heated to reflux for 15 minutes. To the mixture was added methanol (20 mL) and water (5 mL) at room temperature and kept for 30 minutes. The solvent was removed in vacuo to give an oil. The oil was stirred in ether/hexane (15 mL each) for 1 hour to give a suspension. The suspension was filtered and washed with ether to give a yellow solid. The solid was then stirred in ethanol (10 mL) overnight. The suspension was filtered and washed with ethanol to give cyclopropyl-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}carboxamide as a yellow solid (380 mg, 57.4% yield); mp, 153-155° C.; 1H NMR (CDCl3) δ0.92-0.99 (m, 2H, 2CHH), 1.11-1.17 (m, 2H, 2CHH), 1.48 (t, J=6.9 Hz, 3H, CH3), 1.61-1.71 (m, 1H, CH), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.12 (q, J=7.1 Hz, 2H, CH2), 4.57 (dd, J=10.4, 14.3 Hz, 1H, CHH), 5.89 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.84-6.88 (m, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.48 (d, J=7.2 Hz, 1H, Ar), 7.65 (t, J=7.4 Hz, 1H, Ar), 8.76 (d, J=8.5 Hz, 1H, Ar), 9.69 (s, 1H, NH); 13C NMR (CDCl3) δ8.71, 14.62, 16.16, 41.58, 48.59, 54.60, 55.89, 64.50, 111.49, 112.44, 114.83, 117.91, 120.26, 124.99, 129.27, 130.99, 136.02, 137.77, 148.63, 149.76, 167.49, 169.52, 172.79; Anal Calcd for C24H26N2O7S: C, 59.25; H, 5.39; N, 5.76. Found: C, 59.06; H, 5.30; N, 5.69.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O:13][C:14](=[O:17])[CH2:15]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH3:12][O:13][C:14](=[O:17])[CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]=[O:7])=[C:8]([CH3:10])[CH:9]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1cc(C)c(C=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-2,6-dimethylbenzaldehyde (1.3 g, 8.6 mmol) and bromoacetic acid methyl ester (0.98 ml, 10.3 mmol) in DMF (20 mL) was added K2CO3 (1.8 g, 12.9 mmol). The suspension was stirred at ambient temperature overnight then the reaction mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the organic layer was dried with MgSO4, filtered and concentrated. Purification by flash chromatography using heptane/EtOAc (5:1) as eluent gave (4-formyl-3,5-dimethylphenoxy)-acetic acid methyl ester as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:17]([CH:18]=O)[C:16]=1[OH:23])[CH3:13]>C(O)C.O.[Na]>[CH2:12]([O:14][C:15]1[C:16]2[O:23][C:2]([C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=3)=[O:4])=[CH:18][C:17]=2[CH:20]=[CH:21][CH:22]=1)[CH3:13]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOc1cccc(C=O)c1O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOc1cccc2cc(C(=O)c3ccc(Cl)cc3)oc12

Procedure:
23.3 g of ω-bromo-p-chloroacetophenone are added to 17 g of 3-ethoxysalicylaldehyde in 800 ml of ethanol and 4 g of sodium hydrate. After heating the mixture for one hour under reflux, it is allowed to cool, the product which separates is filtered off, and is crystallised from ethanol: M.P. 108°-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+]>Cl.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[NH2:16]
Reactant: CCOC(=O)C(C)(C)c1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(NN)cc1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A solution of 3.725 g (18 mmol) of ethyl 2-(4-aminophenyl)-2-methylpropionate in 18 mL of concentrated hydrochloric acid was stirred at -10 to -5° C. in an ice-acetone bath as a solution of 1.29 g (18.7 mmol) of sodium nitrite in 7.5 mL of water was added dropwise over about 15 minutes. Stirring was continued at this temperature for an additional 30 minutes. Next, a small amount of insoluble solid was removed by filtration into a cold receiving flask. The filtrate was then added dropwise over 10-15 minutes to a solution of 20.3 g (90 mmol) of stannous chloride dihydrate in 14.5 mL of concentrated hydrochloric acid stirred under nitrogen in an ice-acetone bath. The addition was carried out at such a rate that the internal temperature remained at about -5° C. A gummy material separated during the addition. After completion of the addition, stirring was continued at -10 to -5° C. for 1 hour. The aqueous phase was decanted, and the residual gum was dissolved in 250 mL of ethyl acetate. The ethyl acetate solution was treated cautiously with 250 mL of saturated aqueous sodium bicarbonate solution and shaken in a separatory funnel. The ethyl acetate layer was washed with 50 mL of saturated aqueous sodium chloride solution. The entire mixture was filtered before separation of the phases. The ethyl acetate phase was dried over magnesium sulfate, filtered, and concentrated in vacuo at room temperature to yield 2.59 g (65%) of an oil. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure and indicated that only minor impurities were present.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13]Cl)=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C(O)C>[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[N:19]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([CH3:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1ccccc1N
Reactant: Cc1nc2ccccc2c(Cl)c1CCCl
Solvent: CCO
Product: Cc1ccccc1N1CCc2c(C)nc3ccccc3c21
Yield: 43.5 %

Procedure:
2-Methyl-3-(2-chloroethyl)-4-chloroquinoline (45 g, 0.16 mol), 2-methylaniline (35 ml, 0.32 mol) and ethanol (300 ml) were heated to 150° C. in a pressure vessel for 17 hours, then concentrated in vacuo. The product crystallised as the hydrochloride salt. Conversion to free base and recrystallisation from ethyl acetate yielded 1-(2-methylphenyl)-4-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (19.1 g, 43%), m.p. 148°-150°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[NH:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22].[F:26][C:27]([F:40])([F:39])[C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32](O)=[O:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][N:12]([C:32](=[O:33])/[CH:31]=[CH:30]/[C:29]3[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=3[C:27]([F:39])([F:40])[F:26])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[NH:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:24])[CH3:23]
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Reactant: C[Si](C)(C)CCOC(=O)NC1CC2(CCNCC2)c2c(Br)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOC(=O)NC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a stirred solution of (±)-2-(trimethylsilyl)ethyl 7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate (23 mg, 0.056 mmol), ortho-(trifluoromethyl)cinnamic acid (16 mg, 0.074 mmol) and i-Pr2NEt (0.027 mL, 0.15 mmol) in CH2Cl2 (3 mL) was added solid HATU (28 mg, 0.0.074 mmol). The mixture was stirred overnight at rt and evaporated to leave a residue which was purified by preparative HPLC to afford (±)-(E)-2-(trimethylsilyl)ethyl 7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate (16.5 mg, 47%). LC-MS Method 1 tR=2.37 min, m/z=623, 625.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14].ClCC(NN)=O>C1(C(C2C=CC=CC=2)CCN2CCCNCC2)C=CC=CC=1.CO.C(Cl)Cl>[C:1]([NH:9][NH:10][C:13](=[O:14])[CH2:12][Cl:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: NNC(=O)CCl
Agent: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(CCl)NNC(=O)c1ccccc1
Yield: 54.5 %

Procedure:
1-Benzoyl-2-(chloroacetyl)hydrazine (850 mg, 54%) was prepared from benzhydrazide (1.00 g, 7.34 mmol) and chloroacetyl chloride (0.58 mL, 7.34 mmol, 1 equiv) using general procedure. Compound No. 78 (300 mg, 51%) was prepared from 1-(3,3-diphenyipropyl)homopiperazine (100 mg, 0.34 mmol) and 1-benzoyl-2-(chloroacetylhydrazine (80 mg, 0.38 mmol) employing general alkylation procedure. TLC Rf=0.44 (10% CH3OH—CH2Cl2), RPLC tR=5.85 min (>85%), 220 nm (Method B): ESI/MS m/e 471.3 (M++H, C29H34N4O2).
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[S:16])=[CH:13][CH:12]=1>CCO>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]2[S:16][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:1][N:17]=2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: NC(=S)c1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: -20 °C
Yield: 23 %

Procedure:
A solution of ethyl formylchloroacetate (1.45 g, 9.6 mmol; obtained according to Panizzi, L. Gazz. Chim.Ital., 1946, 76, 56) and 4-chlorothiobenzamide (1.76 g, 9.6 mmol) in EtOH (50 mL) was refluxed for 48 h. The reaction mixture was then cooled to -20° C. and the solid formed was filtered and dried to give ethyl 2-(4-chlorophenyl)thiazole-5-carboxylate (0.59 g, 23%): mp 144°-145° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.40 (s, 1H, thiazole), 7.92 (dt, Jt =1.8, Jd =8.6, 2H, arom), 7.44 (dt, Jt =1.8, Jd =8.6, 2H, arom), 4.39 (q, J=7, 2H, OCH2), 1.40 (t, J=7, 3H, OCH2CH3). Analysis calculated for C12H10ClNO2S: C 53.84; H 3.76; N 5.23; S 11.97. Found: C 54.22; H 3.52; N 5.25; S 11.46.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccccc1C=CCCCCCOc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccccc1CCCCCCCOc1ccccc1

Procedure:
1-(2-Methoxyphenyl)-7-phenoxy-heptane (8.3) was synthesized as described in 8.1 using 7.3 (0.35 g, 1.18 mmol), AcOEt (20 mL), and 10% Pd/C (0.050 g, 14% w/w). The title compound (8.3) was isolated as a colorless viscous liquid (0.33 g, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccc(Cl)cc1)CC(F)(F)C(F)F
Yield: 7.5 %

Procedure:
Using 1.0 g of (4-chlorobenzyl)malononitrile, 15 ml of N,N-di-methylformamide, 0.073 g of cesium carbonate, and 1.47 g of 2,2,3,3-tetra-fluoropropyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 0.12 g of 2-(4-chlorobenzyl)-2-(2,2,3,3-tetrafluoropropyl)malononitrile (the present compound (25)).