Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:8]([OH:11])[CH2:9][CH3:10])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1
Reactant: CCC(O)c1cc(Cl)ccc1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
A mixture of 1-(5-chloro-2-fluorophenyl)propan-1-ol (850 mg, 4.5 mmol) and pyridinium chlorochromate (1.7 g, 7.9 mmol) in methylene chloride (30 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with methylene chloride (20 mL), filtered over Celite, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-30% ethyl acetate in heptane) to afford the title compound as a pale yellow oil (550 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.38 (dd, J=8.8, 4.8 Hz, 1H), 7.16 (dd, J=8.3, 3.0 Hz, 1H), 7.09 (ddd, J=8.8, 7.7, 3.0 Hz, 1H), 2.95 (q, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[ClH:15]>CS(C)=O>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: Cl
Reactant: COc1ccc(Br)c2c1CCC(=O)N2
Solvent: CS(C)=O
Product: COc1ccc(Cl)c2c1CCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
22.7 grams of 8-bromo-5-methoxy-3,4-dihydrocarbostyril and 25 g of cuprous chloride are mixed with 100 ml of dimethyl sulfoxide and heated at 135°-140° C. for 4 hours under stirring conditions. After the reaction is completed, the reaction mixture is mixed with 200 g of ice and 50 ml of concentrated hydrochloric acid and stirred at a room temperature for 1 hour. The crystals thus precipitated are separated by filtration, washed first with diluted hydrochloric acid and then with water and dried. The crude crystals thus obtained are recrystallized from ligroin-benzene to obtain 13 g of 8-chloro-5-methoxy-3,4-dihydrocarbostyril in the form of pale organic needle-like crystals with a melting point of 165° C.
Reaction SMILES: [Cl:1][CH:2]([Cl:21])[C:3]([F:20])([F:19])[O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([S:14](Cl)(=[O:16])=[O:15])=[C:7]([CH3:18])[CH:6]=1.[C:22](#[N:25])[CH:23]=[CH2:24].Cl.C(N(CC)CC)C>C(#N)C>[Cl:1][CH:2]([Cl:21])[C:3]([F:20])([F:19])[O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([S:14]([CH:24]=[CH:23][C:22]#[N:25])(=[O:16])=[O:15])=[C:7]([CH3:18])[CH:6]=1
Reactant: Cc1cc(OC(F)(F)C(Cl)Cl)c([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: C=CC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OC(F)(F)C(Cl)Cl)c([N+](=O)[O-])cc1S(=O)(=O)C=CC#N
Yield: 10.4 %

Procedure:
In a 100 ml Fisher-Porter pressure vessel were placed 9.0 g (0.024 mol) of 4-(2,2-dichloro-1,1-difluoroethoxy)-2-methyl-5-nitrobenzenesulfonyl chloride, 2.4 g (0.048 mol) acrylonitrile, 2 ml acetonitrile, 0.07 g cupric chloride and 0.12 g triethylamine hydrochloride. After cooling and evacuating the vessel to 5 mm mercury pressure, it was sealed and heated in an oil bath at 105°-110° C for 38 hours. The vessel was opened and the reaction medium was filtered with the aid of benzene. The insolubles were discarded and the filtrate was treated with 5.0 g of triethylamine, refiltered, and washed with water. After decolorizing wth charcoal and drying over MgSO4, removal of the solvent under reduced pressure afforded a dark amber oil. Recrystallization from methanol provided 1.0 g of the title compound as a white solid, m.p. 109° C.
Reaction SMILES: [Li+].[O-][Al:3]=O.[O-2].[Al+3].[O-2].[O-2].[Al+3].[N+:10]([O-:13])([OH:12])=[O:11]>>[N+:10]([O-:13])([O-:12])=[O:11].[Al+3:3].[N+:10]([O-:13])([O-:12])=[O:11].[N+:10]([O-:13])([O-:12])=[O:11]
Reactant: O=[Al][O-]
Reactant: O=[N+]([O-])O
Agent: [Al+3]
Agent: [Li+]
Agent: [O-2]
Product: O=[N+]([O-])[O-]

Procedure:
A preferred method of preparing the composition of the present invention is to first prepare lithium aluminate powder. This powder may be advantageously prepared using sol-gel techniques so that uniformly sized particles with known properties are achieved. Briefly, aluminium oxide is dissolved in nitric acid to form an aluminum nitrate solution. The aluminum nitrate solution is then reacted with ammonia to return aluminum oxide, now in the form of an alumina sol. At this point, a stoichiometric amount of a soluble lithium compound is added to the solution. Depending upon the neutronic characteristics of the reactor, it may be desirable to use lithium fully enriched in the lithium isotope. The alumina sol-lithium mixture is then added dropwise into a bath of solvent which is at least partially immiscible in the alumina sol. As part of the moisture present in the sol is extracted into the solvent, the sol is converted into perfect spheres of a gel. Through appropriate sizing of the drop-forming means, such as a vibrating nozzle, the resulting particles will be sized between 100 and 500 micrometers. The microspheres may then be heated to drive off remaining moisture and then heated to a high temperature to form the compound lithium aluminate.
Reaction SMILES: [Mg].CI.[CH3:4][C:5]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:6]=1C#N.CC[O:16][CH2:17][CH3:18]>>[Br:11][C:10]1[C:5]([CH3:4])=[C:6]([C:17](=[O:16])[CH3:18])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: Cc1c(Br)cccc1C#N
Agent: [Mg]
Solvent: CI
Product: CC(=O)c1cccc(Br)c1C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 7.3 parts of magnesium, 52.6 parts of methyl iodide in 160 parts of ether, is added dropwise a solution of 19.6 parts of 3'-bromo-2'-methylbenzonitrile in 40 parts of ether. Upon completion, stirring at reflux is continued for 20 hours. The reaction mixture is cooled to 0° C and poured onto 500 parts of ice-water while stirring vigorously. The ethereal phase is separated, dried and evaporated. The residue is boiled in 60 parts of a 6N hydrochloric acid solution for 10 minutes. The separated oil is extracted with ether. The extract is washed with water, dried and evaporated. The residue is distilled, yielding 3'-bromo-2'-methylacetophenone; bp. 125°-128° C at 10 mm. pressure.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(/[CH:15]=[CH:16]/CC#N)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.[C:21]([O:24][CH2:25]C)(=[O:23])[CH3:22]>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(/[CH:15]=[CH:16]/[CH2:22][C:21]([O:24][CH3:25])=[O:23])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(C)=O
Reactant: N#CC/C=C/C1(c2ccc(F)cc2)CCCCC1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)C/C=C/C1(c2ccc(F)cc2)CCCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
HCl gas was bubbled through a solution of (E)-4-(1-(4-fluorophenyl)cyclohexyl)but-3-enenitrile (Intermediate I-11B, 769 mg, 3.16 mmol) in anhydrous methanol (20 mL), and the mixture was stirred in a sealed tube at 60° C. for 1 hr. After cooling, about 10 mL of water was added and the mixture was stirred at room temperature overnight. The mixture was then added to ethyl acetate and washed with water, brine dried over sodium sulfate and concentrated under reduced pressure to give the (E)-methyl 4-(1-(4-fluorophenyl)cyclohexyl)but-3-enoate (560 mg, 2.03 mmol, 64.1% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.30 (2H, dd, J=9.02, 5.28 Hz), 6.99 (2H, t, J=8.80 Hz), 5.51-5.56 (1H, m), 5.35-5.45 (1H, m), 3.68 (3H, s), 3.05 (2H, dd, J=6.82, 1.10 Hz), 1.90-2.00 (2H, m), 1.79-1.88 (2H, m), 1.45-1.63 (6H, m).
Reaction SMILES: [C:1]([C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5])#[N:2].[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[C:1]([C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:8][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[C:4]([F:7])([F:5])[F:6])#[N:2]
Reactant: N#CC(O)(c1ccccc1)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OC(C#N)(c2ccccc2)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 70.9 %

Procedure:
5.2 g (25 mmol) of 1-cyano-2,2,2-trifluoro-1-phenyl-ethanol were dissolved in 50 ml of DMF, and 0.9 g (30 mmol) of sodium hydride (80% strength dispersion in mineral oil) was added. 5.5 g (29 mmol) of toluene-4-sulfonyl chloride were added in portions to the virtually clear solution after about 1 hour. The mixture was stirred for 8 hours, allowed to stand overnight and then poured into water. The oily liquid which separated out solidified on cooling. The solid was filtered off with suction and dried. 6.3 g of 1-cyano-1-phenyl-1-(toluene-4-sulfonyloxy)-2,2,2-trifluoroethane were obtained (colorless crystals, m.p.: 70° C. [from ligroin]).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Reactant: ClCc1coc(-c2ccccc2)n1
Product: c1ccc(-c2nc(COc3cccc(CCCn4ccnc4)c3)co2)cc1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-phenyloxazole to give 4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenyloxazole. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 62-63° C.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([OH:41])[CH2:22][O:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH2:66]([CH2:80][C:81](O)=[S:82])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]>ClCCl>[CH2:1]([O:19][CH:20]([C:81](=[S:82])[CH2:80][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[CH:21]([CH2:22][O:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[OH:41])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(O)COC(=O)CCCCCCCCCCCCCCC
Reactant: CCCCCCCCCCCCCCCC(O)=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOC(C(=S)CCCCCCCCCCCCCCC)C(O)COC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
3-oleyl-1-palmitoylglycerol (2 g, 0.003 mol) was dissolved in dichloromethane (150 ml) and dicyclohexylcarbodiimide (1.040 g, 0.005 mol), dimethylaminopyridine (0.616 g, 0.005 mol) and tetradecylthioacetic acid (1.455 g, 0.005 mol) were then added. The mixture was stirred at room temperature for 24 hours. The dicyclohexylurea precipitate was filtered, washed with dichloromethane and the filtrate was concentrated. The residue obtained was purified by silica gel chromatography (eluent:CH2Cl2-cyclohexane 4:6) to give the desired compound as an oil (yield: 49%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)C(C)C)(C)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:19])[CH3:18]
Reactant: O=C1CNCCN1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCNC(=O)C1
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of piperazin-2-one (2.50 g, 24.9 mmol) and N,N-diisopropylethylamine (4.78 mL, 27.5 mmol) in methylene chloride (50 mL) under an atmosphere of nitrogen, acetic anhydride (2.47 mL, 26.2 mmol) was added and stirred at the temperature for overnight. The resultant solution was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 90:10:1 mixture of chloroform, methanol, and ammonium hydroxide. Collection and concentration of appropriate fractions provided the title product.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)=[O:3].[N+:12]([O-])([OH:14])=[O:13]>O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[N+:12]([O-:14])=[O:13])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(C(C)=O)c1
Solvent: O
Product: COc1cccc(C(C)=O)c1[N+](=O)[O-]
Reaction time: 17 h

Procedure:
50.0 g of 3-methoxyacetophenone was added slowly, drop-by-drop, to 250 ml of 70% nitric acid at room temperature. The mixture was allowed to stand for 17 hours, warmed and held at 40° C. for 1 hour, cooled and diluted to three times its volume with water. The resulting mixture was extracted with ethyl acetate. The extract was washed with water, then with saturated sodium chloride solution, dried (Na2SO4) and the solvent was evaporated. The residue was dissolved in ethyl acetate, hexane was added and the mixture was set in dry ice. The solid that formed was collected and dried under reduced pressure to give 3-methoxy-2-nitroacetophenone (4A), as a cream-colored solid, m.p.: 125°-127°C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].N1C=CN=C1.[Si:60](Cl)([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 30.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (1.04 g) in dry methylene chloride (25 ml) was added an excess of imidazole (280 mg) followed by tert-butyldimethylsilyl chloride (228 mg). After 21 hours of stirring at room temperature, the mixture was quenched by the addition of half-saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and purified by flash chromatography (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (370 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[N:4][N:3]=[N:2]1.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:33][CH2:32]1)[CH3:17]>>[N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([N:41]2[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:34]3[CH2:35][CH2:36][CH:31]([NH:30][C:22]4[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=4)[CH2:32][CH2:33]3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:40]2)=[O:11])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)c1cccc(-n2cnnn2)c1
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cccc(-n5cnnn5)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 3-(1H-tetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [C:1]1(=[O:11])O[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:25])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[CH2:23]([N:24]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:5])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:25]1[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]2[C:1]1=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCCCCCCCCCCN
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCN1C(=O)c2ccccc2C1=O

Procedure:
N,N'-dodecylene bis-phthalimide was prepared from phthalic anhydride and 1,12-dodecanediamine as follows:
Reaction SMILES: S(=O)(=O)(O)N.[O:6]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl([O-])=[O:22].[Na+]>O.CC(C)=O>[O:6]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:22])=[O:18])=[CH:19][CH:20]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Sulfamic acid (7.35 g, 75.7 mmol) in water (5 mL) was added to a stirred solution of 4-phenoxy benzaldehyde (5 g, 25.23 mmol) in acetone (25 mL) at 4° C. Sodium chlorite (9.13 g, 100.9 mmol) in water (5 mL) was then added slowly resulting in formation of a yellow solid with effervescence. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then diluted with cold water and the product extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford 4 g (74% yield) of 4-phenoxy benzoic acid. 1H NMR (DMSO): δ 7.98-7.92 (d, 2H), 7.5-7.44 (t, 2H), 7.28-7.2 (t, 1H), 7.16-7.1 (d, 2H), 7.06-7.0 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH3:21].S(Cl)(Cl)=O.[CH:26]1[CH:27]=[CH:28][N:29]2[CH2:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[NH:32][CH2:31][C:30]=12.C(N(CC)CC)C>O1CCCC1.ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH3:21])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:8]([N:32]2[C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[CH2:35][N:29]3[CH:28]=[CH:27][CH:26]=[C:30]3[CH2:31]2)=[O:10])[CH:7]=1
Reactant: CCOc1ccccc1-c1cc(OC)c(C(=O)O)cc1Cl
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1cc(OC)c(C(=O)N2Cc3cccn3Cc3ccccc32)cc1Cl
Reaction time: 2 h

Procedure:
To a stirred solution of the 2-chloro-2′-ethoxy-5-methoxy[1,1′-biphenyl]-4-carboxylic acid of Step A (0.491 g) in tetrahydrofuran (5 mL) containing a catalytic amount of N,N-dimethyl formamide was added dropwise thionyl chloride (0.210 g, 1.76 mmol). The reaction mixture was stirred for 2 hours, and then added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.294 g, 1.60 mmol) in tetrahydrofuran (5 mL) containing triethylamine (0.357 g, 3.52 mmol). The reaction mixture was stirred for 2 hours, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Trituration of the residue with methanol provided the title compound as an off-white solid, 99.24% pure by analytical HPLC [Primesphere C-18 column (2.0×150 mm); mobile phase 70/30 acetonitrile/water containing 0.1% phosphoric acid], m.p. 213–215° C.
Reaction SMILES: Cl.[N:2]1([C:17](=[O:30])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:7][CH2:6][C:5]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][CH2:8]2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].Cl>C(Cl)Cl>[CH3:40][S:41]([N:9]1[CH2:8][C:5]2([CH2:6][CH2:7][N:2]([C:17](=[O:30])/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:27])[F:29])[CH2:3][CH2:4]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(/C=C/c1ccccc1C(F)(F)F)N1CCC2(CC1)CNCc1ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2ccccc2C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A solution of (E)-1-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one HCl salt (40 mg, 0.09 mmol) in CH2Cl2 (4 mL) was treated with i-Pr2NEt (0.05 mL, 0.28 mmol) and MeSO2Cl (0.014 mL, 0.18 mmol). The mixture was stirred overnight at rt and applied to a 10-mL Chem-Elut cartridge that had been wetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was concentrated and the residue was purified by prep HPLC to afford (E)-1-(2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (20 mg, 45%). 1H NMR (CDCl3) 1.77 (m, 1H), 1.88 (m, 1H), 2.04 (m, 1H), 2.13 (m, 1H), 2.92 (s, 3H), 3.00 (m, 1H), 3.23 (m, 1H), 3.47 (m, 1H), 3.90 (m, 1H), 4.02 (m, 1H), 4.37 (m, 1H), 4.59 (m, 1H), 4.78 (d, 1H), 6.82 (d, 1H), 7.05-7.75 (8H), 7.99 (d, 1H).
Reaction SMILES: C1(S(O[CH2:11][CH2:12][C:13]2([OH:29])[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Cl:27])=[CH:21][C:20]=3[Cl:28])[CH2:15][CH2:14]2)(=O)=O)C=CC=CC=1.[Br-:30].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[Br:30][CH2:11][CH2:12][C:13]1([OH:29])[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Cl:27])=[CH:21][C:20]=2[Cl:28])[CH2:15][CH2:14]1
Reactant: COc1cc(N2CCC(O)(CCOS(=O)(=O)c3ccccc3)CC2)c(Cl)cc1Cl
Reactant: [Br-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(N2CCC(O)(CCBr)CC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 40.8 %

Procedure:
A solution of 2-(1-(2,4-dichloro-5-methoxyphenyl)-4-hydroxypiperidin-4-yl)ethyl benzenesulfonate (300 mg, 0.652 mmol) in acetone (5 mL) was treated with potassium bromide (194 mg, 1.629 mmol) and 18-crown-6 (189 mg, 0.717 mmol). The mixture was stirred at RT for 60 h before being concentrated in vacuo. The resultant residue was dissolved in EtOAc, and the resultant solution was washed with brine, dried (Na2SO4), and concentrated to give a residue. This residue was purified by a flash column using 0-30% EtOAc in heptanes as eluent to give 4-(2-bromoethyl)-1-(2,4-dichloro-5-methoxyphenyl)piperidin-4-ol (102 mg, 0.266 mmol, 41% yield) as a yellow oil.