Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.[C:12]([OH:20])(=[O:19])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>>[C:12]([O:10][CH:3]1[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2]1)(=[O:19])[CH2:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17].[C:16]([O:18][CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2]1)(=[O:17])[CH2:15][CH2:14][CH2:13][C:12]([O:10][CH:3]1[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2]1)=[O:20]
Reactant: O=C(O)CCCC(=O)O
Reactant: CC1CCC(C(C)C)C(O)C1
Product: CC1CCC(C(C)C)C(OC(=O)CCCC(=O)OC2CC(C)CCC2C(C)C)C1
Product: CC1CCC(C(C)C)C(OC(=O)CCCC(=O)[O-])C1

Procedure:
The inventive process is simple to practice using conventional equipment and techniques. Menthol and excess glutaric acid are reacted under conditions effective to produce a mixture comprising monomenthyl glutarate and dimenthyl glutarate. The initial weight ratio of glutaric acid to menthol is adjusted to range from 1.0 to 1.6, preferably from 1.05 to 1.56. This provides a product mixture that comprises from 60 to 70 wt. % of MMG and from 30 to 40 wt. % of DMG.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>CN(C=O)C.O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: COCCO
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
2-Methoxyethanol (5.0 g) was added to a stirred suspension of sodium hydride (2.64 g of a 60% mineral oil suspension) in DMF (200 ml) at ambient temperature and under an atmosphere of argon. The stirred mixture was heated to 60° C. and then cooled to 5° C. Solid 4-bromobenzyl bromide (15 g) was added in one portion. The mixture was stirred for 12 hours at ambient temperature, then for 1 hour at 60° C. and cooled. The mixture was diluted with iced water (600 ml) and extracted with ethyl acetate (3×200 ml). The ethyl acetate extracts were combined, washed with 2M aqueous hydrochloric acid (100 ml), water (2×100 ml), saturated brine (100 ml), dried (MgSO4) and evaporated. The residue, an oil, was distilled using a short path distillation apparatus (furnace temperature 125° C./0.05 bar) to give 1-(4-bromobenzyloxy)-2-methoxyethane (9.8 g); NMR (CDCl3): 3.39(3H,s), 3.51(4H,m), 4.51(2H,s), 7.21(2H,d) and 7.44(2H,d).
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH2:71]([O:73][C:74](=[O:84])[C@H:75]([CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[NH2:76])[CH3:72]>ClCCl.C(N(CC)CC)C>[CH2:1]([N:8]([CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:76][C@H:75]([C:74]([O:73][CH2:71][CH3:72])=[O:84])[CH2:77][C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)=[O:20])=[CH:22][CH:23]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)ccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
A solution of 0.3 g (0.45 mmol) of trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoic acid (preparation 3), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole, of 0.175 g (0.91 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, of 0.19 ml of triethylamine and of 0.165 g (0.91 mmol) of L-phenylalanine ethyl ester hydrochloride in 5 ml of dichloromethane is stirred for 24 h. The solvents are evaporated under reduced pressure. Dichloromethane and water are added and the organic phase is washed three times with water. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The product is obtained in the form of a white solid (0.350 g, 92%) after purification on silica gel (eluent: dichloromethane/methanol 100/00 to 90/10 gradient in 35 min). [M+H+]=835
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[CH3:6][NH:7][CH:8]([CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][C:10]([OH:12])=[O:11].[CH3:26]O>>[ClH:3].[CH3:26][O:11][C:10](=[O:12])[CH2:9][CH:8]([NH:7][CH3:6])[CH:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CNC(CC(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CNC(CC(=O)OC)C(c1ccccc1)c1ccccc1

Procedure:
3 ml (40.9 mmol) of thionyl chloride are added dropwise at 0° C. to a fine suspension of 6.2 g (20.4 mmol) of 3-methylamino-4,4-diphenyl-butyric acid hydrochloride in 70 ml of methanol. After a total of 88 hours at room temperature the reaction mixture is concentrated by evaporation and ether is added. The beige precipitate is filtered off, then washed with ether and dried under a high vacuum. The title compound is obtained in the form of a beige solid. Rt (HPLC)=11.2 min; 1H-NMR (300 MHz, d6 -DMSO, RT) d 9.41 (br, 1H), 8.56 (br, 1H), 7.59-7.18 (m, 10H), 4.56 (m, 1H), 4.43 (d, 1H), 3.46 (s, 3H), 2.87 (dd, 1H), 2.64 (dd,1H), 2.40 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH:45][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)=[CH:42][CH:41]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccc(Cl)cc1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 4-chlorobenzylamine and potassium carbonate essentially as described above in example 4. Purity by LC/MS (APCI)=100%, [M+H]+=399 m/e.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31]>CN(C=O)C.C(N(CC)CC)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: C#CC(C)(C)C
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reaction time: 16 h

Procedure:
To a solution of compounds 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (500 mg, 1.09 mmol) and 3,3-Dimethyl-but-1-yne (385 mg, 4.69 mmol) in DMF (0.5 mL), triethylamine (1.06 mL) and tris(dibenzylideneacetone) dipalladium (0) (70 mg, 0.08 mmol) are added and the reaction mixture is stirred under reflux conditions for 16 h under a N2 atmosphere. DMF and triethylamine are removed under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic layer is separated, dried (Na2SO4), concentrated and the residue is purified by column chromatography using ethyl acetate and hexane (1:2) as eluent to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a solid, 330 mg (66%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Cl.[N+:13]([O-])([O-])=O.[Na+].[CH3:18][CH:19](C(C)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].[OH-].[Na+]>O.C(O)C>[CH2:23]([O:22][C:20](=[O:21])[C:19](=[N:13][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[CH3:18])[CH3:24]
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)=NNc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
4-Fluoro-2-nitroaniline (10 g, 64 mmol) was dissolved in 6N hydrochloric acid (64 ml, 0.27 mol), sodium nitrate (4.4 g, 64 mmol) dissolved in water (50 ml) was slowly added in drops at 0° C., and the mixture was stirred for 30 min at 0° C.˜room temperature. At the same time, ethyl 2-methylacetoacetate (9.2 ml, 64 mmol) and sodium hydroxide (19 g, 0.34 mol) were dissolved in 80% ethanol aqueous solution (95 ml) and stirred for 10 min at 0° C. Thus prepared two solutions were mixed and stirred for 8 h at 0° C.˜room temperature. To the reaction mixture was added water. The solid not dissolved was collected, washed with water and dried to give the title compound (7.9 g, Yield 46%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=C[CH:8]=1.C[CH:14]([S:49][C:50]1[NH:54][N:53]=[N:52][N:51]=1)[C:15]1[CH2:16][S:17][C@@H:18]2[C@H:38]([NH:39]C(=O)CC3SC=CC=3)[C:37](=[O:48])[N:19]2[C:20]=1[C:21]([O:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].CO>C(Cl)Cl>[NH2:39][C@@H:38]1[C:37](=[O:48])[N:19]2[C:20]([C:21]([O:23][CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:15]([CH2:14][S:49][C:50]3[N:54]([CH3:8])[N:53]=[N:52][N:51]=3)[CH2:16][S:17][C@H:18]12
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: c1ccncc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Yield: 81.5 %

Procedure:
A suspension of phosphorus pentachloride (416 mg) in dry methylene dichloride (10 ml.) was stirred at 23° and a solution of pyridine (0.16 ml) added. The warm suspension was stirred for 10 minutes, and cooled to 0°, and treated, over 10 minutes, with a solution of diphenylmethyl 3-(1-methyltetrazol-5-ylthiomethyl)-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate (619 mg) in methylene dichloride (15 ml.). After stirring for a further 45 minutes, during which time the temperature was allowed to rise to 23°, the solution was added, over 5 minutes, to a stirred and cooled (0°) mixture of methanol (5 ml.) and methylene dichloride (15 ml.). The resulting solution was stirred for a further 10 minutes, and washed with N-hydrochloric acid (20 ml.), and stirred for 30 minutes with saturated sodium bicarbonate sodium (50 ml.). The organic phase was separated, and washed with saturated aqueous sodium bicarbonate (25 ml.), and treated with some charcoal. The mixture was filtered through a pad of kieselguhr, and the filtrate evaporated to a gum (640 mg.), which was triturated with ether (20 ml) to give the amine as an off-white solid (403 mg, 81.5%), λmax. (CHCl3) 268.5 nm (ε 7,700), νmax. (CHBr3) 3416 and 3350 (NH2), 1780 (β-lactam), and 1720 cm.-1 (CO2R), τ (CDCl3) values include 5.00 and 5.15 (C-6H and C-7 H, two doublets, J 5 Hz.), 6.14 (CH3 --), and 7.59 (NH2).
Reaction SMILES: CN(C)C=O.[CH3:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]([C:26]23[O:33][CH2:32][C:29]([CH3:34])([CH2:30][O:31]2)[CH2:28][O:27]3)[CH:11]1[CH3:35])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[CH3:51]>C(OCC)(=O)C>[CH3:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:43][C:44]3[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=3[CH3:51])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]([C:26]23[O:33][CH2:32][C:29]([CH3:34])([CH2:28][O:27]2)[CH2:30][O:31]3)[CH:11]1[CH3:35])=[O:9]
Reactant: Cc1ccc(F)cc1CBr
Reactant: CNC(=O)N1CCN(S(=O)(=O)c2ccc(O)cc2)C(C23OCC(C)(CO2)CO3)C1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3cc(F)ccc3C)cc2)C(C23OCC(C)(CO2)CO3)C1C
Temperature: 45 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
To a N,N-dimethylformamide (1.5 ml) solution of 4-(4-Hydroxy-benzenesulfonyl)-2-methyl-3-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazine-1-carboxylic acid methylamide (compound of formula XLV, 0.31 g, 0.7 mmol) was added cesium carbonate (0.45 g) and 2-bromomethyl-4-fluoro-1-methyl-benzene (0.214 g, 1.05 mmol). The reaction mixture was stirred at about 45° C. for about 16 hours and then was allowed to cool and was diluted with ethyl acetate and washed with water. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 0.377 g of a compound of formula XLIV.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[O:12])[CH:10]=1)[C:5](O)=[O:6].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:45][C@@H:46]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C@H:47]([OH:61])[CH2:48][NH:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=1.CCN(C(C)C)C(C)C.O1C2C=CC=CC=2C=C1CNC(=O)OC(C)(C)C>C(Cl)Cl.C(OCC)(=O)C>[OH:61][C@H:47]([CH2:48][NH:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:58])([F:59])[F:60])[CH:52]=1)[C@@H:46]([NH:45][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[O:12])[CH:10]=[C:2]([CH3:1])[CH:3]=1)[CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(C(=O)O)cc(C(=O)N2CCC[C@@H]2c2nc(C)cs2)c1
Agent: CC(C)(C)OC(=O)NCc1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(C(F)(F)F)c2)cc(C(=O)N2CCC[C@@H]2c2nc(C)cs2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To (R)-3-methyl-5-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzoic acid (330 mg, 1 mmol) in CH2Cl2 at rt, EDCI (269 mg, 1.4 mmol) and HOBT (162 mg, 1.20 mmol) were added and stirred at rt for 20 min. In a separate flask (2R,3S)-3-amino-4-phenyl-1-(3-(trifluoromethyl)benzylamino)butan-2-ol was taken in CH2Cl2 and treated with DIPEA (2 ml). After 20 min, flask containing acid was cooled to 0° C. and the amine was added to it. Reaction mixture was stirred at rt for 16 h. Then reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate, water, brine and dried. Crude residue was purified by column chromatography to yield 60% of desired product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[H-].[Na+].[CH2:11]1[O:33][C:32]2[CH:31]=[CH:30][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[S:26](Cl)(=[O:28])=[O:27])=[CH:14][C:13]=2[O:12]1>C1COCC1>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:26]([C:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[S:21][C:17]=2[CH2:16][C:15]2[CH:30]=[CH:31][C:32]3[O:33][CH2:11][O:12][C:13]=3[CH:14]=2)(=[O:28])=[O:27])[O:4][N:3]=1
Reactant: Cc1noc(N)c1C
Reactant: O=S(=O)(Cl)c1c(Cc2ccc3c(c2)OCO3)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc4c(c3)OCO4)sc3ccccc23)c1C

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)-2-(3,4-methylenedioxybenzyl)benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 3,4-dimethyl-5-aminoisoxazole (1.0 mmoles, 0.11 g), NaH (2.5 mmoles, 60 mg) and 2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonylchloride (1.1 mmoles, 0.40 9) in THF (6 ml) yielded, after flash chromatography using 50% ethyl acetate/hexanes followed by recrystallization from chloroform and hexanes, 0.35 g (79%) of a tan solid, m.p. 135-137° C.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[Cl:33].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:28]2[C:27]([Cl:33])=[C:26]([O:25][CH2:24][O:23][CH3:22])[CH:31]=[CH:30][C:29]=2[O:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][O:23][CH3:22])=[C:27]([Cl:33])[C:28]=2[CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(CBr)cc1
Reactant: COCOc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(Cc2c(Oc3ccc(OCOC)c(Cl)c3Cc3ccc(OCCCCCCCCCCCC)cc3)ccc(OCOC)c2Cl)cc1
Yield: 58.7 %

Procedure:
In dimethylformamide, 2 g of 4-dodecyloxybenzyl bromide synthesized in the same manner as described in Referential Example 17 was reacted with 1.5 g of 4-methoxymethyloxy-3-chlorophenol synthesized in the same manner as described in Example 11 in the presence of NaH to obtain 1.5 g of 4-dodecyloxybenzyl(4-methoxymethyloxy-3-chlorophenyl) ether. According to customary procedures, the methoxymethyl group was removed from the so-obtained compound in the presence of zinc in acetic acid to obtain 1.2 g of 4-dodecyloxybenzyl(4-hydroxy-3-chlorophenyl) ether.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:7]([O:28][CH3:29])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)=[C:18]([C:25](=[O:27])[CH3:26])[CH:19]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Oc2ccnc3cc(OCCCCl)c(OC)cc23)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccnc3cc(OCCCN4CCOCC4)c(OC)cc23)c(C(C)=O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
1-(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methoxyphenyl)-1-ethanone (compound 121) (100 mg), morpholine (63 mg), and potassium carbonate (166 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (55 mg, yield 49%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:41])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH:24]([CH3:40])[CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32]C(=O)OC(C)(C)C)[CH:27]=3)=[CH:15][CH:14]=2)[N:7]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][C:28]1[CH:27]=[C:26]([CH2:25][CH:24]([O:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([NH:12][C:11]([NH:10][C:8]3[N:7]([C:42]4[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=4)[N:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:9]=3)=[O:41])=[CH:14][CH:15]=2)[CH3:40])[CH:31]=[CH:30][N:29]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OC(C)Cc3ccnc(NC(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OC(C)Cc3ccnc(N)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
To a stirred solution of the tert-butyl carbamate (50) (158 mg, 0.244 mmol) in DCM (4 mL) at 0° C. under nitrogen was added TFA (2 mL). After 5 min the reaction mixture was warmed to RT and stirred for a further 2 hr. The mixture was evaporated in vacuo and the residue was subjected to SCX capture and release to afford the title compound (Intermediate J) (138 mg, >100%): m/z 549 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:17]([NH2:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>C(#N)C>[CH2:17]([NH:24][CH:13]1[CH2:12][C:11](=[O:16])[N:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:14]1=[O:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCN
Reactant: CCCCCCCCCN1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCN1C(=O)CC(NCCCCCCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-nonyl maleimide (0.01 M) prepared as described in Example 12 above, heptylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]([CH3:54])([CH2:52][CH3:53])[CH2:12][C:13]1[N:14]=[C:15]([CH2:37][CH:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[CH:42][CH:41]=2)O)[N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][C:11]([CH3:54])([CH2:52][CH3:53])[CH2:12][C:13]1[N:14]=[C:15]([CH2:37][CH:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[CH:42][CH:41]=2)[F:7])[N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)c2ccc(-c3ccccn3)cc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(F)c2ccc(-c3ccccn3)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diethylaminosulfur trifluoride (0.1 mL, 0.78 mmol) was added to a 0° C. solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-(4-pyridin-2-ylphenyl)ethanol (385 mg, 0.65 mmol) in methylene chloride (10 mL). After stirring at 0° C. for 30 min then warming to ambient temperature then letting sit at −20° C. overnight, triethylamine (1 mL) was added. After stirring for a further 5 min, the reaction mixture was concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 2-(4-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-fluoroethyl}phenyl)pyridine.