Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[C-:25]#[N:26].[Na+].CCCCCC.CCOC(C)=O>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:11][C:9]1[CH:10]=[C:2]([C:25]#[N:26])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: Cc1cc(C#N)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
A mixture of 5-bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.600 g, 1.5 mmol), Pd(PPh3)4 (0.175 g, 0.14 mmol), sodium cyanide (0.163 g, 3.4 mmol), and CuI (0.029 g, 0.15 mmol) in acetonitrile (6 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane-EtOAc) afforded 7-methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile (0.491 g, 95%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.78 (s, 3H), 4.26 (s, 2H), 4.79 (s, 2H), 7.18 (d, 2H), 7.35 (d, 2H), 7.52 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][NH2:12].S([O-])([O-])(=O)=O.[Mg+2].CC1C=CC(S([CH2:29][N+:30]#[C-:31])(=O)=O)=CC=1>ClCCl>[C:2]([C:5]1[N:12]([CH2:11][CH2:10][CH2:9][O:8][CH3:7])[CH:31]=[N:30][CH:29]=1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C=O
Reactant: COCCCN
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COCCCn1cncc1C(C)(C)C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
Into a 50 mL round bottomed flask was added pivaldehyde (500 mg, 5.8 mmol), 3-methoxypropylamine (569 mg, 6.4 mmol) and magnesium sulfate. Dichloromethane (20 mL) was added and the mixture was stirred overnight under nitrogen. The mixture was filtered through a pad of Celite and the solvent was removed form the filtrate under vacuum. The residue was dissolved in methanol (10 mL); 3-methoxypropylamine (466 mg, 5.2 mmol) and TOSMIC (942 mg, 4.8 mmol) was added and the mixture was again stirred overnight. Solvent was removed under vacuum, and the residue was purified by preparatory LC/MS (10-25% CH3CN in H2O) to give 5-tert-butyl-1-(3-methoxypropyl)-1H-imidazole (133A) as a yellow oil (376 mg, 40% yield). ESI-MS:m/z 197.4 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:9][SiH:10]([CH3:12])[Cl:11]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([Si:10]([CH3:12])([CH3:9])[Cl:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C[SiH](C)Cl
Reactant: C=CCCCCCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](C)(C)Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
123 g (1.1 mol) 1 -octene and 100 microliters of a 2% toluene solution of chloroplatinic acid were placed in a 500-mL four-neck flask equipped with a stirrer, thermometer, addition funnel, and condenser and were heated to 70° C. After the temperature had been raised, the heating mantle was removed and 94.5 g (1 mol) dimethylchlorosilane was added dropwise from the addition funnel. Heat generation was observed immediately, and the dropwise addition was carried out gradually so as to avoid having the temperature of the reaction solution exceed 80° C. After the completion of this addition, the reaction was continued for 30 minutes at 80° C. Gas chromatographic analysis of the resulting reaction solution gave 88% octyldimethylchlorosilane. The reaction solution was cooled to room temperature and 200 g toluene was introduced. The addition funnel was then replaced with a Teflon tube and ammonia was bubbled in until the pH of the reaction solution reached 10. The ammonium chloride product was removed by filtration, and the filtrate was then distillatively purified at 160° C./0.5 mmHg to obtain the following disilazane in a purity of 98 weight %.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[F:37]>CC#N>[F:37][C:29]1[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:28]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 51.3 %

Procedure:
A solution of 6,7-dimethoxyquinolin-4-ol (50 g, 0.244 mol) and Cs2CO3 (159 g, 0.488 mol) in CH3CN (300 mL)/DMF (300 mL) was stirred at room temperature for 30 min. 1,2-Difluoro-4-nitrobenzene (42.7 g, 0.268 mol) was then added dropwise. After stirring at rt for 3.5 h, the reaction solution was concentrated in vacuo. Ice (500 mL) was added to the residual suspension and the mixture was stirred overnight for precipitation. The solid was collected by filtration and further purified by a silica gel column chromatography (EtOAc) to give the title compound as a pale yellow powder (43.1 g, 51.2%).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:16]2[C:11](=[C:12]([OH:31])[C@:13]3([OH:30])[C:21](=[O:22])[C:20]([C:23]([NH2:25])=[O:24])=[C:19]([OH:26])[C@@H:18]([N:27]([CH3:29])[CH3:28])[C@@H:14]3[C@H:15]2[OH:17])[C:9](=[O:10])[C:8]2[C:7]([OH:32])=[CH:6][CH:5]=[CH:4][C:3]1=2.C1(C)C=CC([S:39]([O-:42])(=[O:41])=[O:40])=CC=1.C(N(CC)CC)C.C([OH:53])C>O>[CH3:1][C@@H:2]1[C@@H:16]2[C:11](=[C:12]([OH:31])[C@:13]3([OH:30])[C:21](=[O:22])[C:20]([C:23]([NH2:25])=[O:24])=[C:19]([OH:26])[C@@H:18]([N:27]([CH3:28])[CH3:29])[C@@H:14]3[C@H:15]2[OH:17])[C:9](=[O:10])[C:8]2[C:7]([OH:32])=[CH:6][CH:5]=[CH:4][C:3]1=2.[S:39]([O:22][C:21]1[C:20](=[CH:19][CH:18]=[CH:14][CH:13]=1)[C:23]([O-:24])=[O:53])([OH:42])(=[O:41])=[O:40]
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: C[C@H]1c2cccc(O)c2C(=O)C2=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3[C@@H](O)[C@@H]21
Solvent: O
Solvent: CCN(CC)CC
Product: O=C([O-])c1ccccc1OS(=O)(=O)O

Procedure:
Doxycycline p-toluenesulphonate (40.0 g) prepared according to the process above was suspended in a mixture of ethanol (72.0 ml) and water (24.0 ml), with stirring. A solution of triethylamine (9.04 ml) in ethanol (9.04 ml) was added, causing dissolution followed by crystallisation. After stirring for 20 minutes, ethanol (144 ml) was added and the mixture stirred for a further 1 hour 30 minutes. The crystals were filtered, washed with ethanol (25 ml), then with acetone (12.5 ml) and dried at 35° C. The product, doxycycline monohydrate, weighed 22.12 g and complied with the U.S. Pharmacopoeia monograph requirements. The mother liquors were diluted with an equal volume of water and 5-sulphosalicylic acid (2.0 g) was added. After stirring overnight, the deposited solid was filtered, washed with 66% aqueous methanol and then with acetone, dried at 35° C., and gave 1.53 g of doxycycline sulphosalicylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[N:6][C:5]=1[NH2:12].[C-:14]#[N:15].C([Al+]CC)C.C1(C)C=CC=CC=1.[Cl-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:14]#[N:15])=[N:6][C:5]=1[NH2:12]
Reactant: C=Cc1ccc(C(=O)OC)c(N)n1
Reactant: [C-]#N
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC#N)nc1N
Reaction time: 8 h
Yield: 21 %

Procedure:
To a solution of 2-amino-6-vinyl-nicotinic acid methyl ester (760 mg, 4.26 mmol) in tetrahydrofuran (76 mL) was added a solution of diethyl aluminum cyanide in toluene (12.8 mL, 12.8 mmol) dropwise under sodium chloride—an ice bath cooling, at an internal temperature of −5° C. or below, then, the solution was gradually allowed to room temperature and stirred overnight. The reaction solution was partitioned into an aqueous solution of saturated ammonium chloride and ethyl acetate. This organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography, and the title compound (180 mg, 0.878 mmol, 21%) was obtained as a yellow oil.
Reaction SMILES: C[Mg]Br.Cl.[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1.[CH2:24](OCC)[CH3:25]>>[CH3:18][C:13]1[CH2:11][C:5]2[C:10]([CH:14]=1)=[C:9]([CH2:24][CH3:25])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOCC
Reactant: Cc1ccccc1
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Product: CCc1cccc2c1C=C(C)C2
Temperature: 25 °C

Procedure:
140 ml (420 mmol) of a 3 M ethereal methylmagnesium bromide solution were added to a solution of 22.4 g (140 mmol) of a3 in 500 ml of diethyl ether at room temperature under Ar protection in the course of 1 hour. The mixture was then stirred under reflux at room temperature for another 2 hours, and was stirred at room temperature for a further 15 hours. The mixture was poured onto ice acidified with HCl, and extracted with ether. After the extract had been dried over sodium sulfate, the solvent was stripped off. The yellow oil which remained (20.3 g) was taken up in 800 ml of analytical grade toluene, 2.2 g (11.5 mmol) of p-toluenesulfonic acid hydrate were added and the mixture was refluxed for 45 minutes. After cooling, the solution was washed several times with water, dried over sodium sulfate and evaporated. The residue was chromatographed on 620 g of silica gel 60.5.5 g (25%) of the indene a4 (yellowish oil) could be eluted with hexane/methylene chloride (20:1). Still unused starting material a3 could be recovered with hexane/ethyl acetate (9:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)(=[O:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: c1c[nH]cn1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)n1ccnc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
2.36 g of 5-nitro-2-methyl-phenylsulfonyl chloride (0.01 mol) and 1.36 g of imidazole (0.02 mol) were dissolved in 15 ml of pyridine, and the mixture was stirred at 50° C. for 3 hours to react. After the reaction, the reaction mixture was poured into water, and extracted with chloroform. The chloroform layer was washed with water and dehydrated. Evaporation of chloroform gave 1.70 g of 1-(5-nitro-2-methyl-phenylsulfonyl)-imidazole of the m.p. 119°-120° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[NH2:14]>C(O)C>[NH2:12][C:11]1[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:14]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccccn1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccccn2)c1N
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A solution of ethyl 2-(ethoxymethylene)-2-cyanoacetate (33.8 g, 200 mmol) and 2-hydrazinopyridine (21.8 g, 200 mmol) in ethanol (100 mL) was heated under reflux for 20 minutes. The solution was cooled to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and air dried to give the title compound (33.8 g, 73% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:32])[CH:16]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33].Cl.N1(C(C2C=CC=CC=2)C(O)CN2CCN(C)CC2)C2C(=CC=CC=2)C=C1.C(OC(N1CCNCC1)=O)(C)(C)C.Cl.O1CCOCC1>C(OCC)C>[ClH:33].[ClH:33].[N:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]([OH:32])[CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)C(c2ccccc2)n2ccc3ccccc32)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN1CCN(CC(O)C(c2ccccc2)n2ccc3ccccc32)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: OC(CN1CCNCC1)C(c1ccccc1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In an analogous manner to EXAMPLE 1, step 3 (2SR,3RS)-4-(2-hydroxy-3-indol-1-yl-3-phenyl-propyl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from (2RS,3RS)-toluene-4-sulfonic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3, 0.211 g, 0.5 mmol) and tert-butyl-1-piperazine carboxylate (0.19 g, 1.0 mmol). The product was dissolved in diethyl ether (3 mL) and treated with a 4N solution of hydrochloric acid in dioxane (0.75 mL, 3.0 mmol). The reaction mixture was then stirred at room temperature for 15 hours, and the crude solid product was filtered and recrystallized from ethanol with a minimum amount of diethyl ether to give the titled compound, (1RS,2SR)-1-(1H-indol-1-yl)-1-phenyl-3-piperazin-1-ylpropan-2-ol dihydrochloride as a tan solid. MS (ESI) m/z 336 ([M+H]+); HRMS: calcd for C21H25N30+H+, 336.20704; found (ESI, [M+H]+), 336.2085.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH:10]([CH3:20])[C:11]([O:18][CH3:19])=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CC(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH:10]([CH3:20])[C:11]([O:18][CH3:19])=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCOC(=O)C=C(OC)C(C)Br
Solvent: CC(C)=O
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(O)cc1

Procedure:
The above 3-oxo ester is reduced using NaBH4 in ethanol to yield ethyl 4-[4-(6,7-dichloro-2-quinoxalyloxy)phenoxy]-3-hydroxypentanoate. Ethyl 4-(4-hydroxyphenoxy)-3-methoxy-2-pentenoate is prepared by the reaction of hydroquinone and ethyl 4-bromo-3-methoxy-2-pentenoate in the presence of base in acetone or the like under reflux.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:23]3[O:24][C:20]([CH3:19])=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 95 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (2 g, 0.0061 mol), 5-methyl-2-furanboronic acid pinacol ester (1.1 g, 0.0091 mol), sodium carbonate (0.969 g, 0.0092 mol), DMF (80 mL) and water (20 mL) were added and degassed the reaction vessel with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.213 g, 0.0003 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified; using column chromatography (60-120 silica gel, 0-20% ethyl acetate in hexane) to yield the desired product [1.4 g, 70%]. 1H NMR: (400 MHz, CDCl3): δ 8.01 (d, J=1.6 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.68 (dd, J′=8.8 Hz, J″=1.6 Hz, 1H), 6.78 (d, J=3.2, 1H), 6.14-6.45 (m, 1H), 3.88 (m, 8H), 2.42 (s, 3H); LC-MS (ESI): Calculated mass: 329.1; Observed mass: 330.0 [M+H]+ (RT: 1.71 min).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:36])[CH:4]([CH:25]([OH:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:5]([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH:6]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].N12CCCN=C1CCCCC2.S([O-])(O)(=O)=O.[K+]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:36])[CH:4]([CH:25]([O:35][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:5]([O:20][Si:21]([CH3:22])([CH3:24])[CH3:23])([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH:6]=1.[Cl:1][C:2]1[C:3](=[O:36])[C:4](=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:5]([O:20][Si:21]([CH3:22])([CH3:24])[CH3:23])([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCCCC(O)C1C(=O)C(Cl)=CC1(CCCc1ccc(OC)c(OC)c1)O[Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: COC(=O)CCCCCC(OS(C)(=O)=O)C1C(=O)C(Cl)=CC1(CCCc1ccc(OC)c(OC)c1)O[Si](C)(C)C
Product: COC(=O)CCCCCC=C1C(=O)C(Cl)=CC1(CCCc1ccc(OC)c(OC)c1)O[Si](C)(C)C
Reaction time: 2.5 h
Yield: 17 %
Yield: 28 %

Procedure:
46 mg of 2-chloro-4-trimethylsilyloxy-4-[3-(3,4-dimethoxyphenyl)propyl]-5-(1-hydroxy-6-methoxycarbonylhexyl)-2-cyclopentenone was dissolved in 1 ml of pyridine, and 100 microliters of methanesulfonyl chloride was added. The mixture was stirred for 2.5 hours. 150 microliters of 1,8-diazabicyclo[5.4.0]undec-7-ene was added, and the mixture was stirred for 6 hours. A saturated aqueous solution of potassium hydrogen sulfate was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. After filtration and concentration, the residue was chromatographed on a silica gel column to give 15 mg (yield 28%) of 2-chloro-4-tri-methylsilyloxy-4-[3-(3,4-dimethoxyphenyl)propyl]-5-(1-methanesulfonyloxy-6-methoxycarbonylhexyl)-2-cyclopentenone and 7.7 mg (yield 17%) of 2-chloro-4-trimethylsilyloxy-4-[3-(3,4-dimethoxyphenyl)propyl]-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:32][CH2:31][N:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=4)[CH2:35][CH2:34]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Br-]
Agent: [K+]
Product: COc1cccc(N2CCN(C(=O)Oc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)CC2)c1
Yield: 96 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-methoxy-phenyl)-piperazine, yield 96%. White solid, m.p. 109-111° C.; IR (KBr): ν 1721 (C═O) cm−1.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:39])[CH2:16][NH:17][C:18](=[O:38])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[NH:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[C@H:10]([CH2:40][CH2:41][CH3:42])[CH2:9]1)(C)(C)C.ClCCl>C(O)(C(F)(F)F)=O>[NH2:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([CH2:16][NH:17][C:18]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[NH:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])=[O:38])=[O:39])[C@H:10]([CH2:40][CH2:41][CH3:42])[CH2:9]1
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@@H]1C[C@H](N)CC[C@@H]1NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Examples 2o and 2p, Step 4: A sample of (1R,3R,4S)-[4-(2-{2-[(morpholine-4-carbonyl)-amino]-5-trifluoromethyl-benzoylamino}-acetylamino)-3-propyl-cyclohexyl]-carbamic acid tert-butyl ester (200 mg) was dissolved in 1:2 TFA:dichloromethane and stirred for 30 min at RT before being concentrated in vacuo. The residue was redissolved in 1:2 TFA:dichloromethane and stirred for 30 min at RT before being concentrated in vacuo. The residue was dissolved in 1 N HCl and washed with Et2O; the aqueous phase was then basified (sat. NaHCO3 & a small amount of 1 N NaOH) and extracted (EtOAc, 2×). The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford morpholine-4-carboxylic acid (2-{[(1S,2R,4R)-(4-amino-2-propyl-cyclohexylcarbamoyl)-methyl]-carbamoyl}-4-trifluoromethyl-phenyl)-amide as the free base (90 mg). MS found: (M+H)+=514.2.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[CH3:15][S:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30])(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:15][S:16]([OH:19])(=[O:18])=[O:17].[CH3:15][S:16]([OH:19])(=[O:18])=[O:17].[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][C:21]=2[N+:29]([O-:31])=[O:30])=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1[N+](=O)[O-]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc(C(=N)N)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into 300 ml of dried pyridine, were dissolved 7.0 g of 4-guanidinobenzoyl chloride hydrochloride and 7.4 g of 4-amidino-2-nitrophenol methanesulfonate. The solution was stirred overnight at room temperature. The precipitate which was formed was collected by filtration, suspended in methanol and filtered. The filtrate and 300 ml of ethyl ether was stirred to precipitate a colorless solid substance which was collected by filtration, dissolved in a small volume of methanol, and stirred together with a saturated sodium bicarbonate solution to precipitate the intended carbonate. The precipitated carbonate was collected by filtration, then air-dried, suspended in a small volume of methanol, admixed with methanesulfonic acid at room temperature. After 10 minutes, ethyl ether was added to the reaction mixture to precipitate crystals. The crystals were collected by filtration, washed thoroughly with ethyl ether to obtain 4-amidino-2-nitrophenyl 4-guanidinobenzoate dimethanesulfonate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]2=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:8][N:9]=[C:5]2[CH:4]=1.[C-:18]#[N:19].[K+].O1CCOCC1.O>C(Cl)Cl>[C:10]1([C:7]2[O:8][N:9]=[C:5]3[CH:4]=[C:3]([CH2:2][C:18]#[N:19])[CH:17]=[CH:16][C:6]=23)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: BrCc1ccc2c(-c3ccccc3)onc2c1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccc2c(-c3ccccc3)onc2c1

Procedure:
A mixture of 10.9 g (0.038 mole) of slightly impure 6-(bromomethyl)-3-phenyl-2,1-benzisoxazole, 9.8 g (0.15 mole) of potassium cyanide, 80 ml of dioxane, and 50 ml of water was heated at reflux under a nitrogen atmosphere for 2.5 hr. The mixture was diluted with 200 ml of methylene chloride and the layers were separated. The organic layer was washed twice with water, once with brine, and dried over sodium sulfate, and concentrated to give 7.5 g of gray solid as residue. The solid was chromatographed on 150 g of silica gel and the title compound was eluted with 1% methanol in benzene to yield 3.3 g (37%) of product, m.p. 148°-155° C.