Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:10]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[N:10]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(F)cc1F
Yield: 72 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(2,4-difluorophenyl)-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.056 g; 0.139 mmol), sodium hydroxide 10N (0.200 mL; 2.00 mmol) in methanol (2 mL) at 60° C. for 18 h to afford 0.039 g (69%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][O:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O1CCOCC1.[Br:26]Br.O>C(OCC)C>[Br:26][CH:6]([O:5][CH2:4][C:3]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=1[Cl:1])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: BrBr
Reactant: O=C(COCc1ccc(Cl)cc1Cl)c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)C(Br)OCc1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 76.4 %

Procedure:
2-(2,4-Dichlorobenzyloxy)acetophenone (29.52 g, 100 mmole) was dissolved in a mixture of diethyl ether (100 ml) and 1,4-dioxane (100 mmole) and bromine (16 g, 100 mmole) was added dropwise over 1 hour. After stirring at the same temperature for additional 1 hour, water (200 ml) was added and the mixture was separated into layers. The aqueous layer was extracted with diethyl ether (200 ml). The organic layers were combined, washed with 1% aqueous solution of sodium bicarbonate (180 ml) and dired over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and a mixture of benzene/n-hexane was added to the residue to crystallize. The crystals were filtered off to obtain a crude product of the title compound (28.57 g). The crude product (1 g, 2.67 mmole) was recrystallized from benzene/n-hexane to obtain the title compoud (0.79 g, 79%), m.p. 89°-91° C.
Reaction SMILES: C(OC([NH:8][C:9]([NH:23]C(OC(C)(C)C)=O)=[N:10][C:11]1[N:12]=[CH:13][N:14]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=2)[CH:15]=1)=O)(C)(C)C.[ClH:31]>ClCCl.O1CCOCC1>[ClH:31].[ClH:31].[CH3:22][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([N:14]2[CH:15]=[C:11]([NH:10][C:9]([NH2:23])=[NH:8])[N:12]=[CH:13]2)[CH:21]=1
Reactant: Cc1ccnc(-n2cnc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccnc(-n2cnc(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(1-(4-methylpyridin-2-yl)imidazol-4-yl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at ambient temperature for 23 hours. The solvent was evaporated under reduced pressure. To the residue was added 2-propanol, and the resultant precipitate was collected by filtration and dried under reduced pressure to give (1-(4-methylpyridin-2-yl)imidazol-4-yl)guanidine dihydrochloride (94 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C>N1C=CC=CC=1.[Pd]>[C:12]1(/[CH:11]=[CH:10]\[CH2:9][CH2:8][NH2:7])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCC#Cc1ccccc1
Agent: [Pd]
Solvent: c1ccncc1
Product: NCC/C=C\c1ccccc1
Reaction time: 1 h

Procedure:
A suspension of palladium on barium sulfate (15 mg) was stirred for 15 min in 1 mL pyridine. (4-phenyl-but-3-ynyl)-carbamic acid tert-butyl ester (66 mg) was added and the solution was purged with hydrogen then stirred for 1 h under a hydrogen-filled balloon. The solution was diluted with ethyl acetate (10 ml) and washed 3 times with 1 N hydrochloric acid (10 ml). The ethyl acetate layer was dried over sodium sulfate and filtered. The filtrate was evaporated and the resulting residue (54 mg) is primarily cis-(4-phenyl-but-3-enyl)-carbamic acid tert-butyl ester along with (4-phenyl-but-3-ynyl)-carbamic acid tert-butyl ester, 4-phenylbutylamine, and trans-(4-phenyl-but-3-enyl)-carbamic acid tert-butyl ester. The combined minor products constitute ˜20% of the crude material. The tert-butoxycarbonyl group of the desired product was removed by Procedure P to give cis-4-phenyl-but-3-enylamine, which was used in subsequent transformations without further purification.
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][O:26][CH3:27]>>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([N:25]([O:26][CH3:27])[CH3:24])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Agent: Cl
Product: CON(C)C(=O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2) and N,O-dimethylhydroxylamine hydrochloride.
Reaction SMILES: C(O)C.[OH-].[K+].[Br:6][C:7]1[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([O:37]CC)=[O:36])[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([CH2:16][N:17]1[C:21]([CH2:22][OH:23])=[C:20]([Cl:24])[N:19]=[C:18]1[CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11]2>O>[Br:6][C:7]1[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([OH:37])=[O:36])[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([CH2:16][N:17]1[C:21]([CH2:22][OH:23])=[C:20]([Cl:24])[N:19]=[C:18]1[CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11]2
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)c(Br)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nn(-c3ccccc3C(=O)O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.8 %

Procedure:
Ethanol (1.2 ml), ion-exchanged water (0.3 ml), and potassium hydroxide (45 mg) were added to 1-[3-bromo-2-(2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazole (106 mg, 0.205 mmol) as obtained in Example 2, and the mixture was stirred at room temperature for one day. The mixture was concentrated in an evaporator, and partitioned by ion-exchanged water (2.5 ml) and diethyl ether (5 ml). The water layer was separated and conc. hydrochloric acid was dropwise added thereto to adjust its pH to 5-6. The resultant solid was filtered off and washed twice with ion-exchanged water (1 ml). One drop of conc. hydrochloric acid was added to the filtrate to precipitate solid, which was filtered off, washed with water, and combined with the previously-obtained solid. They were dried in vacuo at 37° C. for two days to give 56 mg of 1-[3-bromo-2-(2-carboxyphenyl)-2H-indazol-5-yl]methyl-2-butyl-4-chloro-5 -(hydroxymethyl)-1-H-imidazole.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C(C)=CC=CC=1>O>[CH2:8]([N:17]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCN
Reactant: O=C1C=CC(=O)O1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCN1C(=O)C=CC1=O
Temperature: 120 °C

Procedure:
One equivalent each of maleic anhydride and n-nonylamine are charged into a 1 liter 3-neck round bottom glass flask containing 300 ml xylene, a reflux condenser with a Dean-Stark attachment, Teflon-coated magnetic stirring bar, and a thermometer. The contents are heated to 120° C. for about 15 hours, the reaction extent being monitored by the amount of water collected. After 1 equivalent of water is collected, the reaction solvent is flash distilled off. The absence of an infrared absorbance at 1830 cm-1 and 1791 cm-1 is evidence of anhydride consumption; the presence of an infrared absorbance at 1772 cm-1 is evidence of imide formation.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH2:21])=[O:20])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]1[O:30][C@@H:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([NH2:21])=[O:20])=[CH:16][CH:17]=1)[CH2:22][C@H:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: NC(=O)Cc1ccc(OCCNCc2ccccc2)cc1
Solvent: CC(C)O
Product: NC(=O)Cc1ccc(OCCN(Cc2ccccc2)C[C@H](O)c2ccccc2)cc1
Yield: 64.8 %

Procedure:
A mixture of 4-[2-(benzylamino)ethoxy]phenylacetamide (OLS 2135678) (14.0 g), (R)-styrene oxide (5.92 g) and propan-2-ol (200 ml) was heated under reflux for 72 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was purified by dry, flash column chromatography. Elution with 10% methanol in dichloromethane gave (R)-4-[2-(N-benzyl-N-(2-hydroxy-2-phenylethyl)amino)ethoxy]phenylacetamide as an oil (12.9 g). This reaction may also be performed in t-amyl alcohol under reflux.
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[N+:40]([C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][C:44]=1[C:52]([F:55])([F:54])[F:53])([O-:42])=[O:41]>>[N+:40]([C:43]1[CH:51]=[CH:50][C:46]([C:47]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]2[CH2:27][N:26]([CH:28]3[CH2:33][CH2:32][CH:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:30][CH2:29]3)[CH2:25]2)=[O:48])=[CH:45][C:44]=1[C:52]([F:53])([F:54])[F:55])([O-:42])=[O:41]
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in Step D of Example 66) and 4-nitro-3-trifluoromethyl-benzoic acid (Aldrich) using the procedure described in Step F of Example 1.
Reaction SMILES: Cl[O-].[Na+].C(O)(=O)C.[CH3:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[OH-].[K+].[CH:17]#[N:18].Cl.[OH-].[Na+]>O.C(O)C>[CH3:8][CH:9]1[CH2:14][CH2:13][NH:12][CH:11]([C:17]#[N:18])[CH2:10]1
Reactant: C#N
Reactant: CC1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC1CCNC(C#N)C1
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
To 500 g of 10% sodium hypochlorite solution cooled in an ice bath, there was added dropwise a solution of 33.6 g (0.21 mole) of 4-methylpiperidine acetate in 10 ml of water over a period of 1 hour. At the end of this period, the reaction product was extracted twice with 500 ml of ethyl ether and dried over anhydrous sodium sulfate. After evaporation of ethyl ether, the residue was added dropwise to a solution of 11.8 g (0.21 mole) of potassium hydroxide in 100mls of 96% ethanol under reflux. Refluxing was continued for an additional 10 minutes. Ethanol was evaporated, and the residue was dissolved into 50 ml of 2N sodium hydroxide solution and then extracted with ether. The ether layers was dried over anhydrous sodium sulfate and then ether evaporated. The residue was added to an ice-cooled solution of 27 g (1 mole) of hydrogen cyanide and 25 ml of concentrated hydrochloric acid in 300 ml of water. The solution was stirred at a temperature of 10° to 20° C for 4 hours and thereafter made basic by the addition of solid sodium hydroxide. The reaction product was extracted with ether, dried over anhydrous sodium sulfate and then distilled under reduced pressure to give 17 g (66%) of 4-methyl-2-piperidinecarbonitrile, B.P. 96°-97° C/10 mmHg. The following 2-piperidinecarbonitriles not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as taught by Grundon et al., J. Chem. Soc., 1963, 3898, Grundon et al., J. Chem. Soc., 1964, 2448, R. Bonnett et al., J. Chem. Soc., 1959, 2092 and H. Bohme et al., Ber., 92 1613 (1959).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[C:37]#[N:38])=[CH:4][C:5](=[O:29])[N:6]([CH:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[C:37]#[N:38])=[CH:4][C:5](=[O:29])[N:6]([CH:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:23][CH:24]=2)=[O:10])[CH:7]=1
Reactant: CC(C)CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
45 mg (0.08 mmol) of tert-butyl 4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 28 mg (purity 90%, 62% of theory)
Reaction SMILES: [Na].[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[SH:7].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>CN(C)C=O>[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[S:7][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(S)Nc1ccc(F)c(F)c1F
Reactant: COc1ccc(CCl)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)=C(Nc1ccc(F)c(F)c1F)SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Diethyl [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate sodium salt (68.5 g) was dissolved in N,N-dimethylformamide (200 ml) and thereto p-methoxybenzyl chloride (28.9 g) was added dropwise at 3° to 5° C. over a period of 5 minutes. After the reaction mixture was stirred at room temperature for 1 hour and evaporated to dryness under reduced pressure, water was added to the residue and the mixture was extracted with chloroform. After the extract was washed with a NaCl solution and dried over magnesium sulfate, the solvent was distilled off under reduced pressure to give the title compound (82.9 g) as colorless solid, which was then recrystallized from a mixed solvent of haxane-benzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C(CCc1ccc(O)c(Br)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br

Procedure:
Tert-butyl 2-(2-bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(3-bromo-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:21][CH2:22][C:23]([OH:25])=[O:24]>FC(F)(F)C(O)=O>[C:7]([S:21][CH2:22][C:23]([OH:25])=[O:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 94.4 %

Procedure:
This compound was synthesized by the condensation of triphenylmethanol (2.84 g, 10.8 mmoles) with mercaptoacetic acid (0.75 ml, 10.8 mmoles) in 19 ml trifluoracetic acid. The TFA was removed in vacuo, giving an orange oil, which was purified by dissolution in ether and extraction with 1 N NaOH. The aqueous phase was acidified with 6N HCl, and extracted with two 30 ml portions of ether. The ethereal phase was dried over MgSO4 and evaporated to give 3.41 g (93%) of a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:47])[C:19]2[CH:20]=[C:21]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:38]=3)[S:22][C:23]=2[C:24]2[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:25]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:19]2[CH:20]=[C:21]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:38]=3)[S:22][C:23]=2[C:24]2[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:25]=2)=[O:47])=[CH:16][CH:17]=1
Reactant: CC(=O)Nc1cc(-c2cc(C(O)c3ccc(Cl)cc3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)Nc1cc(-c2cc(C(=O)c3ccc(Cl)cc3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (63.1 uL, 0.746 mmol) in methylene chloride (1.50 mL, 23.4 mmol) was cooled to −78° C. To this solution was added dimethyl sulfoxide (65.1 uL, 0.918 mmol) in methylene chloride (1.00 mL) dropwise. The reaction was stirred for 10 min under an atmosphere of Nitrogen. To this mixture was added a solution of N-{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide (319 mg, 0.574 mmol) in methylene chloride (1.50 mL) dropwise. In 1 hr, triethylamine (0.400 mL, 2.87 mmol) was added dropwise to the reaction and the resulting mixture was warmed to rt. In 1 hr, the solution was diluted with CH2Cl2 and washed with water. The aqueous layer was extracted with CH2Cl2(×2). The combined org layer was washed with NaHCO3(aq) saturated solution, dried, and concentrated to provide N-{4-[4-(4-chlorobenzoyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide as a yellow solid (325 mg, quantative). LCMS: (AA) 554, 556; 1H NMR (400 MHz, CDCl3) δ 8.56-8.47 (s, 1H), 8.32-8.24 (m, 1H), 8.11-8.03 (s, 1H), 8.03-7.92 (s, 1H), 7.87-7.77 (m, 2H), 7.63-7.57 (s, 1H), 7.42-7.32 (m, 3H), 5.37-5.32 (s, 2H), 3.53-3.40 (t, J=8.1 Hz, 2H), 2.27-2.19 (s, 3H), 0.94-0.80 (t, J=8.1 Hz, 2H), 0.02-−0.04 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: Cc1cc(CCCCCBr)no1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2ccc(C#N)cc2)no1
Yield: 53.6 %

Procedure:
A mixture of 5.1 g of 4-cyanophenol, 10 g of 3-(5-bromopentyl)-5-methylisoxazole, 8 g of potassium carbonate, 1 g of potassium iodide and 75 ml of acetonitrile was heated at reflux for 24 hours. The product was isolated and distilled, first at 115°-200° C.(0.1 mm) and then at 160°-190° C.(0.05 mm) to yield a yellow oil which crystallized upon cooling. Recrystallization from hexane-ether afforded 6.2 g of 3-[5-(4-cyanophenoxy)pentyl]-5-methylisoxazole, m.p. 61°-62° C.
Reaction SMILES: CN(C1C=CC=CN=1)C.Cl.CN(C1C=CC=CN=1)C.Cl.[CH3:21][N:22]([CH3:27])[CH2:23][C:24]([OH:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])O.[Na+].O[CH2:49][CH:50]1[C:56]2[CH:57]=[C:58]([Cl:61])[CH:59]=[CH:60][C:55]=2[N:54]([C:62](=[O:79])[C:63]2[CH:68]=[CH:67][C:66]([NH:69][C:70](=[O:78])[C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=3[CH3:77])=[CH:65][CH:64]=2)[CH2:53][CH2:52][CH2:51]1>C(Cl)(Cl)Cl.C(O)(=O)C.CO>[ClH:61].[CH3:21][N:22]([CH3:27])[CH2:23][C:24]([O:26][CH2:49][CH:50]1[C:56]2[CH:57]=[C:58]([Cl:61])[CH:59]=[CH:60][C:55]=2[N:54]([C:62](=[O:79])[C:63]2[CH:68]=[CH:67][C:66]([NH:69][C:70](=[O:78])[C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=3[CH3:77])=[CH:65][CH:64]=2)[CH2:53][CH2:52][CH2:51]1)=[O:25]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CO)c3cc(Cl)ccc32)cc1
Reactant: CN(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(COC(=O)CN(C)C)c3cc(Cl)ccc32)cc1
Yield: 141.6 %

Procedure:
In a solution of 5-hydroxymethyl-7-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) in chloroform (10 ml) are dissolved with heating dimethylaminopyridine (0.41 g) and dimethylaminopyridine hydrochloride (0.35 g), and thereto is added N,N-dimethylglycine hydrochloride (0.15 g) at room temperature with stirring, and further added dicyclohexylcarbodiimide (0.46 g). The mixture is stirred at room temperature overnight. To the mixture are added methanol (1.3 ml) and acetic acid (0.4 ml), and the mixture is stirred at room temperature for two hours. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted with dichloromethane, and the extract is dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent; methyl acetate), and thereto is added a mixture of hydrochloric acid/methanol. The mixture is stirred at room temperature for one hour to give 5-[(2-dimethylaminoacetyloxy)methyl]-7-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (0.36 g) as colorless amorphous.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH2:3][CH2:2]1.[O:25]=[C:26]1[NH:30][C@@H:29]([C:31](O)=[O:32])[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[O:25]=[C:26]1[NH:30][C@@H:29]([C:31]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:24])[C:10]3[CH:11]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=3)[CH2:3][CH2:2]2)=[O:32])[CH2:28][CH2:27]1
Reactant: O=C(NCC1CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CC[C@H](C(=O)O)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CC[C@H](C(=O)N2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide (48 mg, 0.14 mmol), TEA (95 μL, 0.68 mmol), and (R)-5-oxopyrrolidine-2-carboxylic acid (20.66 mg, 0.16 mmol) in DMF (1.5 mL) was treated with a solution of HATU (77 mg, 0.20 mmol) in DMF (1 mL). The reaction mixture was stirred overnight then transferred to a test tube containing saturated aqueous NaHCO3 (4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigorously and allowed to separate for 15 min. After separation, the mixture was cooled to −20° C. until the aqueous layer was frozen. The organic layer was then poured off and the solvent was removed in vacuo at 50° C. The resulting residue was dissolved in CH2Cl2 (1 mL) and treated with 2M HCl in Et2O (3 mL) and allowed to stir overnight at room temperature. The solvent was removed under reduced pressure and the crude solid was purified by HiTOPs.