Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:2]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:2]1
Reactant: COC(=O)Cc1c[nH]c2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC1CNc2ccccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
To a solution of indole 74 (10.9 g, 57.4 mmol) in trifluoroacetic acid (200 mL) was added triethylsilane (20 mL, 121 mmol) at room temperature. The mixture was stirred at 60° C. for 3 h, cooled to room temperature and concentrated in vacuo to remove solvent. The residue was diluted with EtOAc and washed with aq. saturated Cs2CO3 solution. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography to provide the titled compound 75 (8.5 g, 77%). MH+192.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.Cl>O1CCOCC1.CCCCCC>[N:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: BrCCCCCCN1CCCCC1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(CCCCCCN2CCCCC2)c2ccccc21
Temperature: 70 °C

Procedure:
To a suspension of 33.2 g (0.157 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 875 ml of anhydrous dioxan, 173 ml (approx. 0.45 mol) of a 2.6 molar solution of n-butyl-lithium in n-hexane was added dropwise at ambient temperature and the resulting mixture was then stirred for another hour at the same temperature. It was then heated to 70° C. and at a reaction temperature of not more than 75° C. 83.0 g (0.034 mol) of 1-bromo6-(1-piperidinyl)hexane were added dropwise, then to complete the reaction the mixture was stirred for a further 4 hours at 80° C. After cooling, the solvent was distilled off in a water jet vacuum, the residue was adjusted to pH 7 with dilute aqueous hydrochloric acid and the mixture was then filtered. The filtrate was made alkaline with concentrated aqueous potassium hydroxide solution and extracted exhaustively with dichloromethane. The dichloromethane extracts were dried over sodium sulphate and then evaporated down and the residue remaining was digested with 100 ml of boiling diethyl ether and filtered while hot. The residue remaining after the ether had been removed was purified by chromatography on silica gel (Macherey-Nagel, 0.2-0.5 mm) using dichloromethane/methanol/cyclohexane/ethyl acetate/conc. ammonia 59/7.5/7.5/25/1 (v/v/v/v/v) as eluant. By evaporating the desired fractions and subsequently recrystallising from acetonitrile, a colourless crystalline product with a m.p. of 131° to 132° C. was obtained in a yield of 11.29 g (19% of theory). The hydrochloride melted at 223° C. (ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][CH2:20][OH:21])[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1.[CH2:26]([O:28][C:29](=[O:39])[C:30]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)=[O:31])[CH3:27].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:26]([O:28][C:29](=[O:39])[C:30](=[O:31])[C:32]1[CH:37]=[CH:36][C:35]([O:21][CH2:20][CH2:19][CH2:18][C:16]2[S:17][C:13]3[N:12]4[C:22]([CH3:25])=[N:23][N:24]=[C:11]4[CH2:10][N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:14]=3[CH:15]=2)=[CH:34][CH:33]=1)[CH3:27]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: Cc1nnc2n1-c1sc(CCCO)cc1C(c1ccccc1Cl)=NC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(OCCCc2cc3c(s2)-n2c(C)nnc2CN=C3c2ccccc2Cl)cc1

Procedure:
As in Example 15, 4-(-2-chlorophenyl)-2-(3-hydroxy-1-propyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (0.322 g) was treated with 4-hydroxyphenylglyoxylic acid ethyl ester (0.168 g) in the presence of diethyl azodicarboxylate (0.155 g) and triphenylphosphine (0.227 g) in dichloromethane (23 mL). The crude ester, isolated in the usual manner, was purified by flash chromatography over silica gel (150 g; ethanol-dichloromethane; 3.5:96.5) to furnish 0.354 g of 4-[3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl] propoxy]-alpha-oxobenzcneacetic acid ethyl ester as a white foam.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[P:18]([NH:26][NH2:27])(=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>C(Cl)Cl>[CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[N:27][NH:26][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(C2CCCCC2)CC1
Reactant: CCOP(=O)(NN)OCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOP(=O)(NN=C1CCC(C2CCCCC2)CC1)OCC
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To a solution of 4-cyclohexylcyclohexanone (27.04 g) and acetic acid (3 ml) in CH2Cl2 (400 ml) was added a solution of diethyl phosphorohydrazidate (28.91 g) in CH2Cl2 (100 ml). The reaction was stirred at room temperature for 27 hours and then was concentrated under reduced pressure. Toluene was added (2×) and removed under reduced pressure in order to aid in the removal of acetic acid by co-distillation. The residual yellow liquid was the product and was used without further purification. TLC Rf=0.52 (20% acetone in CH2Cl2, silica gel).
Reaction SMILES: [CH2:1]([O:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[O:19])=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCOCc1ccc(CO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCCCCCCOCc1ccc(C=O)cc1

Procedure:
p-(n-Undecyloxymethyl)benzyl alcohol (10 mmoles) is dissolved in methylene chloride and treated with pyridinium chlorochromate (12 mmoles) at room temperature. When the reaction ceases, the reaction mixture is filtered through a pad of silica gel. The solvent is evaporated from this filtrate to afford the product, p-(n-undecyloxymethyl)benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([N:7]1[CH2:12][CH2:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]3[CH:28]=[CH:27][NH:26][N:25]=3)[N:18]=2)([C:13]([OH:15])=O)[CH2:9][CH2:8]1)=[O:6].[Cl-].[NH4+].O.OC1C2N=N[NH:42]C=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([N:7]1[CH2:12][CH2:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]3[CH:28]=[CH:27][NH:26][N:25]=3)[N:18]=2)([C:13]([NH2:42])=[O:15])[CH2:9][CH2:8]1)=[O:6]
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(c1cccc(Cl)c1F)N1CCC(Cc2cccc(Nc3cc[nH]n3)n2)(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC(=O)C1(Cc2cccc(Nc3cc[nH]n3)n2)CCN(C(=O)c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 82.8 mg of 1-(3-chloro-2-fluorobenzoyl)-4-((6-(1H-pyrazol-3-ylamino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid in 5 ml of chloroform were added 97 mg of ammonium chloride, 0.252 ml of triethylamine, 83 mg of hydroxybenzotriazole hydrate and 104 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature, followed by stirring the reaction mixture at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The resulting ethyl acetate layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a preparative thin-layer chromatography (Kieselgel™ 60F254, Art5744 (Merck), chloroform/methanol=6/1) to give the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22]Br)[CH3:19]>CN(C=O)C>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][O:10][C:5]1[C:4]([CH3:11])=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH3:19]
Reactant: CCOC(CBr)OCC
Reactant: Cc1cc(F)cc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1c(C)cc(F)cc1C=O)OCC
Yield: 20 %

Procedure:
To a stirred suspension containing 5-fluoro-2-hydroxy-3-methylbenzaldehyde (1.0 g, 6.49 mmol) and K2CO3 (980 mg, 7.10 mmol) in DMF (8 mL), bromoacetaldehyde diethyl acetal (1.10 mL, 7.15 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography. The product was eluted with hexane/EtOAc (4:1) to give 20 (350 mg, 20%) as an oil, 1H NMR (500 MHz, CDCl3): δ: 10.40 (1H, s, CHO), 7.32 (1H, d, J=7.30 Hz, ArH), 7.14 (1H, d, J=7.75 Hz, ArH), 4.85 (1H, s, CH), 3.95 (2H, s, CH2), 3.75 (2H, t, J=7.15 Hz, CH2CH3), 3.61 (2H, t, J=7.20 Hz, CH2CH3), 2.36 (3H, s, CH3), 1.24 (6H, t, J=5.65 Hz, 2×CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5]([OH:7])=O.[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34]([C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:14])([F:16])[F:15])=[C:2]([Cl:1])[CH:3]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC(=O)C1CCN(C(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)CC1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid, Example 26, step 3, was reacted with piperidine-4-carboxylic acid ethylester and HBTU at 80° C. 1.5 h to give the title compound as a white solid. MS (m/e)=532.8 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH:9]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:10]([NH:12][NH:13][C:14]2[S:15][CH2:16][C:17]([CH3:20])=[N:18][N:19]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(C)C.O>C(O)(=O)C>[CH3:20][C:17]1[CH2:16][S:15][C:14]2=[N:13][N:12]=[C:10]([CH:9]([O:8][C:7]3[CH:33]=[CH:34][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:19]2[N:18]=1
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)NNC1=NN=C(C)CS1
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)c1nnc2n1N=C(C)CS2
Temperature: 95 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A solution of 33.0 g of the above substituted acylhydrazine 1b in 132 ml of acetic acid is heated with stirring at 95° C. for 2 hours. At the end of the reaction, 65 ml of isopropyl alcohol is added to the reaction mixture. And then the whole mixture is added with stirring to 200 ml of 70° C. water. After cooling to 20° C. and stirring at that temperature for an hour, the product is collected, washed with water, dried, and recrystallized from isopropyl alcohol to give 27.2 g (47% overall from 3b or 86% from 1b) of 6-methyl3-(1-[4-nitrophenoxy]tridecyl)-7H-1, 2,4 triazolo(3,4-b)-1,3,4 -thiadiazine (4) with 95 area % by HPLC.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[N:11]=[C:12]([N:28]2[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]2)[C:13]2[N:18]=[N:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:14]=2[N:15]=1.Cl>C1COCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]2[C:14]3[N:15]=[C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[N:11]=[C:12]([N:28]4[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29]4)[C:13]=3[N:18]=[N:17]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2nnc3c(N4CC[C@H](O)C4)nc(Cl)nc32)cc1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc3c(N4CC[C@H](O)C4)nc(OCC(F)(F)F)nc32)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2,2,2-trifluoroethanol (936 mg, 9.35 mmol) in THF was treated with NaH for 1 h at room temperature. (S)-1-[5-Chloro-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 109, c) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was poured into 1 M HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield the crude title compound which was used in the consecutive step without further purification. MS (m/e): 425.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([C:11]2(O)[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([C:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCCCCC1CCC(O)(c2ccc(OCC)c(Cl)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CC=C(c2ccc(OCC)c(Cl)c2F)CC1
Yield: 57.4 %

Procedure:
39.5 g of the compound (3), 0.4 g of p-toluenesulfonic acid and 120 mL of toluene were mixed, and the mixture was refluxed under heating for 2 hours while water distilled out was removed. After cooling the resulting reaction mixture to 30° C., 200 mL of water and 100 mL of toluene were added to and mixed with the reaction mixture, which was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography using heptane as eluent, and then further purified by recrystallization from Solmix A-11 (produced by Japan Alcohol Trading Co., Ltd.) to obtain 21.5 g of 2-chloro-1-ethoxy-3-fluoro-4-(4-pentylcyclohexa-1-enyl)benzene (No. 23). The yield based on the compound (2) was 58.7%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cn[nH]c2c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccc2cnn(CCOC3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 6-fluoro-1H-indazole (2.0 g, 14.7 mmol), and 2-(2-bromo-ethoxy)-tetrahydro-pyran (3.38 g, 16.2 mmol) in DMF (25 mL) was treated with caesium carbonate (6.1 g, 18.7 mmol) and stirred at RT for 18 h. The solvent volume was reduced in vacuo, and the residue partitioned between EtOAc (100 mL) and water (100 mL). The aqueous layer was extracted into EtOAc (3×). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-50% cyclohexane in EtOAc, to afford the title product and a yellow oil. LCMS (Method 1): Rt 3.42 min, m/z 181 [MH+] (M-THP). 1H NMR (300 MHz; CDCl3) 1.52-1.56 (6H, m), 3.39-3.49 (1H, m), 3.57-3.68 (1H, m), 3.89-3.91 (1H, m), 4.19-4.21 (1H, m), 4.56-4.57 (3H, m), 6.88 (1H, td, J 9.15 and 2.26), 7.30 (1H, m), 7.62 (1H, m), 8.04 (1H, s).
Reaction SMILES: [C:1]([N:4]1[C@H:12]([C:13]([O-:15])=O)[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2].C([N:44]1[C@H:52]([C:53]([O-:55])=[O:54])CC(=O)C2C=CC=CC=2N(CC2C=CC=CC=2)C(=O)[C@H]1CC12CC3CC(CC(C3)C1)C2)(=O)C>>[C:1]([N:4]1[C@H:12]([C:13]([NH:44][CH2:52][C:53]([OH:55])=[O:54])=[O:15])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:38][CH:37]3[CH2:39][CH:33]([CH2:34][CH:35]([CH2:36]3)[CH2:40]1)[CH2:32]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2cccc(Cl)c2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Product: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2cccc(Cl)c2)c2ccccc2C(=O)C[C@H]1C(=O)NCC(=O)O

Procedure:
The compound was prepared by an identical route to that used to prepare example 22 except that (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-(3-chlorobenzyl)-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate was used in step a in place of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[O:4][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: Oc1ccc(O)c(Cl)c1
Reactant: CCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(O)cc1Cl

Procedure:
In ethanol, chlorohydroquinone was reacted with dodecylbromide in ethanol by using 1 equivalent of potassium hydroxide to obtain 3-chloro-4-dodecyloxyphenol. Then, 3.1 g of this 3-chloro-4-dodecyloxyphenol was reacted with 2.0 g of 2,4-acetoxybenzoic acid chloride in pyridine and the reaction mixture was treated by customary procedures to obtain 4 g of 3-chloro-4-dodecyloxyphenyl 4-acetoxybenzoate. This ester was dissolved in a THF/methanol liquid mixture and 1 equivalent of 1N LiOH was added to selectively isolate the acetoxy group, whereby 3-chloro-4-dodecyloxyphenyl 4-hydroxybenzoate was obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][C:28]([N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:14][CH2:13]1)=[O:29]
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: O=C(Cl)Cc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc2ccccc2c1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Yield: 75.7 %

Procedure:
By operating as described in Example 6(a), 7 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine are reacted with 6.15 g of 2-naphthylacetyl chloride in the presence of 4.15 g of triethylamine in methylene chloride to give 9 g of 1-(2-naphthylacetyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; m.p. 125°-130° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]1[CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:21][CH2:20][OH:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CO1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(I)ccc2C1
Product: CC(C)(C)OC(=O)N1CCc2cc(CCO)ccc2C1

Procedure:
6-(2-Hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared as example 7c from 8.30 g (23.1 mmol) 6-iodo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 10a) and 4.07 g (92.4 mmol) oxirane.
Reaction SMILES: [OH-].[K+].O.[OH:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH:10]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[Br:22][CH2:23][CH2:24][CH2:25]Br>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[Br:22][CH2:23][CH2:24][CH2:25][O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH:10]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: BrCCCBr
Reactant: CC1(C)Oc2c(O)cccc2C1N1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)Oc2c(OCCCBr)cccc2C1N1CCCCC1
Reaction time: 20 h

Procedure:
Potassium hydroxide (1.47 g), tetrabutyl ammonium chloride (0.77 g) and H2O (1 ml) are added to a solution of the product obtained in Step 6. (6.6 g) in 1,3-dibromopropane (27 ml). The reaction mixture is stirred for 20 hours and diluted with diethyl ether and washed with 5% aq. HCl. The acidic solution is washed with ether and basified, affording an oil which is taken up in ether, washed with sat'd NaCl, dried, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3][C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18].[OH:21]O>C(O)(=O)C>[F:20][C:2]([F:1])([F:19])[S:3]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18])=[O:21]
Reactant: O=c1c2ccccc2ccn2cc(SC(F)(F)F)cc12
Reactant: OO
Solvent: CC(=O)O
Product: O=c1c2ccccc2ccn2cc(S(=O)C(F)(F)F)cc12

Procedure:
A solution of 3gm. of 2-trifluoromethylthio-11H-pyrrolo[2,1-b][3]benzazepin-11-one in 25 ml. of acetic acid containing 3 ml. of 50% hydrogen peroxide is stirred at 25° C. for 6 hrs. The solvent is evaporated and the residue dissolved in 100 ml . of methylene chloride. The solution is washed with 2 × 25 ml. of 5% Na2CO3 solution, dried and evaporated. Chromatography of the residue on silica gel yields 2-trifluoromethylsulfinyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:29])([F:28])[F:27].[SH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1>>[Cl:1][C:2]1[C:7]([S:33][C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[C:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:23][C:24](=[O:32])[C@:25]([OH:31])([CH3:30])[C:26]([F:27])([F:28])[F:29]
Reactant: O=C(O)c1ccc(S)cc1
Reactant: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2F)cc1
Product: CN(C)C(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Sc2ccc(C(=O)O)cc2)cc1

Procedure:
(R)-N-{2-Chloro-3-fluoro-4-[4-(N,N-dimethylcarbamoyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 18) was treated with 4-mercaptobenzoic acid according to the procedure of Example 50 to yield the title compound as a white solid.(0.39 g, 25%). NMR: 1.60 (s, 3H), 2.90 (s, 3H), 3.00 (s, 3H), 7.55-7.65 (m, 4H); 7.90-7.95 (m, 4H), 8.05 (s, 1H), 8.55 (d, 1H), 8.65 (d, 1H), 9.95 (s, 1H); 10.60 (s, 1H); m/z: 629.