Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Br[CH2:23][C:24](=O)[CH3:25].C(O)C.CN(C)C(=O)C>O>[CH3:25][C:24]1[N:20]=[C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])[S:21][CH:23]=1
Reactant: CC(=O)CBr
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: CCO
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1csc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.30 g), bromoacetone (0.10 mL), ethanol (2 mL) and N,N-dimethylacetamide (2 mL) was stirred at 80° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.24 g, yield 72%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 181-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[CH:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[H-].[Na+].Br[CH2:17][CH2:18][Cl:19].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[CH:9][N:8]([CH2:17][CH2:18][Cl:19])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: ClCCBr
Reactant: O=C1NC=COc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2cc(Cl)ccc2OC=CN1CCCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
50 mg of 7-chloro-4,5-dihydro-1,4-benzoxazepin-5-one was dissolved in dimethylformamide (1 ml), then 12 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 54 mg (1.5 equivalents) of 1-bromo-2-chloroethane was added and the result was agitated at room temperature for 10 hours. Ice water was added to the reaction solution, and extraction was performed by ethyl acetate. This ethyl acetate extract was washed by saline and was dried with anhydrous magnesium sulfate. The solvent was distilled off and the resultant crude product was refined with silica gel column chromatography (hexane: ethyl acetate=4:1) to obtain the above-referenced compound in an amount of 28 mg (yield of 42%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COc2cc3c(cc2-c2cc(C=CC(=O)O)ccc2OC)C(C)(C)CCC3(C)C)cc1
Yield: 105.2 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 1.23 g (3 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 490 μl (3.6 mmol) of 4-methoxybenzyl chloride, 1.58 g (100%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: CON(C)C(C1C(NS(C2C=CC(Cl)=C(C(F)(F)F)C=2)(=O)=O)=CC=CN=1)=O.C(=O)([O-])[O-].[K+].[K+].COCCl.[CH3:38][O:39][N:40]([CH3:68])[C:41]([C:43]1[C:48]([N:49]([CH2:64][O:65][CH3:66])[S:50]([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([C:60]([F:63])([F:62])[F:61])[CH:54]=2)(=[O:52])=[O:51])=[CH:47][C:46](Cl)=[CH:45][N:44]=1)=[O:42]>C1COCC1>[CH3:38][O:39][N:40]([CH3:68])[C:41]([C:43]1[C:48]([N:49]([S:50]([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([C:60]([F:63])([F:62])[F:61])[CH:54]=2)(=[O:51])=[O:52])[CH2:64][O:65][CH3:66])=[CH:47][CH:46]=[CH:45][N:44]=1)=[O:42]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: COCCl
Agent: CON(C)C(=O)c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COCN(c1cccnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared from 1.05 g (2.48 mmol) of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide, 1.71 g of potassium carbonate and 566 μL of methoxymethyl chloride in 7 mL THF using procedure used in the preparation of Intermediate 12. Yield: 420 mg of a white solid. LC-MSD, m/z for C17H17ClF3N3O5S [M+Na]+=490.0, 491.9; HPLC retention time: 2.5 minutes.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([Cl:9])[C:5](=O)[CH2:6][CH3:7].[Cl-].[CH:12]([NH2:14])=[NH2+:13].C[O-].[Na+]>CO>[Cl:9][C:4]1[C:3]([OH:2])=[N:13][CH:12]=[N:14][C:5]=1[CH2:6][CH3:7]
Reactant: NC=[NH2+]
Reactant: CCC(=O)C(Cl)C(=O)OC
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCc1ncnc(O)c1Cl

Procedure:
To a solution of 8.6 g (0.049 mol) of 2-chloro-3-oxopentanoic acid methylester (content 94 percent) and 6.04 g (0.075 mol) of formamidinium chloride in 10 ml of methanol, there was added within 2 hours at 20° to 22° C., while stirring, 21.6 g of sodium methylate solution (30 percent in methanol, 0.12 mol). After another 3 hours of stirring, neutralization with conc. hydrochloric acid (pH about 5) and evaporation to dryness on the rotary evaporator were performed. The residue was taken up with 20 ml of water and extracted out three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, the solvent was distilled off and the solid residue was dried at 50° C. and 100 torr. The following data concerns the product of this example:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[NH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20]([O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=1[O:31][CH2:32][O:33][CH3:34])[CH3:21].O>CN(C)C=O>[CH2:20]([O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([N:5]2[C:6]3[C:11](=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=3)[C:3]([C:1]#[N:2])=[CH:4]2)=[CH:26][C:25]=1[O:31][CH2:32][O:33][CH3:34])[CH3:21]
Reactant: N#Cc1c[nH]c2cc(F)c(F)cc12
Reactant: CCOC(=O)c1ccc(F)cc1OCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(F)c(F)cc32)cc1OCOC
Temperature: 75 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of 3-cyano-5,6-difluoroindole (0.25 g) in N,N-dimethylformamide (10 mL) were added cesium carbonate (0.91 g), 4-fluoro-2-methoxymethoxybenzoic acid ethyl ester (0.32 g), and this mixture was stirred at 75° C. overnight. This reaction mixture was poured into water, and this resulting mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=10/90-75/25) to give the title compound (0.12 g).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:21])[C:7](=[O:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:64]=[N+:65]=[N-:66])(=O)=O)(C)C.C(O)(=O)C>O1CCCC1>[N:64]([CH:8]1[C:7](=[O:18])[N:6]([CH2:19][C:20]([N:22]([CH:31]([CH3:33])[CH3:32])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:21])[C:5]2[CH:34]=[CH:35][C:2]([F:1])=[CH:3][C:4]=2[N:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:9]1=[O:17])=[N+:65]=[N-:66]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(N=[N+]=[N-])C(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
A solution of 262 mg of 2-(7-Fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (0.550 mmol) in 5 mL of anhydrous tetrahydrofuran at -78° C. under nitrogen was treated dropwise with 1.54 mL of potassium bis(trimethylsilyl)amide (0.5M in toluene, 0.770 mmol, 1.4 eq). After stirring 15 min., 212 mg of 2,4,6-triisopropylbenzenesulfonyl azide (0.687 mmol, 1.25 eq, J. Org. Chem. 1984, 49, 1430-1434) was added. After stirring 4 min., the reaction mixture was quenched by addition of 78.6 mL of glacial acetic acid (1.38 mmol, 2.5 eq) and allowed to warm to ambient temperature. The reaction mixture was evaportated in vacuo to a residue and purified on flash grade silica with 1:1 ethyl acetate / hexane. The appropriate fractions were combined, evaporated in vacuo and dried under high vacuum to provide 170 mg of the title compound as an amorphous solid. Low resolution MS (FAB)m/e 518 (MH+); TLC (silica) 3:1 Ethyl acetate: hexane Rf=0.68.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH:10]([O-])([O-])OC>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:10][O:9][CH:7]1[CH2:6][CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:8]1
Reactant: COC([O-])[O-]
Reactant: O=C1CCCNC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC1CCCNC(=O)C1
Yield: 63 %

Procedure:
2,4-Dioxohexahydroazepine (4.57 g), methyl orthoformate (8.15 g) and p-toluenesulfonic acid (215 mg) are treated in the same manner as described in Example 1-(1) to give 4-methoxy-2,4,6,7-tetrahydroazepine-2-one (3.24 g, 63.8%) as colorless prisms. m.p. 70°-73° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Cl.C(N(CC)CC)C>C(#N)C>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: ClCc1ccccn1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Under anhydrous conditions (positive nitrogen pressure, presence of 3Å molecular sieves), a mixture of N-hydroxyphthalimide (10.0 g, 0.061 mole), 2-picolylchloride hydrochloride (10.0 g, 0.061 mole), and triethylamine (18.5g, 0.183 mol) in 100 ml of anhydrous acetonitrile was refluxed for 6 hours. After overnight stirring at ambient temperature, TLC showed that the starting materials were practically consumed. The solvent was evaporated and the residue dissolved in 200 ml of EtOAc. The solution was washed with 1N NaOH (100 ml), water (2×200 ml), brine (1×200 m ml) and dried (MgSO4). After removal of the solvent, the crude product was recrystallized from EtOAc/hexane to afford 11.4g (73.6%) of title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C>[CH2:32]([N:15]1[C:14](=[O:17])[N:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[C:10]2=[N:16]1)[CH2:33][CH2:34][CH3:35]
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 31.4 %

Procedure:
To a stirring mixture of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.14 mmol) and K2CO3 (40 mg, 0.28 mmol) in DMF (0.47 mL) at 20° C. was added 4-bromobutane (40 mg, 0.28 mmol). The resulting reaction mixture was heated at 80° C. for 30 min. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature, diluted with water, and extracted twice with diethyl ether. The combined organic extract was washed with saturated aqueous NaHCO3 solution, then brine, then dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (18 mg, 0.044 mmol) as a light yellow solid. MS: [M+H]+=412.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][C:18]([O:20]C(C)C)=[O:19].Cl>[OH-].[Na+]>[NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(C)OC(=O)COCCOCCOCCOCCOCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCOCCOCCOCCOCCOCC(=O)O
Reaction time: 0.5 h

Procedure:
Isopropyl 17-amino-3,6,9,12,15-pentaoxahepta-decanoate (see part I of the experimental part) (1.1 g, 3.2 mmole) was dissolved in 3 ml of 1 M sodium hydroxide solution and left at room temperature for 30 min. 1.5 ml of 6 M hydrochloric acid was added and the mixture was evaporated to dryness. The residue was taken up in dichloromethane and filtered to give 545 mg of 17-amino-3,6,9,12,15-pentaoxaheptadecanoic acid after evaporation of the solvent. 460 mg (1,39 mmoles) of this compound were dissolved in 10 ml of borate buffer pH 8.4. The solution was deaerated with nitrogen gas. A solution of 432 mg (1.52 mmoles) of N-succinimidyl 2-iodoacetate in 5 ml of dioxane was added dropwise during 1 min pH was kept at 8.4 by addition of 5 M NaOH. The reaction solution was stirred for 15 min during inlet of nitrogen gas. According to thin layer chromatography (eluent: CH2Cl2-MeOH 60:35) the reaction was completed in some few minutes. After 15 min the pH of the reaction solution was adjusted to 3 and the solution was frozen and lyophilized. The reaction mixture was fractionated on a reversed phase column PEP-RPC HR 30/26 (Pharmacia Biosystems AB) using a gradient of 0-13% acetonitrile with 0.1% trifluoroacetic acid followed by isocratic separation at 13% acetonitrile, 0.1% TFA. Fractions from the desired peak were pooled and lyophilized giving 351 mg of 17-iodoacetylamino-3,6,9,12,15-pentaoxa-heptadecanoic acid (A). Yield: 76%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([NH:38][C:39]([CH3:41])=[O:40])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:43].O1CCOCC1>O1CCOCC1>[ClH:43].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([NH:38][C:39]([CH3:41])=[O:40])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 60 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-acetamino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The solvent was removed under reduced pressure and the resulting solid was recrystallized in methanol-ethyl acetate to give 18 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-acetaminoquinolin-2(1H)-one hydrochloride as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH:7]([C:19]([F:22])([F:21])[F:20])[N:8]1C(=O)C2=CC=CC=C2C1=O)C>Cl>[NH2:8][CH:7]([C:19]([F:20])([F:21])[F:22])[CH2:6][CH2:5][C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)CCC(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Agent: Cl
Product: NC(CCC(=O)O)C(F)(F)F

Procedure:
To a solution of 30 mmole of 4-trifluoromethyl-4-oxobutyric acid ethyl ester in 20 ml of ethanol cooled to 0° C. is added 30 mmole of sodium borohydride. The reaction mixture is stirred at 0° C. for 4 hours then acidified with M HCl to a pH of 1. The solvent is evaporated under reduced pressure and the residue is partitioned between water and ether. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give 4-trifluoromethyl-4-hydroxybutyric acid ethyl ester. A mixture of 20 mmole of 4-trifluoromethyl-4-hydroxybutyric acid ethyl ester, 22 mmole of triphenylphosphine, 20 mmole of phthalimide and 22 mmole of diethyl azodicarboxylate in 60 ml of tetrahydrofuran is heated at reflux temperature under nitrogen for 24 hours. The solvent is evaporated under reduced pressure, and the residue chromatographed on silica gel to give 4-trifluoromethyl-4-phthalimidobutyric acid ethyl ester. A suspension of 30 mmole of 4-trifluoromethyl-4-phthalimidobutyric acid ethyl ester in 20 ml of concentrated HCl is heated at reflux temperature for 24 hours. The solid which separates on cooling is filtered, and the filtrate concentrated under reduced pressure. The residue is dissolved in the minimum quantity of water, and the pH of the solution adjusted to 5 by the addition of sodium hydroxide. Acetone is added, and the precipitated 4-amino-4-trifluoromethylbutyric acid collected by filtration.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17](O)([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:9]2=[O:10])=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>CN(C=O)C>[Cl:28][C:17]1([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[N:8]1[CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1Cc1ccccc1

Procedure:
Distilled THF (25 mL) was added to 2-benzyl-3-(4-chlorophenyl)-3-hydroxy-2,3-dihydroisoindolin-1-one (400 mg, 1.145 mmol), thionyl chloride (299.6 mg, 2.51 mmol, 0.18 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-benzylisoindolin-1-one was produced as a colourless oil (421 mg, 1.145 mmol) which was used immediately without further purification. Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-benzylisoindolin-1-one (421 mg, 1.145 mmol), cis-cyclopentene diol (572 mg, 5.725 mmol) and potassium carbonate (792.9 mg, 5.725 mmol) as for general procedure B. Removal of the solvent yielded the crude product as a pink oil (354 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as a cream oily solid (277.5 mg, 0.643 mmol, 56% yield). 1H NMR: (300 Hz, CDCl3) δ ppm 0.84, 1.66 (m, 1H, H16/H16′) 1.26 (m, 1H, H16/H16′) 3.85 (m, 1H, H17) 3.36 (m, 1H, H15) 4.15 (d, 1H, J=15.27 Hz, H9/H9′), 4.62 (d, 1H, J=15.31 Hz, H9/H9′), 4.68, 5.73 (dd, 1H, H18/H19), 5.21, 5.64 (dd, 1H, H18/H19), 7.18 (m, 10H, H1-H5, H10-H14), 7.62 (m, 2H, H6-H7), 7.83 (d, 1H, H8). Mp: 63.4-63.9° C. IR: 1489, 1683, 3061, 3379 cm−1.
Reaction SMILES: C1(N(CCO)C(C2C(OCC3C=CC=CC=3)=C(O)N=C(CC3(C4C=CC=CC=4)CCCC3)N=2)=O)CC1.[Si]([O:44][CH2:45][CH2:46][N:47]([CH2:77][CH:78]1[CH2:80][CH2:79]1)[C:48]([C:50]1[C:55]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]2([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:70][CH2:69][CH2:68][CH2:67]2)[N:51]=1)=[O:49])(C(C)(C)C)(C)C.C(OC1C(C(O)=O)=NC(CC2(C3C=CC=CC=3)CCCC2)=NC=1O)C1C=CC=CC=1>>[CH:78]1([CH2:77][N:47]([CH2:46][CH2:45][OH:44])[C:48]([C:50]2[C:55]([O:56][CH2:57][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]3([C:71]4[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=4)[CH2:70][CH2:69][CH2:68][CH2:67]3)[N:51]=2)=[O:49])[CH2:80][CH2:79]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Product: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1
Yield: 96.5 %

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (285) from 5-Benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (304) (380 mg, 0.62 mmol). The product was obtained as a light yellow sticky solid (300 mg, 96.93%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22](=[O:25])[CH2:23][O:16][C:13]1[CH:14]=[N:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])=[CH:11][CH:12]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1ccc(-c2ccccc2F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 63.4 mg (1.45 mmol) of sodium hydride (55% in mineral oil) were added to 250 mg (1.32 mmol) of 6-(2-fluoro-phenyl)-pyridin-3-ol in 10 ml of DMF. The mixture was stirred at room temperature for 60 min. Then 283.5 mg (1.45 mmol) of bromoacetic acid tert-butyl ester were added, and the reaction mixture was stirred at room temperature for 2 h. After evaporation, water was added, and the mixture was extracted with ethyl acetate. The combined extracts were dried and concentrated. Yield: 311 mg.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][OH:23])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].CCN(C(C)C)C(C)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>C(Cl)Cl>[CH3:43][S:40]([O:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:14][N:13]=2)[CH:16]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COCc1cc(-c2nc(-c3cccc(CCO)c3)no2)ccc1-c1ccccc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc(-c2nc(-c3cccc(CCOS(C)(=O)=O)c3)no2)ccc1-c1ccccc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)ethanol (0.2 mmol) in DCM (2 mL) at 0° C. was added DIEA (71 μL, 0.4 mmol) and mesyl chloride (17 μL, 0.22 mmol). The resulting mixture was stirred at 0° C. for 10 minutes, allowed to warm to RT and stirred for 2 hours. The mixture was diluted with DCM (20 mL) and washed with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM (3×20 mL). The combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was all used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[N:15]12[CH2:22][CH2:21][CH2:20][C:19]1([CH2:23][NH2:24])[CH2:18][CH2:17][CH2:16]2>>[N:15]12[CH2:22][CH2:21][CH2:20][C:19]1([CH2:23][NH:24][C:2]1[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1)[CH2:18][CH2:17][CH2:16]2
Reactant: NCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1ccc(Cl)c2ccccc12
Product: O=[N+]([O-])c1ccc(NCC23CCCN2CCC3)c2ccccc12
Yield: 50.9 %

Procedure:
1-Chloro-4-nitronaphthalene and (1-azabicyclo[3.3.0]octan-5-yl)methylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 50.9%.