Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH3:2]I.[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[CH:7][CH:6]=1.[BH4-].[Na+]>CO.CCOCC>[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([NH2:16])[CH3:2])=[CH:7][CH:6]=1
Reactant: CI
Reactant: N#CCCCCCOc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Mg]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(N)CCCCCOc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 30 %

Procedure:
Magnesium (120 mg, 5 mmol) was added to Et2O (15 mL), followed by Methyl iodide (310 μl, 5 mmol). After reflux has ceased, the mixture was heated to reflux for 20 min. The solution was than cooled to 0° C. and 6-(4-chloro-phenoxy)-hexanenitrile (1119 mg, 5 mmol) was added. The ice bath was removed and the mixture was stirred at ambient temperature for 20 h. The mixture was then diluted with dry THF (5 mL) ad cooled to −78° C. NaBH4 (190 mg, 5 mmol) was added followed by MeOH (3.5 ml) and stirring was continued at −78° C. for 4.5 h. The reaction was quenched by careful addition of 1M aqueous HCl (20 mL). The layers were separated, the aqueous layer was washed with Et2O (1×25 mL), the organic layer was extracted with 1M aqueous HCl (3×30 mL). The aqueous layers were adjusted to pH 12 by addition of 10M aqueous NaOH (8 mL) and extracted with EtOAc (3×50 mL). The combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound (ca 30% of total by integration of HPLC trace at 218 nm) together with two more hydrophobic byproducts (total: 766 mg).
Reaction SMILES: CS[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].O[O:17][S:18]([O-:20])=O.[K+].[CH3:22]O>O>[CH3:22][S:18]([CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])(=[O:20])=[O:17]
Reactant: CSCCN1C(=O)c2ccccc2C1=O
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-methylsulfanyl-ethyl)-isoindole-1,3-dione (400 mg) in methanol (10 mL) was added a solution of oxone (1.67 g) in water (10 mL) and the reaction stirred at room temperature for 16 h. The reaction was then diluted with water (20 mL) and extracted into dichloromethane (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and reduced in vacuo to give 2-(2-methanesulfonyl-ethyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27]OS(C)(=O)=O)[CH:17]=2)=[CH:3]1.[Na].[SH:36][C:37]1[N:41]([CH3:42])[N:40]=[N:39][N:38]=1.O>CS(C)=O>[CH3:1][N:2]1[C:10]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][S:36][C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: Cn1nnnc1S
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: Cn1nnnc1SCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 55 °C
Yield: 46.1 %

Procedure:
100 mg of the product of Example 58 in 10 ml of DMSO were treated with 120 mg of 5-mercapto-1-methyltetrazole sodium salt. The solution was heated at 55° C. for 6 hours, then cooled and poured into water. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extracts were dried and concentrated. Chromatography on silica gel with dichloromethane/ethyl acetate (4:1) gave 48 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(1-methyl-5-tetrazolylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 95°-97° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][C:22]([CH3:28])=[N:23]4)[CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:29][S:30]([Cl:33])(=[O:32])=[O:31]>>[ClH:33].[ClH:33].[CH3:1][O:2][C:3]1[C:9]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][C:22]([CH3:28])=[N:23]4)[CH2:16][CH2:17]2)=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(N)cccc1CCN1CCN(c2cccc3nc(C)ccc23)CC1
Product: COc1c(CCN2CCN(c3cccc4nc(C)ccc34)CC2)cccc1NS(C)(=O)=O
Product: Cl
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield according to the general procedure for the preparation of amides (Method B) starting from 2-(methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline and methanesulfonyl chloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([OH:20])=O)=[CH:16][N:17]=3)[CH:14]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:32][C:33]1[CH:34]=[C:35]([C:40]2[N:44]=[C:43]([CH:45]3[CH2:48][N:47]([C:49]([O:51][CH3:52])=[O:50])[CH2:46]3)[O:42][N:41]=2)[CH:36]=[CH:37][C:38]=1[CH3:39]>ClCCl.N1C=CC=CC=1>[CH3:39][C:38]1[CH:37]=[CH:36][C:35]([C:40]2[N:44]=[C:43]([CH:45]3[CH2:46][N:47]([C:49]([O:51][CH3:52])=[O:50])[CH2:48]3)[O:42][N:41]=2)=[CH:34][C:33]=1[NH:32][C:18]([C:15]1[N:13]2[CH:14]=[C:9]([CH2:8][CH2:7][N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[CH:10]=[CH:11][C:12]2=[N:17][CH:16]=1)=[O:20]
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Reactant: O=C(O)c1cnc2ccc(CCN3CCOCC3)cn12
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCN6CCOCC6)cn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-(2-morpholinoethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (241) (50 mg, 0.182 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (17 uL, 0.200 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated. A stirring mixture of the acid chloride and methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (26 mg, 0.0908 mmol) in anhydrous pyridine (1.5 mL) was stirred at room temperature for 2 hours. The crude product was purified by reverse phase preparative HPLC to give methyl 3-(3-(4-methyl-3-(6-(2-morpholinoethyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F66). 1H NMR (400 MHz, d6-DMSO) δ 10.07 (s, 1H), 9.46 (s, 1H), 8.61 (s, 1H), 8.12 (d, J=1.6 Hz, 1H), 7.86-7.83 (m, 2H), 7.52-7.49 (m, 2H), 4.39-4.36 (m, 2H), 4.31-4.26 (m, 1H), 4.21-4.17 (m, 2H), 4.03-4.00 (m, 2H), 3.69-3.63 (m, 2H), 3.59 (s, 3H), 3.54-3.44 (m, 4H), 3.14-3.10 (m, 4H), 2.38 (s, 3H). MS m/z 546.24 (M+1)+.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[O:9]=[C:7]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(=O)SC/C(=C\c1ccc(-c2ccccc2)cc1)C(=O)O
Product: CC(=O)SC/C(=C\c1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
The (Z)-2-acetylthiomethyl-3-(4-phenylphenyl)propenoic acid obtained in step C is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.Cl.[CH3:48][N:49]([CH3:54])[CH2:50][C:51](O)=[O:52].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:51](=[O:52])[CH2:50][N:49]([CH3:54])[CH3:48])=[CH:42][CH:41]=2)=[N:17]1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 16 %

Procedure:
The title compound was prepared as described in Example 379, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.304 g, 0.50 mmol) in methylene chloride (3 mL) was added N,N-dimethylglycine hydrochloride (0.137 g, 0.98 mmol), 1-hydroxybenzotriazole (0.081 g, 0.60 mmol), and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.115 g, 0.60 mmol). The final crude product was purified by preparative HPLC (10–70% acetonitrile in H2O, 20 min.) (0.029 g, 16% yield): 1H NMR (DMSO-d6) δ 14.3 (br s, 1H), 13.38 (br s, 1H), 9.91 (s, 1H), 8.69 (s, 1H), 8.08 (d, 1H), 7.95 (d, 2H), 7.87 (d, 2H), 7.68 (d, 1H), 3.12 (s, 2H), 2.30 (s, 6H); ES-MS (m/z) 362 [M+1]+.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16]>C(Cl)Cl>[CH3:14][Si:15]([CH3:17])([CH3:16])[O:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)O
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C(C)(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
To a solution of 1.2 mL (10.4 mmol) of methyl 2-hydroxyisobutyrate in 50 mL of CH2Cl2 were added 1.2 g (17.6 mmol) of imidazole and 2.1 mL (16.6 mmol) of TMSCl. The mixture was stirred at r.t. for 1.5 h and quenched with 20 mL of H2O. The organic layer was dried over MgSO4, concentrated and passed through a short plug of silica gel eluted with 9:1 hexane/EtOAc. Evaporation of solvent afforded 1.27 g of the title compound as a colorless oil.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1)(=O)=O.[I-:19].[Na+]>CC(C)=O.O>[I:19][C@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](I)C1
Yield: 42.7 %

Procedure:
A solution of tert-butyl N-[(1S,3R)-3-(methanesulfonyloxy)cyclopentyl]carbamate (2.1 g, 7.52 mmol, 1.00 equiv) and sodium iodide (7 g, 46.70 mmol, 6.21 equiv) in acetone (40 mL) was stirred at 50° C. for 30 min. The reaction mixture was diluted with 100 mL of water then extracted with 2×30 mL of ethyl acetate. The combined organic layers was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/5) to give 1.0 g (43%) of tert-butyl N-[(1S,3S)-3-iodocyclopentyl]carbamate as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[NH2:24][C@@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@@H:26]1[OH:34].CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[OH:34][C@H:26]1[CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:25]1[NH:24][C:16]1[S:17][C:13]2[CH:12]=[C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:23])[CH:9]=3)[CH:22]=[CH:21][C:14]=2[N:15]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4c5ccccc5C[C@@H]4O)sc3c2)ccn1
Temperature: 105 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (300 mg, 0.86 mmol) in 5 ml of NMP was added (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (597 mg, 4 mmol) and DIPEA (300 μL, 1.73 mmol). The reaction solution was stirred at 105° C. for 24 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give 4-(2-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (347 mg, 0.63 mmol) as TFA salt. ES/MS m/z 433.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH:10]=[CH2:11])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>C(OCC)C>[Cl:15][CH2:11]/[CH:10]=[CH:9]/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: C=CC(O)c1ccc(OC)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(/C=C/CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the allylic alcohol obtained in step 1 (200 mg) in diethyl ether (3 ml) was added thionyl chloride (0.087 ml) and the solution was stirred at room temperature for 1 h. The solution was concentrated in vacuo to give 221 mg of the desired product (100%) as a colorless solid. Mp=70° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH2:6]([S:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17])[C@H:7]([NH2:11])[C:8]([OH:10])=[O:9].B([O-])([O-])[O-]>>[C:1]([CH2:2][N:11]([CH2:2][C:1]([OH:5])=[O:4])[C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][S:12][S:13][CH2:14][C@H:15]([N:19]([CH2:15][C:16]([OH:18])=[O:17])[CH2:7][C:8]([OH:10])=[O:9])[C:16]([OH:18])=[O:17])([OH:5])=[O:4]
Reactant: O=CC(=O)O
Reactant: N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Agent: [O-]B([O-])[O-]
Product: O=C(O)CN(CC(=O)O)[C@@H](CSSC[C@@H](C(=O)O)N(CC(=O)O)CC(=O)O)C(=O)O

Procedure:
The alternative route, relying on in-solution phase synthesis of an intermediate product starts with addition of a large excess (40 times) of glyoxylic acid to L-cystine in an alkaline borate buffer. The intermediate product, following pH manipulation and conductivity adjustment of the reaction mixture, purified with ion exchange chromatography to give N,N,N′,N′-tetrakis(carboxymethyl)-L-cystine.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH3:4][S:5]([CH2:8]P(=O)(OCC)OCC)(=[O:7])=[O:6].C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[C:27]([C:32](=O)[C:33]([F:36])([F:35])[F:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1.[C:38]1(C)[CH:43]=[CH:42]C=[CH:40][CH:39]=1>O.C(#N)C>[C:4]1([S:5]([CH:8]=[C:32]([C:27]2[CH:26]=[C:25]([Cl:24])[CH:30]=[C:29]([Cl:31])[CH:28]=2)[C:33]([F:36])([F:35])[F:34])(=[O:6])=[O:7])[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1ccccc1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CCOP(=O)(CS(C)(=O)=O)OCC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=S(=O)(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
Magnesium chloride (dry, 241 mg, 2.53 mmol) was put in a flask under a nitrogen atmosphere and acetonitrile (3.5 mL) was added. The mixture was stirred for five minutes at room temperature. Diethyl [(methylsulfonyl)methyl]phosphonate (500 mg, 2.17 mmol) was added. After 10 minutes stirring the magnesium chloride was nearly dissolved. Triethylamine (378 μL, 2.72 mmol) was added and after 10 minutes at room temperature a slightly orange solution was obtained. Then 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (468 mg, 94% purity, 1.81 mmol) was added. After thirty minutes water (10 mL) and toluene (10 mL) were added and the phases were separated. After extracting the aqueous phase with toluene (10 mL) the combined organic phases were dried over sodium sulfate, filtered and the solvents evaporated. 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfone was obtained (540 g, >98% purity, 78% yield, E/Z (not assigned)=56/44).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:20][C:21]([N:23]1[CH2:27][C@@H:26]([F:28])[CH2:25][C@H:24]1[C:29]#[N:30])=[O:22]>>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][C:10]([C:5]12[CH2:6][CH2:7][C:2]([NH:1][CH2:20][C:21]([N:23]3[CH2:27][C@@H:26]([F:28])[CH2:25][C@H:24]3[C:29]#[N:30])=[O:22])([CH2:9][CH2:8]1)[CH2:3][CH2:4]2)=[O:11]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Reactant: NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Yield: 79.6 %

Procedure:
In a similar manner to Example 2, 2-tetrahydropyranyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (62.9 mg) and (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (53.1 mg) were used to obtain (2S,4S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (73.3 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.CN(C)C=O.C1(C)C=CC=CC=1>O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:1][C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(C(=O)OC)c1
Yield: 68 %

Procedure:
Into a 2 liter four-necked flask equipped with a thermometer, a stirrer and a Dean Stark distillation apparatus, 133.24 g (0.63 moles) of dimethyl 5-hydroxyisophthalate, 107.33 g (0.76 moles) of 4-fluoronitrobenzene, 60 ml of N,N-dimethylformamide and 190 ml of toluene were placed. The resultant mixture was stirred at 165° C. for 4 hours while water formed as the byproduct was removed by azeotropic distillation. After cooling, the obtained reaction mixture was poured into 3 liters of ion-exchanged water and the product was precipitated. The formed precipitates were separated by filtration and washed with ion-exchanged water and ethanol. The obtained light yellow solid substance was dried under a reduced pressure at 50° C. for 1 day and 142.01 g of a product was obtained (the yield: 68%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C@H:13]2C[C@@H:14]2C(O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:7]1([C@H:13]2[CH2:14][C@@H:1]2[C:2]([Cl:4])=[O:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@H]1C[C@@H]1c1ccccc1
Solvent: ClCCl
Product: O=C(Cl)[C@H]1C[C@@H]1c1ccccc1
Reaction time: 2.5 h

Procedure:
In a dry 100 ml round-bottomed flask was added oxalyl chloride (2.0 ml, 23 mmol) to 8B (0.25 g, 1.5 mmol) in CH2Cl2 at room temperature to give a yellow solution. In 2.5 hours, the reaction was complete. The crude mixture was concentrated in vacuo and residual TFA was removed azeotropically with toluene 3 times to give the desired product (1S,2S)-2-phenylcyclopropanecarbonyl chloride (8B-1), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][N:22]1[CH:30]=[N:29][C:28]2[C:23]1=[N:24][C:25]([NH2:32])=[N:26][C:27]=2Cl)[C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=[O:34]>O>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][N:22]1[CH:30]=[N:29][C:28]2[C:27](=[O:34])[NH:26][C:25]([NH2:32])=[N:24][C:23]1=2)[C@H:11]([OH:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COCc1ccccc1)Cn1cnc2c(Cl)nc(N)nc21
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@@H](O)[C@@H](COCc1ccccc1)Cn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 48 h

Procedure:
A solution of 24 (4.3 g, 9.03 mmol) in a mixture of TFA (60 ml) and water (20 ml) was kept at room temperature for 2 days until almost no starting 24 was seen by HPLC analysis. The reaction was concentrated, co-evaporated with acetionitrile (3×100 ml) to remove most of TFA and water and re-dissolved in THF (100 ml), triethylamine (2 ml) was added to neutralize residual TFA followed by 12 ml of 1 M tetrabutylammonium fluoride in THF. The reaction was allowed to proceed for 2 hrs (monitored by HPLC), concentrated and treated with water (70 ml) and ethyl acetate. At this point crystallization of 25 started as a gelatinous solid. After being allowed the solid to form for several hours the mixture was filtered to collect the solid, which was washed with 33% ethyl acetate in hexane and dried to afford 1.65 g of 25. The aqueous phase was extracted with ethyl acetate. All ethyl acetate extracts, including the very first one, were combined, concentrated and chromatographed on silica in a gradient of MeOH (10-20%) in dichloromethane to afford 0.75 g of 25 (combined yield—2.4 g, 77%). 1H NMR (DMSO-d6): δ 10.53 (s, 1H), 7.57 (s, 1H), 7.30 (m, 5H), 6.42 (s, 2H), 4.80 (d, J=4.8 Hz, 1H), 4.36 (d, J=1.5 Hz, 2H), 4.11 (m, 1H), 3.99 (m, 1H), 3.67 (m, 1H), 3.32 (m, 2H), 2.10 (m, 1H), 1.09 (d, J=6.3 Hz, 3H).
Reaction SMILES: [N:1]1([C:7](=[O:29])[CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH:22]=[CH:23][CH2:24][CH:25]=[CH:26][CH2:27][CH3:28])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:30](O)(=[O:38])[C:31]1[C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:33].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[OH:33][C:32]1[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=1[C:30]([N:4]1[CH2:5][CH2:6][N:1]([C:7](=[O:29])[CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH:22]=[CH:23][CH2:24][CH:25]=[CH:26][CH2:27][CH3:28])[CH2:2][CH2:3]1)=[O:38]
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCNCC1
Reactant: O=C(O)c1ccccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCN(C(=O)c2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
To a mixture of 1-(piperazin-1-yl)-docosa-4,7,10,13,16,19-hexaen-1-one (1.17 g, 2.95 mmol), salicylic acid (0.61 g, 4.43 mmol) and Et3N (0.89 g, 8.85 mmol) in CH3CN (10 mL) was added HATU (1.68 g, 4.43 mmol), and the mixture was stirred (RT, 16 h). The solvent was removed under reduced pressure and the residue was extracted with EtOAc (4×50 mL). The combined organic layers were washed successively with 1N HCl, water, 5% NaHCO3 and water, and dried over MgSO4. The solvent was removed under reduced pressure. Purification of the crude product by preparative HPLC afforded 1-(4-(2-hydroxybenzoyl)piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (300 mg, 19.6%) as a light yellow oil. Mass calculated for C33H44N2O3=516.71; found: [M+H]+517.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]([CH3:13])(O)[CH2:6][CH2:5]2.C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[CH:3]=1
Reactant: CC1(O)CCc2cc(Cl)ccc2C1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2cc(Cl)ccc2c1

Procedure:
A solution of 6-chloro-2-methyl-1,2,3,4-tetrahydronaphthalene-2-ol (11.3 g, 57.5 mmol) and Ph3COH (16.5 g, 63 mmol) in 80 mL of TFA is stirred for 2.5 days. After this time, the solution is concentrated to dryness. The residue is dissolved in CH2Cl2. The organic layer is washed with H2O, saturated NaHCO3, and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with hexanes. The title compound is obtained as a white solid (4.05 g, 22.9 mmol). 1H NMR (CDCl3, 300 MHz) δ7.78 (s, 1H), 7.69 (m, 2H), 7.58 (s, 1H), 7.50 (m, 2H), 2.49 (s, 3H).