Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1N.Cl.N([O-])=O.[Na+].[I-:18].[K+]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[I:18]
Reactant: [I-]
Reactant: CS(=O)(=O)c1ccc(N)c(Cl)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)c1ccc(I)c(Cl)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-4-Methylsulfonylaniline in a 1:1:3 mixture (0.4 M) of Acetic Acid, Hydrochloric Acid, 37% and Water was cooled to 0° C. and slowly treated with a 4 M solution of sodium nitrite in water. The reaction was stirred at 5° C. for 30 minutes then treated dropwise with a 2M solution of potassium iodide in water. The reaction evolved a gas and turned brown. The reaction was stirred 15 minutes at 0° C., 40 minutes at rt and 1 h at 60° C. The brown solid was filtered, dissolved in ethyl acetate and the solution washed with acidified sodium thiosulfate and then brine. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. During evaporation, a precipitate appeared and was filtered. The mother liquors were evaporated further and 2 more crops were collected. The last mother liquor was transferred with diethyl ether and upon evaporation yields more products.
Reaction SMILES: Cl[Si:2]([CH3:22])([CH3:21])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4]1.CCN(CC)CC.[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31]>CCCCCC>[CH3:31][C:30]([NH:34][Si:2]([CH3:22])([CH3:21])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4]1)([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: C[Si](C)(Cl)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)N[Si](C)(C)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Reaction time: 24 h
Yield: 88.7 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-3-phenyl-s-indacen-1-yl)silane (10.8277 g, 0.03322 moles) was stirred in hexane (150 mL) as NEt3 (3.5123 g, 0.03471 moles) and t-butylamine (2.6074 g, 0.03565 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a thick red-yellow oil (10.6551 g, 88.7% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:24][C:21]1[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Reactant: COc1ccc(N)cn1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cn1
Reaction time: 8 h

Procedure:
6-Bromo-4-chloro-3-nitroquinoline (compound of step 1, 5.2 mmol) and 6-methoxypyridin-3-amine (commercially available, 5.2 mmol) was dissolved in acetic acid (5 mL) and the mixture was stirred overnight. Water was added and the yellow precipitate was filtered off. The precipitate was washed with water and dried. The solid obtained was partitioned and extracted with EtOAc and THF, washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the title compound. 1H NMR (DMSO-d6, 300 MHz): 10.03 (s, 1H), 9.01 (s, 1H), 8.72 (d, J=1.5 Hz, 1H), 8.04-7.90 (m, 3H), 7.50 (dd, J=2.4, 8.7 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 3.85 (s, 3H); MS (m/z): 377.0 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][S:16][C:10]=2[S:9][CH2:8][CH2:7]1.[Br:17]Br.O>C(O)(=O)C>[Br:17][C:15]1[S:16][C:10]2[S:9][CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:12](=[O:13])[C:11]=2[CH:14]=1
Reactant: BrBr
Reactant: O=C1c2ccsc2SCCN1CCCCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cc(Br)sc2SCCN1CCCCCl
Temperature: 60 °C

Procedure:
To a solution of 3.0 g of 4-(4-chlorobutyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 60 ml of acetic acid was added 1.5 ml of bromine with stirring at 60° C. and the mixture was stirred for 20 minutes at the same temperature. The mixture was poured into chilled water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The resulting crystals were recrystallized from ethanol to give 2.0 g of 7-bromo-4-(4-chlorobutyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one as white crystals, melting at 81°-89° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]([OH:14])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:20][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[CH:7][C:8]=2[OH:14])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Product: CC(C)(C)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 53.8 %

Procedure:
Using 5-[(1,1-dimethyl)ethyl]salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1cc(CN2CCCCC2)ccc1NC1CCCCC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyclohexylamino-3-nitrobenzaldehyde (10.3 g, 41.3 mmol) in dichloroethane (50 mL) was added piperidine (4.10 g, 48.2 mmol) followed by acetic acid (0.20 mL, cat.). The reaction mixture was heated to 60° C. and stirred for 1 hr, then cooled to room temperature and sodium triacetoxyborohydride (10.5 g, 49.5 mmol) was added in a single portion. After stirring for 18 hr at room temperature, the reaction was quenched by the addition of sodium bicarbonate (sat., aq., 100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were then evaporated to afford crude N-cyclohexyl-2-nitro-4-(1-piperidinylmethyl) aniline as a yellow oil (15.4 g crude yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:9][CH2:8][CH2:7][S:6]1)=[O:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:35]([S:38][CH2:39][CH:40]([CH3:44])[C:41](O)=[O:42])(=[O:37])[CH3:36]>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[N:9]([C:41](=[O:42])[CH:40]([CH3:44])[CH2:39][S:38][C:35](=[O:37])[CH3:36])[CH2:8][CH2:7][S:6]1)=[O:4]
Reactant: COC(=O)C1NCCS1
Reactant: CC(=O)SCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)C1SCCN1C(=O)C(C)CSC(C)=O
Temperature: 0 °C

Procedure:
2-Thiazolidinecarboxylic acid methyl ester (C.A. 53, 12, 281) (4.4 g.) and 3-hydroxybenzotriazole (4.0 g.) are dissolved in dichloromethane (40 ml.) and the solution is stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g.) in dichloromethane (5 ml.). After fifteen minutes stirring in the ice bath, and sixteen hours at room temperature, the precipitate is filtered off and the filtrate is washed neutral. The organic layer is dried and concentrated to dryness in vacuo to give 3-(3-acetylthio-2-methylpropanoyl)-2-thiazolidinecarboxylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[Br-].[CH2:16]([Zn+])[CH:17]([CH3:19])[CH3:18]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN1CCCC1=O>[C:13]([C:12]1[C:2]([CH2:16][CH:17]([CH3:19])[CH3:18])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:14]
Reactant: CCOC(=O)c1cnc(Cl)c(C#N)c1
Reactant: CC(C)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnc(CC(C)C)c(C#N)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 145 mg (0.69 mmol) of ethyl 6-chloro-5-cyanonicotinate (from Step B), 1.65 mL (0.83 mmol) of isobutylzinc bromide (0.5 M in THF), and 100 mL of 1-methyl-2-pyrrolidinone was added 18 mg (0.03 mmol) bis(tri-tert-butylphosphine)palladium(0). After stirring at 65° C. overnight, the reaction mixture was cooled to rt and filtered through a cake of Celite. The filtrate was concentrated. Chromatography on a Biotage 40S cartridge using 1:19 v/v EtOAc/hexanes as the eluant gave 75 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 0.99 (d, J=6.7, 6H), 1.43 (t, J=7.1, 3H), 2.27 (m, 1H), 2.99 (d, J=7.3, 2H), 4.45 (q, J=7.1, 2H), 8.50 (d, J=2.1, 1H), 9.28 (d, J=2.3, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][Si](C(C)(C)C)(C)C)=[CH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)CC2CCN(Cc3ccccc3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(CC1CCN(Cc2ccccc2)CC1)c1ccc(O)cc1
Yield: 26.9 %

Procedure:
A mixture of 1-benzyl-4-(2'-(4''-t-butyldimethylsilyloxyphenyl)-2'-oxoethyl)piperidine (Example 75, 1.21 g, 2.86 mmol), a solution of tetra-n-butylammonium fluoride (1.0 M in tetrahydrofuran, 5.7 mL, 5.7 mmol) and tetrahydrofuran (10 mL) were stirred at ambient temperature under a nitrogen atmosphere overnight. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate and filtered. Drying in vacuo gave the title compound (238 mg): mp 197°-198° C.; 1H-NMR (CDCl3, 300 MHz): 7.8(d,2H,J=8), 7.4-6.8(m,7H), 3.5(s,2H), 3.2-3.0(br s,4H), 3.0-2.8(dd,4H,J=10,7), 2.5(s,1H), 2.1-1.2(m,4H); Anal.:Calcd for C20H23NO2 ·0.25H2O: C,76.53, H,7.55, N, 4.40; Found: C,76.63,76.54, H,7.47,7.31, N,4.23,4.26.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])(OCC)=O>C1C=CC=CC=1>[C:14]1(=[O:23])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: NCCCCCO
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
To a solution of 5-amino-1-pentanol (5.00 g, 48.5 mmol) in benzene (150 mL) was added N-carboethoxyphthalimide (11.0 g, 50.2 mmol) and the solution was stirred at room temperature for 5 h). The solvents were removed under reduced pressure to yield a yellow oil. Purification by flash column chromatography using 25% ethyl acetate in petroleum ether yielded the target compound as a clear colorless oil (9.6 mg, 84%).
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([O:17]C)=[O:16])=[CH:12][CH:11]=2)[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH:22]([OH:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C@H:4]([OH:29])[CH2:3]1.Cl[C@H]1[C@H](CCCC2SC(C(O)=O)=CC=2)[C@@H](/C=C/[C@@H](O)CC(O)CCC)[C@H](O)C1>>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=2)[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH:22]([OH:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C@H:4]([OH:29])[CH2:3]1
Reactant: CCCCC(O)[C@H](O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)OC)s2)[C@H](Cl)C[C@H]1O
Agent: CCCC(O)C[C@H](O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)O)s2)[C@H](Cl)C[C@H]1O
Product: CCCCC(O)[C@H](O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)O)s2)[C@H](Cl)C[C@H]1O
Yield: 95 %

Procedure:
Compound 18 (60.9 mg) was prepared in 95% yield using compound 17 according to the procedures described for compound 14 (see Schemes 1 and 2).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)=[N:12]2)[C:7](=[O:33])[CH2:6]1)=[O:4].[OH-].[Na+].Cl>CO>[C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[C:19]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)=[N:12]2)[C:7](=[O:33])[CH2:6]1)([OH:4])=[O:2]
Reactant: COC(=O)[C@@H]1CC[C@H](n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1CC[C@H](n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C(=O)C1
Temperature: 50 °C
Yield: 73.6 %

Procedure:
A mixture of cis-3-[2-(4-methoxycarbonyl-2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (80 mg) and 1N aqueous sodium hydroxide (2 ml) in methanol (4 ml) was heated at 50° C. for 4 hours. The solution was acidified with 1N aqueous hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diethyl ether to give cis-3-[2-(4-carboxy-2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (57 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([S:21][C:22]2[NH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][N:26]=2)[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl.O>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([S:21][C:22]2[NH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][N:26]=2)[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Sc1ncc(-c2ccccc2)[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(Cc1ccc(OCc2ccccc2)cc1)Sc1ncc(-c2ccccc2)[nH]1
Yield: 42 %

Procedure:
The crude product from Step A was dissolved in a MeOH/H2O mixture (2:1, 4 ml). 0.7 g KOH was then added to the solution and the mixture was refluxed for 2 h. Subsequently, the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2; ethyl acetate). The yield was 42%.
Reaction SMILES: [C:1]([C:3]1([CH2:6]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][CH2:4]1)#[N:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=[O:25].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:6][C:3]2([C:1]#[N:2])[CH2:5][CH2:4]2)=[C:23]([CH:24]=[O:25])[CH:26]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2(C#N)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1(COc2ccc(Cl)cc2C=O)CC1
Temperature: 25 °C

Procedure:
To a solution of the crude toluene-4-sulfonic acid 1-cyano-cyclopropylmethyl ester in DMF (30 mL) was added 5-chloro-2-hydroxy-benzaldehyde (5.9 g, 38 mmol) and K2CO3 (10.5 g, 76 mmol) slowly. The reaction mixture was placed in a sealed tube and irradiated by microwave reactor at 75° C. for 30 min. After cooled to room temperature, the mixture was poured into water. The solution was diluted with EtOAc (200 mL), washed with water, dried and concentrated to give the title compound as a black oil (4.76 g). The oil was used for next step reaction directly without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1.CCCCCC.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[CH3:27][N:28]([CH:30]=[C:10]1[CH2:9][C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:18])[CH3:29]
Reactant: O=C1CC[C@@H](c2ccccc2F)c2ccccc21
Reactant: COC(OC)N(C)C
Solvent: CCCCCC
Product: CN(C)C=C1C[C@@H](c2ccccc2F)c2ccccc2C1=O
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of (R)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one (8.0 g, 33.33 mmol) in N,N-dimethylformamide dimethylacetal (80 mL) was heated at 100° C. for 40 h. After the reaction mixture was cooled to room temperature, hexane (50 mL) was added. Product was collected by filtration and dried under high vacuum overnight to yield the title compound as yellow needles (6.95 g, 70% yield). 1H-NMR (DMSO-d6) δ 7.92 (dd, J=7.2 and 1.6 Hz, 1 H), 7.57 (s, 1 H), 7.42-7.34 (m, 2 H), 7.31-7.21 (m, 2 H), 7.09 (t, 1 H), 6.91-6.88 (m, 2 H), 4.48 (t, J=7.2 Hz, 1 H), 3.25-3.13 (m, 2 H), 3.02 (s, 6 H). LCMS m/e 296 [M+H].
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[OH:1][C:2]1[C:3]([C:12]([NH:20][C:19]2[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=2)=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc2ccccc2cc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc2ccccc2cc1O
Yield: 46.9 %

Procedure:
Using 3-hydroxynaphthalene-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:23]([OH:25])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.C[N:27]([CH3:30])C=O>>[NH2:27][C@H:30]([C:16]([NH:18][C@H:19]([C:23]([OH:25])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CN(C)C=O
Product: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
9-Fluorenylmethyloxycarbonyl-L-valine esterified to p-alkoxybenzyl alcohol derivitized 2% crosslinked polystyrene (0.25 gm, 0.13 mmol valine) was placed in a solid phase peptide synthesis vessel. Dimethylformamide (5 mL) was added and the slurry was shaken for 30 min. The dimethylformamide was removed and the swollen resin treated twice with 10% piperidine in dimethylformamide (5 mL for 5 min followed by 5 mL for 15 min) to remove the 9-fluorenylmethyloxycarbonyl protecting group. The resin was washed with dimethylformamide (4×5 mL) and reacted with 9-fluorenylmethyloxycarbonyl-L-leucine-N-carboxyanhydride (145 mg, 0.38 mmol) in dimethylformamide (6 mL) for 45 min. The fluorenylmethyloxycarbonyl protecting group was removed as above and the resin washed with dimethylformamide (3×5 mL) and methylene chloride (3×5 mL). The resulting dipeptide was cleaved from the resin by treatment with methylene chloride/trifluoroacetic acid (6 mL, 1/1) for 45 min. The solution was removed and the resin washed with methylene chloride (3×5 mL) and methanol (2×5 mL). The combined solution and washes were evaporated in vacuo to a semi-solid, which was taken up in distilled water and filtered. The aqueous solution was freeze-dried, the resulting solid triturated with ether(3× ) to remove resin related contaminants, and dried under reduced pressure to give L-leucyl-L-valine in >90% yield. The identity of the dipeptide was confirmed by HPLC analysis (flow rate=1.5 mL/min, detection at 215 nm, 30% methanol in 0.5M perchloric acid) by co-elution with a known standard (Retn. time 8.49 minutes). The purity was determined to be >97%, with all contaminants being traceable to the resin. No D-leucyl-L-valine (Retn. time 32 minutes) could be detected (detection limits <0.1%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:19][CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1>C(#N)C.C(OCC)(=O)C>[CH2:1]([NH:8][CH2:19][CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: BrCCC1OCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc(CNCCC2OCCO2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
To a mixture of benzylamine (2.18 mL, 20.0 mmol) and di-iso-propylethylamine (2.61 mL, 15.0 mmol) in acetonitrile (30 mL) was added 2-(2-bromoethyl)-1,3-dioxolane (1.17 mL, 10.0 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0 to 4% methanol/dichloromethane to afford the title compound (0.836 g, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:5]([CH3:17])[N:6]2[CH2:11][C:12]([O:14]CC)=[O:13].C(N(CC)CC)C.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34].Cl>CC#N.CO.[OH-].[Na+].O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[N:6]([CH2:11][C:12]([OH:14])=[O:13])[C:5]=2[CH3:17])=[CH:24][CH:23]=1
Reactant: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2c(N)cccc21
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)Nc1cccc2c1c(Oc1ccc(Cl)cc1)c(C)n2CC(=O)O
Reaction time: 20 h

Procedure:
The product from step (iv) (250 mg) was dissolved in CH3CN (10 ml). Triethylamine (300 μl) added, followed by ethanesulphonyl chloride (170 μl) and the mixture stirred for 20 h. The reaction was then diluted with MeOH (5 ml), 1M sodium hydroxide (2.1 ml) added and stirred for 5 h. The mixture was diluted with water, acidified with 2M hydrochloric acid, extracted with EtOAc, dried (MgSO4) and evaporated. The residue was purified using reverse phase preparative chromatography (eluent MeCN/NH3(aq)) to give the title compound. Yield 190 mg.