Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:12]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][CH:14]=[C:13]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)[CH2:9][CH2:10][CH3:11].[O-:28][C:29]#[N:30].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO>[CH2:8]([N:12]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][CH:14]=[C:13]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:29]([NH2:30])=[O:28])[CH:22]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1c(CCC)ccc1Cc1cccc(N)c1
Reactant: N#C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCn1c(CCC)ccc1Cc1cccc(NC(N)=O)c1
Yield: 90.5 %

Procedure:
A solution of 11.4 ml (148 mmol) of trifluoroacetic acid in 100 ml of methylene chloride was added dropwise to a mixture of 20 g (74 mmol) of 1-butyl-2-(3'-aminobenzyl)-5-propylpyrrole dissolved in 80 ml of methylene chloride, 20 ml of methanol, and 9.6 g (148 mmol) of sodium cyanate, at room temperature and under stirring. The reaction mixture was stirred for an hour further, poured into 500 ml of saturated sodium carbonate solution and extracted with 200 ml of methylene chloride and 200 ml of ethyl acetate. The combined extracts were washed with water, dried and evaporated under reduced pressure. The residue was purified by column chromatography on 500 g of silica gel, using methylene chloride-methanol (95:5) as eluant, to produce 21 g (91%) of the title compound, 1-butyl-2-(3'-ureidobenzyl)-5-propylpyrrole, which was recrystallized from acetone-hexane.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][CH2:13][CH2:14]CCC.C([Li])CCC.C(Br)C#C>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][N:2]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[C:12]#[C:13][CH3:14]
Reactant: CNc1nc2ccccc2s1
Reactant: CCCCCC
Agent: C#CCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC#CN(C)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
2-Methylaminobenzothiazole (c) (14.0 g) was dissolved in anhydrous tetrahydrofuran (250 ml) and a hexane solution (73 ml) of butyl lithium (6.53 g) was added thereto at -78° C. with stirring. The mixture was stirred for 1.5 hours under cooling and 2-propynyl bromide (8.4 ml) was dropwise added thereto. The resultant mixture was allowed to stand at room temperature overnight and then evaporated to remove the solvent. After addition of water, the residue was extracted with ether. The extract was washed with water, dried and evaporated to remove the solvent. The resultant residue was applied to column chromatography on silica gel (280 g) to give 2-(N-methyl-N-propynylamino)benzothiazole (d) (14.5 g, yield 84%) from chloroform eluate.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[C:3]([O:7][C:8]([NH:10][C@@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH:14]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: BrCC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(CC2CCC2)c2ccccc12)C(=O)O
Reaction time: 0.33 h

Procedure:
In a 20 mL vial, NaH (60% in mineral oil) (0.092 g, 2.30 mmol) was added to a solution of N-(tert-butoxycarbonyl)-D-tryptophan (0.200 g, 0.657 mmol) in anhydrous N,N-dimethylformamide (4 mL) at 0° C. The reaction mixture was placed in a shaker for 20 min. at 0° C. (Bromomethyl)cyclobutane (0.074 mL, 0.657 mmol) was added to the solution and allowed to react for 10 hours at 0° C. The reaction mixture was quenched with H2O and acidified with 1M NaHSO4 until pH=3. The solution was extracted with CH2Cl2, washed with brine, dried over Na2SO4, and concentrated to give the title compound.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:18]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccoc1=O
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(Cc2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A heterogeneous mixture of methyl 2-oxo-2H-pyran-3-carboxylate (2.0 g, 13 mmol, 1.0 eq, Aldrich) and 4-fluorobenzylamine (1.5 mL, 13 mmol, 1.0 eq) in DMF (10 mL) was stirred at room temperature for 3 h. The reaction mixture was treated with EDCI (3.4 g, 18 mmol, 1.4 eq) and DMAP (0.11 g, 9.91 mmol, 0.07 eq) at room temperature and the resulting solution was stirred for 12 h. The reaction mixture was quenched with 1 N aqueous HCl and the solution was extracted with ethyl acetate (4×50 mL). The combined organic extracts were washed with 10% aqueous LiCl (3×70 mL), dried (Na2SO4), filtered and the filtrate concentrated in vacuo to afford the product (2.5 g, 73%) as a solid, which was used without further purification. 1H NMR (DMSO-d6) δ 8.17-8.20 (m, 1H), 8.03-8.05 (m, 1H), 7.38-7.46 (m, 2H),7.16-7.22 (m, 2H), 6.37 (dd, 1H, J=6.94 Hz), 5.13 (s, 2H), 3.73 (s, 3H); HRMS(ESI): calcd.: 262.0879, found: 262.0885.
Reaction SMILES: [C:1]([C:6]1[S:13][C:12]2[C:11]3[S:14][C:15]4[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CCCCCCC)=[C:18]([C:37]([O:39]CC)=[O:38])[S:17][C:16]=4[C:10]=3[S:9][C:8]=2[C:7]=1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]CCCCCCC)([O:3]CC)=[O:2].CO.[OH-].[Li+]>O1CCCC1.O>[CH2:20]([C:19]1[C:15]2[S:14][C:11]3[C:12]4[S:13][C:6]([C:1]([OH:3])=[O:2])=[C:7]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:8]=4[S:9][C:10]=3[C:16]=2[S:17][C:18]=1[C:37]([OH:39])=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCc1c(C(=O)OCC)sc2c1sc1c3sc(C(=O)OCC)c(CCCCCCCCCCCCCCCCC)c3sc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCc1c(C(=O)O)sc2c1sc1c3sc(C(=O)O)c(CCCCCCCCCC)c3sc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
Ester deprotection (Step C) The 2,6,-dicarboethoxy-3,7-diheptadecylthieno[3,2-b]thieno[2′,3′:4,5]thieno[2,3-d]thiophene (5.00 g, 7.39 mmol) product of Example 6, was dissolved in tetrahydrofuran (THF) (280 mL) then methanol (40 mL) was added. Lithium hydroxide (707 mg, 29.5 mmol) was dissolved in water (7 mL) and added to the stirred methanol and THF solution. A condenser was fitted and the reaction mixture was heated in an oil bath at 90° C. for 16 hr. The THF and methanol were removed under reduced pressure. 60 mL of methanol and 10 mL of conc. hydrochloric acid were added then stirred for 4 h. Next 50 mL of water was added and the solid was filtered off. The product was dried under vacuum to give the 3,7-didecanyl thieno[3,2-b]thieno[2′,3′:4,5]thieno[2,3-d]thiophene-2,6-dicarboxylic acid (4.50 g, 98% yield). 1H NMR (D8-THF)(of the di-lithium salt) δ 0.88 (6H, t, J=6.9 Hz), 1.20-1.47 (28H, m), 1.70-1.86 (4H, m), and 3.24 (4H, t, J=7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[K+].CS(C)=O.Br[CH2:22][CH2:23][CH2:24][Cl:25]>O>[ClH:25].[ClH:25].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: ClCCCBr
Reactant: Cc1ccc(CN2CCNCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(CN2CCN(CCCCl)CC2)cc1
Product: Cl
Reaction time: 0.75 h
Yield: 274.5 %

Procedure:
A mixture of 14.0 g of 1-(4-methylbenzyl)piperazine, 8.0 g of potassium hydroxide and 125 ml of dimethyl sulfoxide was stirred for 45 minutes. 11.8 g of 1-bromo-3-chloropropane were then added, and the mixture was stirred for an additional hour. Water was added, and the product was extracted with ether, and the extract was dried (sodium sulfate) and treated with ethereal hydrochloric acid to give 23.3 g (94% of theory) of 1-(4-methylbenzyl)-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid. (b) The procedure described in Example 1(b) was followed, using 7.7 g of thiourea, 23.0 g of 1-(4-methylbenzyl)-4-(3-chloropropyl)piperazine dihydrochloride, 6.5 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 6.0 g of sodium hydroxide in 40 ml of water. Work-up, as described above, gave 16.4 g (72% of theory) of 3-[4-(4-methylbenzyl)piperazin-1-yl] propanethiol dihydrochloride as a white crystalline solid, M.p. 273°-277° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[S:3]1.I[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[CH:8]=2)[S:3]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)S2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)S3)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A solution of 110.7 mg (0.481 mmol) of 2,2,4,4,-tetramethyl-6-ethynylthiochroman (Compound 3) and 142.3 mg (0.516 mmol) of ethyl 4-iodobenzoate (Compound 97) in 2 ml of triethylamine was placed in a heavy walled glass tube and degassed under argon. The mixture was then treated with a finely ground mixture of 42 mg (0.221 mmol) of cuprous iodide and 63 mg (0.09 mmol) of bis (triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed under argon again and the tube was sealed. The mixture was stirred at room temperature for 40 hours. The triethylamine was removed under vacuum and the residue purified by flash chromatography (silica, 3% ethyl acetate in hexanes) to give the title compound as a pale yellow solid. PMR (CDCl3): δ 1.37-1.42 (15H, m), 1.96 (2H, s), 4.38 (2H, q, J~7.0 Hz), 7.25 (1H, dd, J~8.2 Hz, 1.8 Hz), 7.33 (1H, d, J~1.8 Hz), 7.37 (1H, d, J~8.2 Hz), 7.65 (2H, d, J~8.6 Hz), 8.01 (2H, d, J~8.6 Hz). MS exact mass, m/e 378.1636 (calcd. for C24H26O2S, 378.165.3).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)C(C)C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1C=CC=CC=1>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: CCOC(=O)CCCCCNc1ccccc1-c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCN(C(=O)c1ccc(Cl)cc1)c1ccccc1-c1ccccc1
Yield: 44.3 %

Procedure:
20.0 g of 2-aminobiphenyl, 15.3 g of ethyldiisopropylamine and 26.3 g of ethyl 6-bromocaproate are reacted, analogously to Example 47a), to obtain 36.0 g of ethyl 6-(biphenyl-2-yl)aminocaproate as a non-crystallizing oil. 18.0 g of this ester are reacted, analogously to Example 47b), with 7.5 g of ethyldiisopropylamine and 10.1 g of p-chlorobenzoyl chloride in 70 ml of benzene. The resulting reaction product is purified chromatographically over a silica gel column (eluent: methylene chloride) to obtain 11.5 g (44.2% of theory) of ethyl 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproate as a viscous non-distillable oil. Saponification of this ester yields 8.1 g (75.1% of theory) of 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproic acid, MP 93° to 95°.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:40]([O:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:48][CH2:49][N:50]([C:30]2[CH:31]=[CH:32][C:24]([NH:23][C:21]3[C:20]([C:36]([F:38])([F:37])[F:39])=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:12]=[CH:11][C:10]([CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:5][CH2:6][CH3:7])=[O:8])=[CH:15][CH:14]=4)[N:22]=3)=[C:25]3[C:29]=2[CH2:28][N:27]([CH3:34])[C:26]3=[O:35])[CH2:51][CH2:52]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(CC(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and piperazine-1-acetic acid tert-butyl ester. MS (ES+): m/z 748.41 (100) [MH+]; HPLC: tR=0.85 min (UPLC, purity).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:34]([N:38]1[C:43](=[O:44])[C:42](COS(C)(=O)=O)=[CH:41][C:40]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)=[N:39]1)[CH:35]([CH3:37])[CH3:36].[CH3:61]N1CCNCC1>>[CH2:34]([N:38]1[C:43](=[O:44])[C:42]([N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[C:41]([CH3:61])[C:40]([C:51]2[CH:52]=[CH:53][C:54]([C:57]([F:59])([F:60])[F:58])=[CH:55][CH:56]=2)=[N:39]1)[CH:35]([CH3:37])[CH3:36]
Reactant: CN1CCNCC1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(COS(C)(=O)=O)c1=O
Product: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(CC(C)C)c(=O)c1N1CCN(C)CC1
Yield: 81.1 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 81.1%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](=[O:9])[CH3:8])=[C:5]([CH3:10])[O:4][N:3]=1.[BrH:11].BrBr.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[Br:11][CH2:8][C:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[CH3:10])=[O:9]
Reactant: CC(=O)c1c(C)noc1C
Reactant: Br
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1noc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
400 mg (2.87 mmol) of 1-(3,5-dimethylisoxazol-4-yl)ethanone are dissolved in 20 mL of glacial acetic acid. 1.42 mL (8.62 mmol) of hydrobromic acid and 163 μl (3.16 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 2 hours. The solution is diluted with water, basified with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 540 mg of 2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone, corresponding to the following characteristics:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH:38][C:39]([C:41]2([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[F:54])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:40])=[CH:32][CH:31]=1)[CH3:29].[F:55][C:56]1[CH:61]=[CH:60][C:59]([CH2:62][CH2:63][C:64](O)=[O:65])=[CH:58][CH:57]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH2:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH:38][C:39]([C:41]2([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[F:54])[CH2:42][CH2:43][N:44]([C:64](=[O:65])[CH2:63][CH2:62][C:59]3[CH:60]=[CH:61][C:56]([F:55])=[CH:57][CH:58]=3)[CH2:45][CH2:46]2)=[O:40])=[CH:32][CH:31]=1)[CH3:29]
Reactant: CCc1ccc(CCNC(=O)C2(Cc3ccccc3F)CCNCC2)cc1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1ccc(CCNC(=O)C2(Cc3ccccc3F)CCN(C(=O)CCc3ccc(F)cc3)CC2)cc1
Yield: 40.3 %

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.266 g, 0.602 mmol) was added to a solution of 4-(2-fluoro-benzyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide (0.185 g, 0.502 mmol), 3-(4-fluoro-phenyl)-propionic acid (0.101 g, 0.602 mmol) and triethylamine (0.210 mL, 1.51 mmol) in tetrahydrofuran (5 mL). After 1 h the mixture was diluted with ethyl ether (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). The organic layer was collected, concentrated under reduced pressure and the crude product purified by column chromatography to give 0.105 g (40%) of 4-(2-fluoro-benzyl)-1-[3-(4-fluoro-phenyl)-propionyl]-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide LRMS m/z 519.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([Br:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>C(OCC)C>[Br-:11].[CH3:13][NH+:14]1[CH:18]=[CH:17][N:16]([CH:9]([CH3:10])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:12])[CH2:15]1
Reactant: Cc1ccc(C(=O)C(C)Br)cc1
Reactant: Cn1ccnc1
Solvent: CCOCC
Product: Cc1ccc(C(=O)C(C)N2C=C[NH+](C)C2)cc1
Product: [Br-]
Yield: 10.6 %

Procedure:
A solution 2.24 g (0.01 mol) of 1-(4-methylphenyl)-1-oxo-2-bromopropane and 0.9 g (0.011 mol) of 1-methylimidazole in 50 ml of diethyl ether was stirred at room for approximately 18 hours. The reaction solvent was decanted, and the residue was washed with diethyl ether and dissolved in acetonitrile. The resulting solution was diluted with diethyl ether and the precipitated solid was collected by filtration. The solid was recrystallized from acetonitrile/diethyl ether to afford 0.33 g of 1-methyl-3-[1-methyl-2-(4-methylphenyl)-2-oxoethyl]-1H-imidazolium bromide as a solid. (11% yield) mp=175°-177° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Cl[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][N+:12]=1[O-:20].O>C1COCC1>[N+:17]([C:15]1[CH:14]=[CH:13][N+:12]([O-:20])=[C:11]([O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:16]=1)([O-:19])=[O:18]
Reactant: Oc1cccnc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc[n+]([O-])c(Oc2cccnc2)c1
Yield: 83 %

Procedure:
Sodium hydride (0.27 g of an 80% dispersion in oil, 9 mmol) was added to a solution of 3-hydroxypyridine (0.854 g, 9 mmol) in THF (3 ml) at 0° C. The mixture was then stirred for 1 h at room temperature before 2-chloro-4-nitropyridine-N-oxide* (2 g, 9 mmol) was added. The resulting solution was heated at reflux for 16 h, cooled, poured into water (100 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica using ethyl acetate as eluant to afford the title compound (1.74 g, 83%) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH:11]([O-])([O-])OC.[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH3:27])=[C:21]([CH:23]=1)[NH2:22]>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH3:27])=[C:21]([NH:22][CH:11]=[C:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])[CH:23]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCOc1ccc(F)cc1N
Reactant: COC([O-])[O-]
Product: CCCOc1ccc(F)cc1NC=C1C(=O)OC(C)(C)OC1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Meldrum's acid (5.29 g, 36.7 mmol) was added to methyl orthoformate (31 ml), and the mixture was stirred for 2 hours while heating under reflux. The resulting mixture was cooled to 50° C., and 5-fluoro-2-propoxyaniline (4.28 g, 25.3 mmol) and methyl orthoformate (3 ml) were added thereto. The resulting mixture was stirred for 6 hours while heating under reflux. The resulting reaction mixture was then cooled to room temperature, and concentrated under reduced pressure. The residue was recrystallized from methanol to thereby obtain 7.61 g of powdery pale brown 5-[(5-fluoro-2-propoxyphenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (yield: 93%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[C:11]2[CH3:18])=[O:7])[CH3:4].[C:19](Cl)(=[O:21])[CH3:20].O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:19](=[O:21])[CH3:20])[C:12]([CH3:17])=[C:11]2[CH3:18])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
Sodium hydride (0.8 g of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 2,3-dimethylindole-5-carboxylic acid ethyl ester (3.50 g) in dry N,N-dimethylformamide (25 ml) and the mixture was stirred at room temperature for 30 minutes and then cooled to 0°. A solution of acetyl chloride (1.27 g) in dry N,N-dimethylformamide (2.5 ml) was added dropwise with stirring over 2 minutes. The resulting mixture was stirred at room temperature for 3 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform first gave mineral oil followed by product. Evaporation of the product-containing fractions gave a solid which was crystallised from ethyl acetate/petrol (b.p. 60°-80°) to give 1-acetyl-2,3-dimethylindole-5-carboxylic acid ethyl ester (1.22 g), m.p. 98°-101°.
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[NH2:24][CH2:25][CH2:26][S:27]([O-:29])=[O:28].[Na+].OC1C=CC(NC(=O)C)=CC=1.O>C(#N)C>[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][C:1]([NH:24][CH2:25][CH2:26][S:27]([OH:29])=[O:28])=[O:23])=[CH:8][CH:7]=1)(=[O:12])[CH3:11]
Reactant: NCCS(=O)[O-]
Reactant: CC(=O)Nc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: CC(=O)Nc1ccc(O)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc(OC(=O)NCCS(=O)O)cc1

Procedure:
Title compound 11a was prepared according to the General Method for the Reaction of Alkali Metal Salts of Amino Acid Derivatives with 4-Acetamidophenyl 4-Nitrophenyl Carbonate (3). A solution of 410 mg (3.20 mmol) of sodium 2-aminoethanesulfinate (5) in approximately one (1) mL of degassed water was reacted with a solution of 4-acetamidophenyl 4-nitrophenyl carbonate (3) (1.01 g, 3.19 mmol) in 10 mL of acetonitrile (MeCN). After work-up procedures, the aqueous layer was lyophilized off to afford 910 mg (˜quantitative yield) of the crude 2-((4-acetamidophenoxy)carbonylamino)ethanesulfinic acid (11a) which was used directly and without further isolation or purification procedures in the next step. The material thus obtained was contaminated with some sodium chloride (NaCl) and/or other sodium salts. 1H NMR (300 MHz, D2O): δ 7.22 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 3.31 (t, J=6.6 Hz, 2H), 2.42 (t, J=6.6 Hz, 2H), 1.96 (s, 3H). LC/MS (ESI): m/z=287.1 [M+H]+.