Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:12]=2)[C@H:7]([NH:19][C:20](=[O:25])[O:21][CH:22]([CH3:24])[CH3:23])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([C:27](=[O:29])[CH3:28])[CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:12]=2)[C@H:7]([NH:19][C:20](=[O:25])[O:21][CH:22]([CH3:23])[CH3:24])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)CNc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)CN(C(C)=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
1-Methylethyl {(2S,4R)-1-acetyl-2-methyl-6-[(2-oxopropyl)amino]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see Intermediate 111) (200 mg, 0.553 mmol) was dissolved in acetic anhydride (1044 μl, 11.07 mmol) and the resulting mixture was stirred at room temperature under nitrogen for 1 h then partitioned between water (2 mL) and DCM (5 mL). The layers were separated and the organic phase washed with water, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 10 to 100% AcOEt in hexanes) gave 1-methylethyl {(2S,4R)-1-acetyl-6-[acetyl(2-oxopropyl)amino]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (130 mg, 0.274 mmol, 49%) as an orange oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[C:26](=[O:27])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)CCC>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[C:19](=[O:28])[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:26]4=[O:27])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(-c2ccccn2)c1

Procedure:
To a solution of 2-[1-(3-bromo-phenyl)-1H-benzimidazole-5-ylmethyl]-isoindole-1,3-dione (1.0 g, 2.31 mmol) in anhydrous THF (20 ml) was added 2-tributylstannylpyridine (0.82 ml, 2.54 mmol) and a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (60 mg) and the resultant mixture was stirred at reflux in a nitrogen atmosphere for 3 days. The reaction mixture was quenched with aqueous ammonia and extracted with ethyl acetate. The organic extract was dried over magnesium sulphate and concentrated in vacuo. The concentrate was eluted through silica gel with ethyl acetate to afford the desired product. 0.24 g (24%).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([CH:8]=[CH:9]N(C)C)[CH:7]=1>CCO.[Ni]>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[NH2:16])[NH:13][CH:9]=[CH:8]2
Reactant: CN(C)C=Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2[nH]ccc2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
A suspension of [2-(5-fluoro-2,4-dinitro-phenyl)-vinyl]-dimethyl-amine (8 g, 31.4 mmol) and Raney Ni (8 g) in EtOH (80 mL) was stirred under H2 (40 psi) at room temperature for 1 h. After filtration, the filtrate was concentrated and the residue was purified by chromatography (Pet.Ether/EtOAc=5/1) to give 5-fluoro-1H-indol-6-ylamine (B-20) as a brown solid (1 g, 16%). 1H NMR (DMSO-d6) δ 10.56 (br s, 1 H), 7.07 (d,J=12 Hz, 1 H), 7.02 (m, 1H), 6.71 (d,J=8 Hz, 1H), 6.17 (s, 1H), 3.91 (br s , 2H); ESI-MS 150.1 m/z (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Br:21])[C:3]=1[NH2:22].C(N(CC)CC)C.[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[N:42]1[CH:46]=[N:45][CH:44]=[N:43]1)[C:36](O)=[O:37])([O-:32])=[O:31].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:11])([F:13])[F:12])[CH:5]=[C:4]([Br:21])[C:3]=1[NH:22][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:41]([N:42]2[CH:46]=[N:45][CH:44]=[N:43]2)=[C:33]([N+:30]([O-:32])=[O:31])[CH:34]=1
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br
Reactant: O=C(O)c1ccc(-n2cncn2)c([N+](=O)[O-])c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1ccc(-n2cncn2)c([N+](=O)[O-])c1
Yield: 65 %

Procedure:
To a suspension of 2,6-dibromo-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-phenylamine (Example I1) (635 mg, 1.35 mmol) in 1,2-dichloroethane (6.5 ml) was added triethylamine (0.57 ml, 4.06 mmol), followed by 3-nitro-4-(1H-1,2,4-triazol-1-yl)benzoic acid (634 mg, 2.7 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP—Cl”) (689 mg, 2.7 mmol). The reaction mixture was stirred at reflux for 16 hours. The progress of the reaction was followed by thin layer chromatography and, because it was necessary in this case, further doses of 3-nitro-4-(1H-1,2,4-triazol-1-yl)benzoic acid (4×0.675 mmol), bis(2-oxo-3-oxazolidinyl)phosphonic chloride (4×1.35 mmol) and triethylamine (4×1.35 mmol) were added over the course of 48 hours. The reaction was quenched by addition of aqueous hydrochloric acid (1M) and the phases were separated. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:2) to give Compound No. A4 of Table A (605 mg, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([Cl:25])(=[O:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4′-chlorobiphenyl-4-sulfonic acid 12a (15.1 g ,78.1 mmol)in thionyl chloride (150 mL) is added a catalytic amount of N,N-dimethylformamide (0.3 mL). The reaction mixture is heated to reflux for 4 hr. The mixture is then cooled to room temperature, and concentrated under reduced pressure. Toluene is then added and the mixture is concentrated under reduced pressure. The solid crude product is then recrystallized with ethyl acetate and hexanes to give the solid desired product.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1([C:10]2[C:11]([CH3:23])=[C:12]([CH:16]=[CH:17][C:18]=2[S:19]([CH3:22])(=[O:21])=[O:20])[C:13](O)=[O:14])[CH:9]=[CH:8][CH:7]=[N:6]1.[CH3:24][N:25]1[C:29]([NH2:30])=[N:28][N:27]=[N:26]1.Cl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.O>[N:5]1([C:10]2[C:11]([CH3:23])=[C:12]([CH:16]=[CH:17][C:18]=2[S:19]([CH3:22])(=[O:21])=[O:20])[C:13]([NH:30][C:29]2[N:25]([CH3:24])[N:26]=[N:27][N:28]=2)=[O:14])[CH:9]=[CH:8][CH:7]=[N:6]1
Reactant: Cn1nnnc1N
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1-n1cccn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1c(C(=O)Nc2nnnn2C)ccc(S(C)(=O)=O)c1-n1cccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At RT, 178 mg (1.5 mmol) of thionyl chloride are added to 280 mg (1.0 mmol) of 3-(pyrazol-1-yl)-2-methyl-4-(methylsulfonyl)benzoic acid, 148 mg (1.5 mmol) of 1-methyl-5-aminotetrazole and 12 mg (0.1 mmol) of DMAP in 2 ml of pyridine. The mixture is stirred at RT for 12 h and, after having been checked by LCMS, stirred at 50° C. for 3 h. 0.1 ml of water is then added, the mixture is stirred at RT for 30 min and 2N HCl is added. The product is filtered off with suction and dried. Yield 134 mg (37%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(SC)C=CC=CC=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:53]=[CH:54][C:55]=1[OH:56])[C:20]([NH:22][N:23]1[CH2:28][CH2:27][N:26]([S:29]([NH:32][C:33]([N:35]2[CH2:38][C@H:37]([NH:39]C(=O)OCC3C=CC=CC=3)[C:36]2=[O:50])=[O:34])(=[O:31])=[O:30])[C:25](=[O:51])[C:24]1=[O:52])=[O:21]>CCOCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:39][C@H:37]1[CH2:38][N:35]([C:33]([NH:32][S:29]([N:26]2[CH2:27][CH2:28][N:23]([NH:22][C:20](=[O:21])[C:19]3[CH:53]=[CH:54][C:55]([OH:56])=[C:17]([OH:16])[CH:18]=3)[C:24](=[O:52])[C:25]2=[O:51])(=[O:30])=[O:31])=[O:34])[C:36]1=[O:50]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3ccc(O)c(O)c3)C(=O)C2=O)C1=O)OCc1ccccc1
Solvent: CCOCC
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3ccc(O)c(O)c3)C(=O)C2=O)C1=O
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a mixture of 12 ml of trifluoroacetic acid and 3 ml of thioanisole was added 2.92 g (4.94 mmol) of (S)-[1-[[[[4-[(3,4-dihydroxybenzoyl)amino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester at 0° C. After stirring overnight at 10° C., 150 ml of ether was added and the resulting precipitate was filtered off, washed with ether and dried in vacuo. For further purification, the salt was triturated two times with dichloromethane; yield: 2.56 g; melting point 206°-210° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:30]([N:32]3[CH2:36][CH2:35][C:34](=[O:37])[CH2:33]3)=[O:31])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>CCCCC.CCOCC>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:34]1([OH:37])[CH2:35][CH2:36][N:32]([C:30]([C:27]2([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:29][CH2:28]2)=[O:31])[CH2:33]1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Reactant: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1C1(O)CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-(tert-butyl)benzenesulfonamide (569 mg, 0.00267 mol) in ether (10 mL, 0.1 mol) was added 1.7 M of tert-butyllithium in pentane (4.7 mL) under nitrogen at −78° C. The mixture was stirred at −78° C. for 15 minutes, then at 0° C. for 1 hour. The reaction mixture then was cooled down to −78° C. again and a solution of 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one (640 mg, 0.0024 mol) in ether was added. After stirring for 2 hours, the reaction mixture was quenched with saturated NH4Cl aqueous solution and then extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated. The crude product was purified using Combiflash eluting with 30% AcOEt in hexanes to afford the desired product. LC/MS (M+H+) 478.0.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30](=O)[C:31]1[O:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:30][C:31]4[O:35][CH:34]=[CH:33][CH:32]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccco1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccco2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (400 mg) and furfural (485 mg) in 1,2-dichloroethane (15 ml) was added sodium triacetoxyborohydride (536 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 1 day. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (319 mg) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-])=O.Cl.[OH-].[Na+]>C(O)C>[NH2:12][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([NH2:8])[C:2]=1[Cl:1]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N)c(Cl)c(N)c1
Reaction time: 1 h
Yield: 70 %

Procedure:
4-chloro-3,5-dinitrotoluene (9.0 gm.) is dissolved in 50% ethanol (30 ml.). Electrolytically reduced iron powder (14.2 gm.) is added and the stirred reaction mixture heated to reflux. Concentrated HCl (1 ml.) in 50% ethanol (5 ml.) is added dropwise and refluxing continued for one hour. The reaction mixture is allowed to cool slightly and made basic (pH 8) with 20% NaOH, then the iron removed by filtration. The filtrate is taken to dryness under reduced pressure and the residue extracted with hot Skellysolve "B" (700 ml.). The product precipitates in long needles that were collected by filtration (4.57 gm., m.p. 114°-115.5°, 70% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9]1[S:13](=[O:15])(=[O:14])[O:12][CH2:11][CH2:10]1>C(O)C>[S:13]([CH2:9][CH2:10][CH2:11][NH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)([OH:15])(=[O:14])=[O:12]
Reactant: Nc1cccc(O)c1
Reactant: O=S1(=O)CCCO1
Solvent: CCO
Product: O=S(=O)(O)CCCNc1cccc(O)c1

Procedure:
In 3 liters of ethanol were dissolved 330 g of m-amino-phenol and the resulting solution was boiled under reflux and to this solution were added 360 g of propanesultone all together. Continuation of the reflux yielded gradually white powdery crystal. After refluxing for 5 hours, the reaction solution was cooled with ice and the yielded white powdery crystal was collected by filtration and washed several times with ethanol. The yield was 146 g and the melting point was above 250° C.
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.[CH3:40][N:41]([CH3:47])[CH2:42][CH2:43][C:44](O)=[O:45].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:40][N:41]([CH3:47])[CH2:42][CH2:43][C:44]([O:21][CH:3]([C:2](=[O:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:45]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN(C)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C(CCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To a solution of (6Z,9Z,27Z,30Z)-19-hydroxyhexatriaconta-6,9,27,30-tetraen-18-one (1.0 g, 1.9 mmol), 3-(dimethylamino)propanoic acid hydrogen chloride (876 mg, 5.7 mmol) and EDCI (1.2 g, 6.3 mmol), in dichloromethane (20 mL) was added DIPEA (1.0 mL, 5.7 mmol) and DMAP (20 mg). The solution was stirred at room temperature for 16 hours under nitrogen. Upon completion, the reaction was diluted with dichloromethane (50 mL) and washed with sodium bicarbonate solution (50 mL). The dichloromethane layer was dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (100% ethyl acetate) to afford the title compound as a colorless oil (675 mg, 57%). 1H NMR (400 MHz, CDCl3): δ 5.43-5.28 (m, 8H), 5.03-4.98 (m, 1H), 2.80-2.75 (m, 4H), 2.74-2.56 (m, 4H), 2.54-2.36 (m, 2H), 2.28 (s, 6H), 2.09-2.01 (m, 8H), 1.82-1.64 (m, 2H), 1.63-1.52 (m, 2H), 1.42-1.23 (m, 30H), 0.93-0.86 (m, 6H).
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:4]=[CH:5]C(C(O)=O)=[C:7]([NH:9][CH2:10]C([O-])=O)[CH:8]=1.[C:17]([O:20][C:21](=O)[CH3:22])(=[O:19])[CH3:18].[C:24]([O-:27])(=O)[CH3:25].[Na+].C(=O)=O>>[CH3:25][C:24]([N:9]1[C:7]2[CH:8]=[C:3]([Cl:2])[CH:4]=[CH:5][C:22]=2[C:21]([O:20][C:17]([CH3:18])=[O:19])=[CH:10]1)=[O:27]
Reactant: O=C([O-])CNc1cc(Cl)ccc1C(=O)O
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=C=O
Agent: [Na+]
Product: CC(=O)Oc1cn(C(C)=O)c2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a 5 L, 3-neck flask equipped with mechanical stirring, reflux condenser and gas evolution bubbler was placed 335 g (1.33M) of 5-chloro-2-carboxyphenylglycine sodium salt, 2.3 l acetic anhydride and 421 g of anhydrous sodium acetate. The mixture was brought to reflux and maintained for 3 hours until the evolution of carbon dioxide was nearly complete. The mixture was placed in a beaker while hot and chilled to 0° C. overnight. The next day, the product was filtered off and mixed with 2 L water and stirred for 1 hour to hydrolyze any residual acetic anhydride. The solid was filtered off and washed with water and then dried in vacuo. This crude material, when dry, was dissolved in the minimum of hot ethyl acetate and allowed to crystallize overnight at 0° C. After filtering and washing with a little cold hexane, and drying in vacuo, the product weighed 150 g and had a melting point of 112°-113° C.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.C1(C[NH:48][C:49]2[CH:50]=[C:51]([CH2:55][CH2:56][CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH:52]=[CH:53][CH:54]=2)CCCCC1>CN(C=O)C.O>[CH:1]1([C:7]([NH:48][C:49]2[CH:50]=[C:51]([CH2:55][CH2:56][CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64])[CH:52]=[CH:53][CH:54]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(NCC2CCCCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCc1cccc(NC(=O)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of cyclohexanecarboxylic acid (21) (0.23 ml, 1.79 mmol), TBTU (0.56 g, 1.74 mmol) and iPr2EtN (0.33 ml, 1.89 mmol) in DMF (20 ml) was added tert-butyl 3-(3-(cyclohexylmethylamino)phenyl)propylcarbamate (17) (0.40 g, 1.59 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 18 h and then diluted with water. The solution was extracted with ethyl acetate and the combined extracts were washed with water, aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (5 to 50% EtOAc-hexanes gradient) gave tert-butyl 3-(3-(cyclohexanecarboxamido)phenyl)propylcarbamate (22) as a colorless oil. Yield (0.455 g, 78%); Yield (0.2 g, 32%); 1H NMR (400 MHz, CDCl3) δ 7.43 (br s, 1H), 7.26-7.28 (m, 2H), 7.20 (t, J=7.6 Hz, 1H), 7.08 (br s, 1H), 6.89-6.91 (m, 1H), 3.12 (t, J=6.0 Hz, 2H), 2.61 (t, J=8.4 Hz, 2H), 2.17-2.23 (m, 1H), 1.93-1.96 (m, 2H), 1.74-1.86 (m, 3H), 1.65-1.72 (m, 2H), 1.48-1.59 (m, 1H), 1.31-1.42 (m, 2H), 1.43 (s, 9H), 1.22-1.38 (m, 4H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].[CH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)=[O:18]>O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[O:18])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Temperature: 2.5 °C

Procedure:
4-Isopropyl-piperazine (79.53 g, 0.620 mol), THF (444 g, 5.04 mol), water (36 g, 2 mol) and a 50% solution of sodium hydroxide (130.6 g, 1.63 mol) were charged to a reaction vessel and cooled to 0-5° C. 4-Formyl-benzoyl chloride in THF (110.08 g, 0.630 mol) was added to the 4-isopropyl-piperazine reaction mixture while maintaining the temperature below about 10° C. The resulting white suspension was stirred at room temperature until the reaction was deemed complete. Water was added to the reaction slurry and the resulting hazy solution was filtered over Celite to remove insolubles. The filtered reaction solution was settled and the water layer was removed. The product/THF layer was dried sequentially with magnesium sulfate and molecular sieves. The product solution (KF≦0.5%) was stored at 5° C. for use without further manipulations.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[SH:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[S:18][C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cnc(S)n1-c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (3) (4.09 g, 15.34 mmol) in THF (70 mL) was added triethyl amine (4.50 mL, 32.29) and triphenylmethyl chloride (4.67 g, 16.76 mmol) and the solution was stirred for 1 hour at room temperature. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10%-40% EtOAc in hexanes) to give ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate. A solution of ethyl 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylate (6.34 g, 12.47 mmol), sodium hydroxide (0.74 g, 18.39 mmol), methanol (10 mL), THF (20 mL), and water (10 mL) was stirred at room temperature for 16 hour and was then concentrated in vacuo. The aqueous was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to yield 1-(4-fluorophenyl)-2-(tritylthio)-1H-imidazole-5-carboxylic acid (6).