Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[C:2]1(=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:4][C:3]1=O.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>O.Cl>[OH:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[N:25]=[N:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1
Reactant: O=C1C=C(S(=O)(=O)[O-])c2ccccc2C1=O
Reactant: NNc1ccccn1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1cc(N=Nc2ccccn2)c(O)c2ccccc12

Procedure:
1,2-Naphthoquinone-4-sulfonic acid sodium salt (26 g) was dissolved in a mixture of water (500 ml) and concentrated hydrochloric acid (250 ml). To this solution was added 2-pyridylhydrazine (11 g) in water (100 ml). The reaction mixture became warm and the product started to precipitate. After 30 minutes of cooling, the product was filtered off and washed with a small volume of water, acetone and ether. Yield 32 g (96 percent).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8]1)=[O:6].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH3:3][O:4][C:5]([CH:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:6]
Reactant: COC(=O)C1CCC(=O)N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C1CCC(=O)N1Cc1ccccc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a slurry of NaH (22 g of 60% NaH in mineral oil, 0.55 mol) in 400 mL benzene was added the product of Example 1A (0.387 mol) in 100 mL benzene dropwise via addition funnel. The mixture stirred for 30 minutes after the addition was complete, then was warmed to reflux and allowed to stir for 1.5 h. The reaction was cooled to 45° C. and stirred for 16 h. A portion of benzyl bromide (45 mL, 0.38 mol) was added, the mixture was warmed to reflux and an additional amount of benzyl bromide was added (45 mL, 0.38 mol). This solution stirred for 24 h at reflux, then was cooled to ambient temperature, filtered through Celite® diatomaceous earth and the residue was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation. The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc) to give 46.6 g of the title compound (0.2 mol, 52% yield). MS (DCl/NH3) m/z 234 (M+H)+.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:22]Br)=[C:15]([CH:21]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>C(O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:22][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)=[C:15]([CH:21]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)c1cc(F)ccc1CBr
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(F)ccc1COc1cccc(F)c1
Yield: 105.1 %

Procedure:
To a solution of 1.5 g of sodium metal in 100 ml of ethanol are added 8 g of 3-fluorophenol and 17 g of ethyl 5-fluoro-2-bromomethylbenzoate [U.S. Pat. No. 4,082,850]and the mixture is refluxed with heating for 8 hours. After cooling, 300 ml of water is added and the mixture is extracted with toluene. The extract is washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 20 g of ethyl 5-fluoro-2-[(3-fluorophenyl oxy)methyl]benzoate (oil). Mass spectrum m/z: 292(M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([O:11]CC)=O.O.[NH2:15][NH2:16]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([NH:15][NH2:16])=[O:11]
Reactant: NN
Reactant: CCOC(=O)CCc1ccccn1
Solvent: O
Solvent: CCO
Product: NNC(=O)CCc1ccccn1

Procedure:
To a stirring 5 mL EtOH solution of 0.58 g (3.2 mmol) of ethyl 3-(2-pyridinyl)propanoate (4), prepared as described above in Example 4, was added 0.32 g (6.5 mmol) of hydrazine hydrate. The reaction was heated at reflux for three weeks. Although the reaction was still incomplete, the solvent was removed under vacuum. The resulting gum was triturated with diethyl ether (Et2O). The product remained a gum. The yield of 3-(2-pyridyl)propanoic acid, hydrazide (5) was 0.22 g (42%). This product was used immediately in the manner described in Example 6 below.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[Cl:14].[NH2:18][C:19]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH:21][N:20]=1.O>CN(C=O)C>[C:24]([C:22]1[CH:23]=[C:19]([NH:18][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])=[O:15])[NH:20][N:21]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(Nc1cccc(Cl)c1Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)[nH]n1
Yield: 59.1 %

Procedure:
A solution of 2,2,2-trichloroethyl-2,3-dichlorophenylcarbamate (0.400 g, 1.19 mmol) and 3-amino-5-t-butylpyrazole (0.165 g, 1.19 mmol) in DMF (1 mL) was stirred at 80° C. overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×100 mL), dried (MgSO4), concentrated and purified via column chromatography to yield 1-(3-t-butyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (230 mg, 59% yield) as a pink foam. 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J=6.8 Hz, 1H), 7.20-7.14 (m, 2H), 5.85 (brs, 1H), 1.34 (s, 9H), amine and urea protons not visible; MS (EI) m/z: 327.0 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:27]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cn4ccnc4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the solution were added imidazole (49 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[(imidazol-1-yl)methyl]phenyl]-3-(4-methylphenyl)-cinnamamide (Compound 65) (90 mg) as colorless crystals.
Reaction SMILES: [C:1]1([C:7](=[N+]=[N-])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>CC(C(C)C)C.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.[Rh].[Rh]>[CH3:11][O:10][C:8]([C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@@H:22]1[NH:21][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Reactant: COC(=O)C(=[N+]=[N-])c1ccccc1
Agent: [Rh]
Agent: CC(C)C(C)C
Agent: CCCCCCCCCCCCc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](c1ccccc1)[C@H]1CCCCN1
Yield: 49 %

Procedure:
As shown above in Scheme V and Table III, Rh2(S-DOSP)4 7 catalyzed decomposition of methyl phenyldiazoacetate 9a in the presence of N-BOC-piperidine (15, 4 equiv) in 2,3-dimethylbutane at room temperature followed by treatment with trifluoroacetic acid resulted in the formation of a mixture of threo and erythro methyphenidate, 16 and 17, in 49% yield. However, the threo isomer 16 was the minor diastereomer and was formed in only 34% ee. The combined yield of 16 and 17 was improved to 86% by using the N-BOC-peperidine as the limiting reactant. This result is different to what was observed with N-BOC-pyrrolidine, which gave bis C—H insertion when an excess of phenyldiazoacetate was used. A major improvement in enantioselectivity and diastereoselectivity was achieved by carrying out the reaction with the Rh2[bridged (S-TBSP)2]2 8 catalyst. The ratio of 16:17 (73% yield) was improved to 2.5:1 and (2R, 2′R)-threo isomer 16 was, formed in 86% ee and 52% isolated yield. As shown in Table III, Rh2[bridged (S-TBSP)2]2 8 results in opposite asymmetric induction to Rh2(S-DOSP)4 7, and, in the reaction of 9a and 15 catalyzed by 8, the biologically active enantiomer of threo-methylphenidate is formed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH2:16][C:17]3[NH:21][C:20]4[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:19]=4[N:18]=3)[CH3:15])=[O:13])[C:6]=2[CH:28]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Br[CH2:41][CH2:42][O:43][CH2:44][O:45][CH3:46]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH2:16][C:17]3[N:18]([CH2:41][CH2:42][O:43][CH2:44][O:45][CH3:46])[C:19]4[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:20]=4[N:21]=3)[CH3:15])=[O:13])[C:6]=2[CH:28]=1
Reactant: CN(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)C(=O)Cn1c(=O)oc2ccc(Cl)cc21
Reactant: COCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOCCn1c(CN(C)C(=O)Cn2c(=O)oc3ccc(Cl)cc32)nc2cc(Cl)c(Cl)cc21
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-(5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-[(5,6-dichloro-1H-benzimidazol-2-yl)methyl]-N-methylacetamide (150 mg) and DMF (4.5 mL) were added K2CO3 (94 mg) and 1-bromo-2-(methoxymethoxy)ethane (80 μL), followed by heating and stirring at 70° C. for 5 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=50/50-0/100) to obtain 2-(5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-({5,6-dichloro-1-[2-(methoxymethoxy)ethyl]-1H-benzimidazol-2-yl}methyl)-N-methylacetamide (110 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:14](#[N:18])[CH2:15][C:16]#[N:17].N1CCCCC1>C(O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([Br:1])[C:3]=1[O:12][CH3:13])[CH:7]=[C:15]([C:14]#[N:18])[C:16]#[N:17]
Reactant: N#CCC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=C(C#N)C#N)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 5-bromoveratraldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) in ethanol was added piperidine (0.1 ml, 1 mmol). The mixture was stirred at room temperature for 15 min to give the product 3,4-dimethoxy-5-bromobenzylidenemalononitrile as a yellow precipitate.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[Cl:10].[C:11]([O-])(=[O:13])[CH3:12].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:11]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[Cl:10])(=[O:13])[CH3:12]
Reactant: Nc1ccc(O)cc1Cl
Reactant: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(O)cc1Cl
Yield: 84.2 %

Procedure:
Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portionwise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 m z Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS(H2O-GC/MS): m/e 186 (100).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:18][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)[CH3:17])=[O:5]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CC(N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C(C)(C)CCl)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-2,2-dimethylpropionyl chloride (7.0 g) in dichloromethane (50 ml) was added dropwise to a stirred solution of 1-(4-chlorophenyl)ethylamine (7.0 g) and triethylamine (6.3 ml) in dichloromethane (100 ml) at 0°-5° C. under nitrogen. After the addition, the mixture was stirred at 0° C. for 0.5 hours and then stirred at ambient temperature for 2 hours. The mixture was washed with 5M hydrochloric acid and then with water. The mixture was dried and evaporated. The residue was recrystallised from petroleum ether (b.p. 60°-80° C.) to give 3-chloro-N-[1-(4-chlorophenyl)ethyl]-2,2-dimethylpropionamide, m.p. 95°-96° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6]=[C:7]([CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]1)[CH2:8]Br)[CH3:2].[P:23]([O:32]C(C)C)([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6]=[C:7]([CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]1)[CH2:8][P:23]([O:28][CH:29]([CH3:31])[CH3:30])([O:24][CH:25]([CH3:27])[CH3:26])=[O:32])[CH3:2]
Reactant: CCOC(=O)C(C=C(CBr)C1CCN(C(C)=O)CC1)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)C(C=C(CP(=O)(OC(C)C)OC(C)C)C1CCN(C(C)=O)CC1)NC=O
Reaction time: 18 h

Procedure:
2.68 g (7.14 mmol) of 4-(1-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester and 7.5 ml (28.5 mmol) of triisopropyl phosphite (90%) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate/methanol (9:1). 4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:14]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[C:35]1([S:41][C:13]2[C:14]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:23][C:15]=3[S:16][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Cl
Reactant: Sc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--1.46 ml, 9.5 mmol) was added to a mixture of ethyl 3-chloro-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Preparation 4, 3.0 g, 8.6 mmol) and thiophenol (1.76 ml, 17.2 mmol) in dimethylformamide (15 ml) under a nitrogen atmosphere. The solution was heated to 60° C. for 5 hours and then partitioned between diethyl ether and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using diethyl ether, and then ethyl acetate, as eluant. The isolated product was crystallised from diethyl ether and hexane to give the title compound as a colourless solid (2.85 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C(#N)C>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[O:13][C:3]1[C:2]([Cl:1])=[C:7]([CH3:8])[N:6]=[C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])[N:4]=1
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(Cl)(Cl)Cl)nc(OC(=O)N(C)C)c1Cl
Yield: 20 %

Procedure:
A mixture of 3.9 g (0.015 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 1.6 g (0.015 mole) triethylamine, 1.7 g (0.015 mole) dimethylcarbamoyl chloride, and 80 ml acetonitrile was refluxed 3 days. Rotary evaporation to concentrate the solution yielded a precipitate that was removed by filtration. Rotary evaportation of the filtrate gave a residue which was triturated with petroleum ether to give 1.0 g (20% yield; mp 87°-88° C.) of product. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Cl:1][C:2]([Cl:26])([Cl:25])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[C@@H:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].[OH:27][C@@H:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][C:34](/[CH:40]=[CH:41]/[C@@:42]([CH2:47][O:48][CH3:49])([CH3:46])[C:43](O)=[O:44])=[CH:35][CH:36]=2)[N:31]=1)[CH3:29].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:26][C:2]([Cl:25])([Cl:1])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[C@@H:18]([NH:22][C:43](=[O:44])[C@:42]([CH2:47][O:48][CH3:49])([CH3:46])/[CH:41]=[CH:40]/[C:34]2[CH:33]=[C:32]3[C:37]([CH:38]=[CH:39][C:30]([C@H:28]([OH:27])[CH3:29])=[N:31]3)=[CH:36][CH:35]=2)[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6]
Reactant: COC[C@@](C)(/C=C/c1ccc2ccc([C@@H](C)O)nc2c1)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@](C)(/C=C/c1ccc2ccc([C@@H](C)O)nc2c1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1)C(C)C
Temperature: 0 °C
Yield: 52.6 %

Procedure:
To freshly prepared (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (139 mg, 0.321 mmol) in dichloromethane (25 mL) was added (E)-(R)-4-[2-((R)-1-hydroxy-ethyl)-quinolin-7-yl]-2-methoxymethyl-2-methyl-but-3-enoic acid (101 mg, 0.321 mmol) and the mixture was evaporated. The residue was dissolved in anhydrous acetonitrile (6.4 mL) and the mixture cooled to 0° C. with stirring under nitrogen. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (146 mg, 0.38 mmol) and N,N-diisopropylethylamine (168 μL, 0.963 mmol) were added and the reaction mixture stirred for 5 minutes and then allowed to warm to ambient temperature. The mixture was stirred for 19 h and evaporated and the residue dissolved in dichloromethane and washed sequentially with saturated sodium bicarbonate solution, water, saturated ammonium chloride solution, brine then was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified on silica eluting with ethyl acetate to afford the title compound (123 mg, 53%) as a yellow gum. 1H NMR (300 MHz, CDCl3) δ 0.91 (d, J=6.7 Hz, 3H), 0.97 (d, J=6.7 Hz, 3H), 1.33 (d, J=6.7 Hz, 3H), 1.45 (s, 3H), 1.59 (d, J=6.5 Hz, 3H), 1.67-1.78 (m, 2H), 1.90-2.00 (m, 1H), 2.15-2.33 (m, 2H), 2.82-2.91 (m, 1H), 3.47-3.54 (m, 1H), 3.51 (s, 3H), 3.60 (d, J=9.2 Hz, 1H), 3.68-3.76 (m, 1H), 3.73 (d, J=11.4 Hz, 1H), 3.85 (d, J=9.2 Hz, 1H), 4.33-4.45 (m, 2H), 4.72 (d, J=12.0 Hz, 1H), 4.96 (d, J=12.0 Hz, 1H), 4.99-5.08 (m, 2H), 5.27-5.37 (m, 1H), 6.70 (ABq, J=16.5 Hz, 1H), 6.80 (d, J=16.5 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.66 (dd, J=8.6, 1.2 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 8.01 (s, 1H), 8.12 (d, J=8.7 Hz, 1H). LCMS (m/z) 728.3, 730.3 [M+H], Tr=2.25 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[OH:21])[O:17][C:16](=[O:22])[C:15]([C:23]([OH:25])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12>CN(C=O)C>[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:15]3[C:16](=[O:22])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([OH:10])=[C:20]([OH:21])[CH:19]=4)=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12
Reactant: O=C(O)c1cc2cc(O)c(O)cc2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(O)c(O)cc2oc1=O
Temperature: 25 °C

Procedure:
DIEA (43.1 μL, 0.25 mmol) was added to 6,7-dihydroxy-3-carboxy-coumarin (50.0 mg, 0.23 mmol) and HATU (94.1 mg, 0.25 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (47.1 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give the final product: LCMS (ESI) m/z 413 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][Cl:15])[C:6]#[N:7].[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:8]1[CH:9]=[C:10]([O:11][CH2:12][CH2:13][CH2:14][Cl:15])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]#[N:7])([O-:18])=[O:17]
Reactant: COc1cc(C#N)ccc1OCCCCl
Reactant: O=[N+]([O-])O
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCCCCl
Temperature: 30 °C

Procedure:
3-methoxy-4-chloropropoxybenzonitrile (1.350 g, 6 mmol) and nitric acid (6 mL) were added into a round bottom flask. The solution was heated to 30° C. while stirring to react for 2 h, then poured into ice-water, filtered, washed with water and air-dried to yield light yellow solid product (1.555 g) with a recovery rate of 96%.
Reaction SMILES: C([Li:5])CCC.[CH3:6][C:7]1([CH3:15])[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[NH:8]1.C1(S(N2C3C(=CN=CC=3)C=C2)(=O)=O)C=CC=CC=1.C1(S(N2C3C(=CN=CC=3)C=C2[Li])(=O)=O)C=CC=CC=1>O1CCCC1.[Mn](Cl)(Cl)=O>[Li:5][N:8]1[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:7]1([CH3:15])[CH3:6]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: [Li]CCCC
Agent: O=[Mn](Cl)Cl
Agent: O=S(=O)(c1ccccc1)n1ccc2cnccc21
Agent: [Li]c1cc2cnccc2n1S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: [Li]N1C(C)(C)CCCC1(C)C
Temperature: -70 °C
Yield: 100 %

Procedure:
A solution of 0.15 mole of lithium 2,2,6,6-tetramethylpiperidide is prepared by the addition of 0.15 mole of n-butyllithium to 0.15 mole of 2,2,6,6-tetramethylpiperidine in 120 ml of tetrahydrofuran at a temperature lower than -20° C. This solution is then added over a period of a few minutes to 0.1 mole of 1-benzenesulfonyl 5-aza indole cooled to -70° C. while maintaining this temperature throughout the addition. 0.15 mole of anhydrous manganous chloride is then added to the solution of 1-benzenesulfonyl 2-lithio 5-aza indole. The temperature of the medium is then brought from -65° C. to -25° C. in order to bring the exchange reaction to completion and obtain a solution of the desired manganous derivative which is used as such.