Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[CH2:12][N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[O:28])=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cccc(CN2CCC(C(=O)O)CC2)c1)c1ccc(Cl)cc1
Yield: 91.8 %

Procedure:
A solution of 1-[3-(4-chloro-benzoylamino)-benzyl]-piperidine-4-carboxylic acid ethyl ester (1.65 g, 4.12 mmol) in a mixture of THF (20 mL) water (10 mL) and MeOH (10 mL) is treated with lithium hydroxide monohydrate (190 mg, 4.53 mmol) at RT for 2 h. Aq. 2N HCl (2.3 mL) is added and the resulting solution is lyophilized to yield the crude title compound (1.41 g) containing one equivalent LiCl. LC-MS A: tR=0.64 min; [M+H]+=372.93.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1N.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+:21]1[CH:26]=CC=CC=1.C(OCC)(OCC)[O:28][CH2:29][CH3:30]>>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[C:26](=[NH:21])[O:28][CH2:29][CH3:30]
Reactant: CCOC(OCC)OCC
Reactant: c1cc[nH+]cc1
Reactant: Nc1c(Cl)cnnc1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCOC(=N)c1c(Cl)cnnc1Cl
Temperature: 25 °C
Yield: 60 %

Procedure:
To a stirred suspension of 3,5-dichloro-4-aminopyridazine (5 g, 31 mmol) in triethyl orthoformate (205 mL) was added pyridinium para-toluenesulfonate (387 mg, 1.5 mmol) and the resultant solution was heated at 100° C. for 16 hours. The reaction mixture was cooled to room temperature then evaporated in vacuo and the crude residue was purified by silica gel column chromatography eluting with hexane:EtOAc (80:20) to afford the title compound as a light brown oil in 60% yield, 4 g.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[S:3])[NH2:2].Br[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21]>O1CCOCC1>[F:21][C:20]([F:23])([F:22])[C:19]1[N:2]=[C:1]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[S:3][CH:18]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: COC(=O)[C@H](C)c1ccc(NC(N)=S)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of methyl (2R)-2-[4-(carbamothioylamino)phenyl]propanoate (10.7 g, 0.0484 mol) in dioxane (200 ml) was treated at room temperature with 3-bromo-1,1,1-trifluoro-propan-2-one (5 ml, 0.0484 mol) and the resulting mixture was refluxed for 2 h. After cooling at room temperature, the solvent was evaporated under vacuum, the crude diluted with CH2Cl2 (200 ml) and washed with a saturated NaHCO3 aqueous solution (3×100 ml), dried over anhydrous Na2SO4 and evaporated to give pure methyl (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate (12.8 g, 38.7 mmol) as yellow oil (80%). 1H-NMR (CDCl3): δ 8.65 (bs, 1H, NH), 7.30 (m, 4H), 7.05 (s, 1H), 3.75 (q, 1H, J=7 Hz), 3.65 (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: [OH:1][CH:2]([CH3:28])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:7][CH:6]=1.[C:29](Cl)(=[O:33])[CH2:30][CH2:31][CH3:32]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:29]([O:1][CH:2]([CH3:28])[CH:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(=O)Cl
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(C)O)cc2)nc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(C)OC(=O)CCC)cc2)nc1
Reaction time: 4 h
Yield: 88.7 %

Procedure:
1.0 g of (-)-2-(4-(3-hydroxy-1-butenyl)phenyl)-5-decyloxypyrimidine was dissolved in 20 ml of pyridine, added with 0.5 g of butyryl chloride and stirred at 25°-30° C. for 4 hours. The reaction mixture was diluted with 100 ml of toluene and washed with 4N hydrochloric acid, water, a 5% sodium bicarbonate solution and water successively in that order. The toluene layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 1.05 g of (+)-2-(4-(3-butyryloxy-1-butenyl)phenyl)-5-decyloxy-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]([Mg]Cl)([CH3:25])[CH3:24]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([OH:22])[CH:23]([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[C@H](O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To (2S,3R)-3-(tert-butyldimethylsilanyloxy)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (7C) (6.50 g, 19.8 mmol) in THF (100 mL) at −78° C. was added a 2M THF solution of isopropylmagnesium chloride (30.0 mL, 60.0 mmol) over 20 min. The cold bath was removed and the reaction was stirred for 1 h. The reaction was then cooled to 60° C. and was quenched with saturated aqueous ammonium chloride. After warming to rt, the whole was diluted with EtOAc. The layers were separated and the organic layer washed with water and brine, then dried (MgSO4), filtered and concentrated. The resulting residue was purified via flash chromatography eluting with 20% EtOAc/hexane to provide (2R,3R)-3-(tert-butyldimethylsilanyloxy)-2-[(1S)-(1-hydroxy-2-methyl-propyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (10A) (5.90 g).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#[N:12].N(OCCC(C)C)=O.[I-:21]>>[I:21][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: [I-]
Reactant: N#Cc1cc2c(cc1N)CCC2
Agent: CC(C)CCON=O
Product: N#Cc1cc2c(cc1I)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
A mixture of 6-aminoindane-5-carbonitrile (48.5 mg, 0.307 mmol), isoamyl nitrite (82 μL, 0.614 mmol) and iodide (85.7 mg, 0.338 mmol) was stirred at room temperature for 0.5 h. The mixture was then heated at 80° C. under N2 for 2 h. The reaction mixture was quenched with saturated Na2S2O3 and partitioned between dichloromethane and water. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, 1% EtOAc in hexanes) to yield 6-iodoindane-5-carbonitrile (39.7 mg, 50%). LCMS calc.=268.97; found=270.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.48 (s, 1H), 2.96 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.16-2.10 (m, 2H).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[C:6](=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:8])[CH3:7].[NH4+].[Cl-]>O1CCCC1.[Cu]I>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([C:6]([CH:1]1[CH2:3][CH2:2]1)([CH3:7])[CH3:8])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:14]
Reactant: Br[Mg]C1CC1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)C1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
Step A To a suspension of CuI (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at −50° C. was added cyclopropylmagnesium bromide (0.5 M, 160 mL, 80 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to −50° C., a tetrahydrofuran solution (50 mL) of diethyl isopropylidenemalonate (Aldrich) (4 g, 20 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4Cl solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20, 1:10) to give 2-(1-cyclopropyl-1-methyl-ethyl)-malonic acid diethyl ester as a colorless oil (4.3 g, 89%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:15].[H][H]>O1CCCC1.[Pd]>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][C:3](=[O:15])[N:2]2[CH3:1]
Reactant: [H][H]
Reactant: Cn1c(=O)ccc2c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1c(=O)ccc2c(N)cccc21
Yield: 75.8 %

Procedure:
A solution of Example 50A (2.16 g, 10.6 mmol) in tetrahydrofuran (50 mL) was added to 5% Pd—C, wet (0.432 g, 4.06 mmol) in a 250 mL stainless steel pressure bottle. After 3 hours at about room temperature under 30 psi of hydrogen pressure, the mixture was filtered through a nylon membrane and concentrated. EtOH (22 mL) was added, and the yellow slurry was sonicated for 5 minutes and filtered, washing with EtOH (10 mL). The yellow solid was dried in a vacuum oven at 50° C. to provide the title compound (1.40 g, 8.04 mmol, 75% yield). MS (DCI) m/z 175 (M+N)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[CH3:14][NH:15][CH2:16][CH2:17][C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([N:15]([CH3:14])[CH2:16][CH2:17][C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:6]
Reactant: CNCCC#Cc1ccccn1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1cccc(OC)c1C(=O)N(C)CCC#Cc1ccccn1
Temperature: 0 °C
Reaction time: 14 h
Yield: 11.9 %

Procedure:
2,6-Dimethoxy-benzoyl chloride (81 mg, 0.41 mmol) was added to a solution of methyl-(4-pyridin-2-yl-but-3-ynyl)-amine (50 mg, 0.31 mmol) and DIEA (69 μL, 0.41 mmol) in chloroform (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 min., at room temperature for 14 hours, quenched by the addition of water and extracted twice with chloroform. The organic phase was washed with saturated solution of NaHCO3, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 95:5) to yield 2,6-dimethoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide (12 mg, 37 μmol, 12%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([NH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)C(OC(C)(C)C)=O)[C:11]([OH:13])=[O:12])=[O:8])=[CH:5][CH:4]=1.[N+:35]([O-])([O-])=O.C([N:41]([CH2:44]C)CC)C>CN(C=O)C>[NH:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:11]([OH:13])=[O:12])=[O:8])=[CH:33][CH:34]=1)[C:44]([NH2:41])=[NH:35]
Reactant: O=[N+]([O-])[O-]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N(CCCC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)O)Cc1ccccn1
Solvent: CN(C)C=O
Product: N=C(N)NCc1ccc(C(=O)N[C@@H](CCCCNCc2ccccn2)C(=O)O)cc1
Reaction time: 72 h

Procedure:
The compound obtained in Example 41-5 (0.01 g) was dissolved in DMF (0.3 ml). After the addition of dimethylpyrazolecarboxyamidine nitrate (0.01 g), the mixture was adjusted to pH 8 with triethylamine and stirred for 3 days. The reaction solution was concentrated. Chloroform was added to the residue and the mixture was washed with saturated aqueous solution of sodium hydrogencarbonate. The organic layer was concentrated and dried under reduced pressure. The residue was purified by silica gel column chromatography (5 g, chloroform/methanol/water=7/3/0.5) to obtain the title compound (0.01 g) as white foam. The foam was dissolved in methanol (0.3 ml) and 4 mol/l hydrochloric acid/dioxane solution (0.3 ml) was added dropwise. The mixture was stirred for 3 hours at room temperature. The reaction solution was concentrated and dried under reduced pressure to obtain a crude product (0.01 g). The crude product was purified by silica gel column chromatography (0.5 g, chloroform/methanol/water=7/3/0.5) and 1 mol/l hydrochloric acid was added. The mixture was concentrated to obtain hydrochloride of the title compound (0.01 g) as white foam.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([O:50][CH3:51])[N:43]=1.NC(=C)C([O-])=O>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([O:50][CH3:51])[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: COc1nc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: C=C(N)C(=O)[O-]
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(OC)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 3 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.78 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 2-amino-3,5-difluoro-6-methoxypyridine until completion of the conversion into the aminoacrylate form was confirmed by monitoring the reaction by TLC. The solution was concentrated under reduced pressure, and to the residue were added 0.80 g of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol to obtain 615 mg of the title compound as a pale brown powder.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1([C:24](=[O:41])[N:25]([C:32]1[O:40][C:36]2=[CH:37][CH:38]=[CH:39][C:35]2=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1.[OH-].[Na+]>CCO.C1COCC1.O>[O:40]1[C:36]2=[CH:37][CH:38]=[CH:39][C:35]2=[CH:34][CH:33]=[C:32]1[N:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:24]([C:5]1([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[CH:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:16][CH:17]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]1[C:3]([OH:42])=[O:2])=[O:41]
Reactant: COC(=O)C1C=CC=CC1(CCc1ccc(C=CC(C)(C)C)cc1)C(=O)N(c1ccccc1)c1ccc2cccc-2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)C=Cc1ccc(CCC2(C(=O)N(c3ccccc3)c3ccc4cccc-4o3)C=CC=CC2C(=O)O)cc1
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a stirred solution of (R)-4-[2-(4-Benzofuran-2-yl-phenylcarbamoyl)-2-[4-(3,3-dimethyl-but-1-enyl)-phenyl-ethyl]-benzoic acid methyl ester (0.29 g, 0.52 mmol) in EtOH/THF/H2O (4:2:1) (12 mL) at rt, was added aq. 40% NaOH (2.5 ml), The reaction mixture was stirred for overnight, After completion of the reaction, the solvent was removed under reduced pressure. The crude was taken to pH=2 with 4N HCl and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated, the resulting compound was dried under vacuum to afford 4-[2-(4-Benzofuran-2-yl-phenylcarbamoyl)-2-[4-(3,3-dimethyl-but-1-enyl)-phenyl-ethyl]-benzoic acid as a solid (0.27 g, 98%):
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(Br)(Br)(Br)[Br:20].[OH-].[K+]>C1C=CC=CC=1>[Br:20][C:18]#[C:17][CH:16]=[C:13]1[CH2:14][CH2:15][N:10]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:11][CH2:12]1
Reactant: BrC(Br)(Br)Br
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cccnc1N1CCC(=CC#CBr)CC1
Temperature: 65 °C
Reaction time: 11 h

Procedure:
A mixture of Compound 1c (200 mg, 0.82 mmol), CBr4 (0.54 mg, 1.65 mmol), potassium hydroxide (0.138 mg, 2.46 mmol), 18-C-6 crown ether (21.8 mg, 0.823 mmol) and 10 mL of benzene was stirred at 65° C. for 11 h.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:49][Cl:50]>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:49][Cl:50])=[O:26])=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCc1ccc(C(=O)O)cc1
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCc1ccc(C(=O)OCCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoic acid (2.0 g, 5.0 mmole) in 1,4-dioxane (20 ml)was added a 40% solution of tetrabutylammonium hydroxide (3.1 g, 4.75 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and coevaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in dichloromethane (10 ml) and iodochloromethane (13.2 g, 75 mmole) was added The solution was stirred overnight at room temperature and evaporated under reduced pressure. About 50 ml ethyl acetate were added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 0.5 g=23%
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=[CH:15]2>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]([NH:2][OH:3])=[NH:23])[CH:16]=[CH:15]2
Reactant: NO
Reactant: N#Cc1ccc2cc(Br)ccc2c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C

Procedure:
2.48 g hydroxylamine-hydrochloride and 5.68 ml triethylamine are added to 4.10 g of 6-bromo-2-cyano-naphthalene in 100 ml of ethanol and the reaction mixture is refluxed for four hours. After cooling to ambient temperature the solvent is distilled off in vacuo using the rotary evaporator and the flask residue is divided between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate and evaporated down.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C@H:23]3[O:32][C@@H:26]4[O:27]C(C)(C)[O:29][C@@H:25]4[C@@H:24]3[CH2:33][CH2:34][N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>C(OCC)(=O)C.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C@@H:23]3[C@@H:24]([CH2:33][CH2:34][N:35]4[C:36](=[O:45])[C:37]5[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:43]4=[O:44])[C@@H:25]([OH:29])[C@@H:26]([OH:27])[O:32]3)=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC1(C)O[C@H]2O[C@H](CCc3ccc(-c4ccc(Cl)cc4)cc3)[C@@H](CCN3C(=O)c4ccccc4C3=O)[C@H]2O1
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1CC[C@H]1[C@@H](O)[C@@H](O)O[C@@H]1CCc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL) and water (0.5 mL) were added to the compound obtained from step k above (0.04 g). The reaction mixture was stirred at room temperature for 2 hours. The solvents were evaporated at reduced pressure. The residue thus obtained was taken in ethyl acetate and water. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (0.028 g).
Reaction SMILES: Cl[C:2]([F:8])([F:7])C(OC)=O.[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:7][CH:2]([F:8])[O:17][C:16]1[CH:18]=[CH:19][C:11]([CH:10]=[O:9])=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OC(F)F
Temperature: 67.5 °C
Yield: 40.5 %

Procedure:
Methyl chlorodifluoroacetate (1.4 mL, 13 mmol) was added to a suspension of vanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) in DMF (10 mL). The suspension was heated to 65-70° C. for 16 h and the suspension was diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10% EtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41%) as a colourless oil; δH (400 MHz, CDCl3) 3.95 (s, 3H, OCH3), 6.60 (t, J=74 Hz, 1H, OCHF2), 7.30 (d, J5,6=8.0 Hz, 1H, H5), 7.45 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.50 (d, J2,6=2.0 Hz, 1H, H2), 9.93 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.2, 110.9, 115.5 (t, J=256 Hz), 121.5, 125.0, 134.5, 144.9, 151.5, 190.8.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9])#[N:2].OO.C(=O)([O-])[O-:24].[K+].[K+].O>CS(C)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:18]=[C:3]([CH:4]=[CH:5][C:6]=2[O:19][CH3:20])[C:1]([NH2:2])=[O:24])=[CH:12][CH:13]=1
Reactant: COc1ccc(C#N)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
5-Cyano-N-(4-chlorophenyl)-2-methoxybenzamide (9.8 g) obtained in step D was dissolved in 80 mL of dimethyl sulfoxide, and the solution was cooled in a water bath. A solution prepared from 17.4 mL of a 30% aqueous solution of hydrogen peroxide and 9.5 g of potassium carbonate was added dropwise to the solution. After stirring for 1 hour, the mixture was poured into 800 mL of cold water. The precipitate formed was separated by filtration, washed with cold water, and then dried over diphosphorus pentoxide under reduced pressure to obtain 10.3 g (99%) of 3-N-(4-chlorophenyl)-4-methoxyisophthalamide.