Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[O:20]>>[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2([OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: Cc1ccccc1Br
Product: Cc1ccccc1C1(O)C(=O)Nc2ccc(Br)cc21
Yield: 50.1 %

Procedure:
With 9.58 g of 1-bromo-2-methyl benzene and 4.52 g of 5-bromoisatin as starting materials, 3.19 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[CH:16][C:11]([CH:12]=CCN)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.NC1C=CC(C=[O:24])=CC=1.C(CC(=O)C)C(C)=O>>[CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[CH:16][C:11]([CH:12]=[O:24])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc(C=CCN)cc1
Reactant: Nc1ccc(C=O)cc1
Agent: CC(=O)CCC(C)=O
Product: Cc1ccc(C)n1-c1ccc(C=O)cc1

Procedure:
Similarly prepared is N-acetyl-N-acetyloxy-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-cinnamylamine. The starting material is prepared by first condensing p-amino-benzaldehyde with acetonylacetone to obtain 4-(2,5-di-methyl-1H-pyrrol-1-yl)-benzaldehyde which is in turn condensed with diethyl phosphonoacetaldehyde diethylacetal to obtain 4-(2,5-dimethyl-1H-pyrrol-1-yl)-cinnamaldehyde. The aldehyde is then converted to the oxime and reduced to the hydroxylamine according to previously described procedures.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12](=O)([O-])[O-].[K+].[K+].C(=O)(OC)OC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: COc1ccc2c(ccn2C)c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 183 %

Procedure:
A mixture of 5-methoxyindole (1 g, 6.79 mmol), potassium carbonate (0.5 g), N,N-dimethylformamide (10 mL) and dimethyl carbonate (1.7 mL, 20 mmol) was stirred and heated to reflux (˜130° C.). The progress of the reaction was monitored by HPLC. Within 5 h, the starting indole had been consumed and after the mixture was cooled to ˜3° C., it was treated with ice cold water (30 mL). The formed precipitate was filtered off, then was washed in turn with water (2×30 mL) and hexanes (30 mL). The colorless product was dried under vacuum at 25° C. for 48 h to afford 5-methoxy-1-methylindole (1.067 g, 97.4% yield).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.C[O:18][B:19](OC)[O:20]C>C1COCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[B:19]([OH:20])[OH:18]
Reactant: Fc1cccc2ccccc12
Reactant: COB(OC)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: OB(O)c1ccc2ccccc2c1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
1-fluoro naphthalene (14.61 g, 100 mmol, Aldrich Chemical) was dissolved in dry THF (50 mL) and cooled to -78° C. Then, a sec-butyl lithium solution (1.3 M in hexane, 100 mL) was added to the mixture over a period of 5 minutes. This mixture was stirred for 20 minutes at -78° C., then trimethylborate (15 mL, 132 mmol, Aldrich Chemical) was added. Stirring was continued at -78° C. for 15 minutes followed by stirring at room temperature for 30 minutes. The reaction was quenched by adding 100 mL of a 3:1 mixture of AcOH: H2O and stirred overnight at room temperature. Next, 500 mL of a 1:1 mixture of ethyl acetate and water was added. The organic layer was washed with 10% HCl (200 mL×1), water (200 mL×2), and brine (100 mL), dried over sodium sulfate, filtered, and solvent was removed to yield 18 grams of a white solid. This material was purified by silica-gel chromatography (350 grams of silica gel, ethyl acetate-hexane 1:1 mobile phase) to yield 16.3 g of the title compound (86%).
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[C:7](/[CH3:21])\[C:8]#[C:9][C:10]12[O:20][C:11]1([CH3:19])[CH2:12][CH:13]([OH:18])[CH2:14][C:15]2([CH3:17])[CH3:16])(=O)C.C([O-])([O-])=O.[K+].[K+].CO>O>[OH:4][CH2:5]/[CH:6]=[C:7](/[CH3:21])\[C:8]#[C:9][C:10]12[O:20][C:11]1([CH3:19])[CH2:12][CH:13]([OH:18])[CH2:14][C:15]2([CH3:17])[CH3:16]
Reactant: CC(=O)OC/C=C(/C)C#CC12OC1(C)CC(O)CC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C/C(C#CC12OC1(C)CC(O)CC2(C)C)=C/CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A mixture of Z-4-(5-acetoxy-3-methyl-pent-3-en-1-ynyl)-3,4-epoxy-3,5,5-trimethylcyclohexan-1-ol (36 mg, 0.12 mmol), K2CO3 (26 mg, 0.18 mmol), methanol (1 mL) and H2O (1 mL) was stirred at room temperature for 1 h. It was then concentrated by evaporation and the residue was diluted with H2O and extracted with CHCl3. The organic extract was dried over anhydrous Na2SO4. Evaporation of solvent gave compound (5) as a colorless oil (21 mg, 69%), ir: 3620 (sharp, medium, OH) and 3450 (broad, weak, OH) cm-1; 1H nmr d: 5.87 (ddq, J=6.7, 6.7, 1.4 Hz, 1H, =CH), 4.27 (dd, J=6.7, 1.0 Hz, 2H, CH2O), 3.82 (m, 1H, CHOH), 2.18 (ddd, J=14.8, 6.8, 1.4 Hz, 1H, CH2), 1.86 (m, 3 H, vinyl CH3), 1.79 (dd, J=14.8, 9.0 Hz, 1H, CH2), 1.46 (s, CH3), 1.36 (ddd, J=12.7, 4.1, 1.5 Hz, 1H, CH2), 1.16 and 1.17 (2s, 6H, 2CH3); 13C nmr d: 136.36 (d, =CH), 119.95 (s, =C), 90.95 and 83.99 (2s, 2 acetylenic C), 65.08 and 64.52 (2s, C--O--C), 63.29 (d, CHOH), 61.15, 41.84 and 38.16 (3t, 3 CH2), 34.83 (s, C), 27.03, 25.60, 22,98 and 22.92 (4q, 4CH3); ms (NH4Cl CI) m/z: 268 (M+18), 251 (M+1), 233 (M-17).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([O:20][CH3:21])[C:9](=[O:19])[CH:10]=[C:11]2[C:15](=[O:16])[O:14][C:13](C)(C)[O:12]2)=[CH:5][CH:4]=1)#[N:2]>CO>[CH3:13][O:14][C:15](=[O:16])[C:11]([OH:12])=[CH:10][C:9](=[O:19])[N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:23][CH:22]=1)[O:20][CH3:21]
Reactant: CON(Cc1ccc(C#N)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(C#N)cc1)OC
Yield: 52 %

Procedure:
N-(4-Cyanobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D gave the title ester as white crystals (52% yield); mp 110° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.73 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.88 (2H, s, NCH2), 6.47 (1H, s, CH), 7.43 (2H, d, J=8.6 Hz, aromatics), 7.64 (2H, d, J=8.6 Hz, aromatics). Anal. calcd for C14H14N2O5: C, 57.93; H, 4.86; N, 9.65. Found: C, 57.87; H, 4.80; N, 9.67.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[C:15]1([S:21][C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][N:26]1[C:22]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:23][N:24]=[N:25]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Reactant: c1ccc(Sc2nnn[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(Cn2nnnc2Sc2ccccc2)cc([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of 50 g (0.231 mol) of 3,5-dinitrobenzylchloride and 41 g (0.231 mol) of phenylmercaptotetrazole in one liter of dry tetrahydrofuran under nitrogen was added all at once with stirring 23.4 g (0.231 mol) of triethylamine. The temperature rose slowly from 23° to 29°. After stirring overnight the reaction mixture was diluted with one liter of water, cooled to 10° C., filtered and the filter cake was washed well with water. Oven drying at 110° C. for 24 hours gave 78 g (83%) of product mp. 156°-158° C. Recrystallization from tetrahydrofuran gives analytically pure 5, mp. 161.5°-162.5° C.
Reaction SMILES: [CH:1]1[C:15]2=[C:16]3[C:7](=[C:8]([CH:17]=[O:18])[C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:6][CH2:5][C:4]3=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.CCCCCC>[CH:1]1[C:15]2=[C:16]3[C:7](=[C:8]([CH:17]=[O:18])[C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: O=Cc1c2c3c(cccc3c3ccccc13)CC2
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=Cc1c2c3c(cccc3c3ccccc13)C=C2
Yield: 35.8 %

Procedure:
Using the dehydrogenation procedure outlined in Example 7B, 4,5-dihydroacephenanthrylene-6-carbaldehyde (J. P. Hoeffinger, P. Jacquignon, and N. P. Buu-Hoi, Bull. Soc. Chim. Fr. 974 (1970)) gave a 35.8% yield of 6-acephenanthrylenecarbaldehyde, mp 161°-163° (dec), (C, H), (PhCH3 /hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[N:8][NH:9][N:10]=1)[CH3:2].I[CH:13]([CH3:15])[CH3:14].[OH-].[Na+].C(OC(=O)CC1N=NN(C(C)C)N=1)C>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:10]([CH:13]([CH3:15])[CH3:14])[N:9]=[N:8][N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nn[nH]n1
Reactant: CC(C)I
Agent: CCOC(=O)Cc1nnn(C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nnnn1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of (2H-tetrazol-5-yl)-acetic acid ethyl ester (2.0 g, 13 mmol) in dimethylformamide (5 mL) was added 2-iodo-propane (11 g, 64 mmol) and sodium hydroxide (2.6 g, 64 mmol) and the solution was stirred at room temperature for 2 h. Ice water was added and the solution was extracted several times with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography to provide a mixture of (2-isopropyl-2H-tetrazol-5-yl)-acetic acid ethyl ester and (1-isopropyl-1H-tetrazol-5-yl)-acetic acid ethyl ester (2 g, 79% yield).
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][C:16](F)=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[NH:10])=[O:7])=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:31]1([C:16]2[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9](=[NH:10])[NH:8][C:6](=[O:7])[C:5]3[CH:25]=[CH:26][C:2]([N:31]4[CH:35]=[CH:34][N:33]=[CH:32]4)=[C:3]([C:27]([F:30])([F:28])[F:29])[CH:4]=3)=[O:24])=[CH:14][C:15]=2[C:20]([F:23])([F:21])[F:22])[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: N=C(NC(=O)c1ccc(F)c(C(F)(F)F)c1)NC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N=C(NC(=O)c1ccc(-n2ccnc2)c(C(F)(F)F)c1)NC(=O)c1ccc(-n2ccnc2)c(C(F)(F)F)c1
Yield: 39.4 %

Procedure:
0.25 g of bis(4-fluoro-3-trifluoromethylbenzoyl)guanidine, 0.16 g of imidazole and 0.16 g of potassium carbonate are heated for 16 h in 5 ml of DMF, and after that the solvent is evaporated. Separation of the crude product by column chromatography yielded 0.12 g of bis[4-(1-imidazolyl)-3-trifluoromethylbenzoyl]guanidine as a colorless solid, mp 130° C. decomp., Rf (CH2Cl2/MeOH 9:1)=0.4 MS (ES):536 (M+1) and 0.07 g of N-[4-(1-imidazolyl)-3-trifluoromethylbenzoyl]-N′-(4-fluoro-3-trifluoromethylbenzoyl)guanidine as an oil. Treatment with HClg/ether yielded 0.06 g of N-[4-(1-imidazolyl)-3-trifluoromethylbenzoyl]-N′-(4-fluoro-3-trifluoromethylbenzoyl)guanidine hydrochloride as a colorless solid, mp 217-218, decomp., Rf (CH2Cl2/MeOH 9:1)=0.53; MS (ES):488 (M+1)
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C@H:15]3[CH2:19][O:18][C:17](=[O:20])[NH:16]3)[CH:12]=2)[NH:7][C:6]=1C(O)=O.C(=O)=O.C(O)(=O)CCC(O)=O>N1C2C(=CC=CC=2)C=CC=1>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[C:13]2[CH:12]=[C:11]([CH2:14][C@@H:15]3[NH:16][C:17](=[O:20])[O:18][CH2:19]3)[CH:10]=[CH:9][C:8]=2[NH:7][CH:6]=1)[CH3:24]
Reactant: CN(C)CCc1c(C(=O)O)[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Agent: O=C(O)CCC(=O)O
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Product: CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Temperature: 200 °C
Yield: 89.9 %

Procedure:
1 g (3.02 mmoles) of the (S)-3-(2-dimethylaminoethyl)-5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-2-carboxylic acid was suspended in 10 ml of dry quinoline. 20 mg of cuprous oxide was added and the stirred suspension heated to 200° C. under dry nitrogen stream. The reaction mixture was kept at this temperature until no more CO2 was released (15-20 min.). It was left to cool to room temperature and the reaction mixture filtered through decalite. The filtrate was concentrated by vacuum distillation of the solvent, providing a residue which was dissolved with a succinic acid solution and washed three times with 15 ml of dichloromethane. The washed aqueous phase was cooled, the pH adjusted to 12 with a 40% sodium hydroxide solution and extracted three times with 20 ml of dichloromethane. The combined organic phases were dried on anhydrous sodium sulphate and evaporated to dryness. The residue was recrystallised with isopropyl alcohol to give 780 mg (90%) of zolmitriptan as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([O-:5])=[O:4].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16]#[N:17])[CH:11]=[CH:12][C:13]=1[Cl:14].N.[NH2-].[Na+].[Na].CC([O-])(C)C.[K+]>CS(C)=O>[C:16]([CH:15]([C:10]1[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=1)[CH2:2][C:3]([OH:5])=[O:4])#[N:17]
Reactant: O=C([O-])CCl
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: N
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(CC(=O)O)c1ccc(Cl)c(Cl)c1

Procedure:
3-Cyano-3-(3,4-dichlorophenyl) propionic acid (III) is prepared by reacting sodium chloroacetate with 3,4-dichlorophenylacetonitrile (II), for example in liquid ammonia in the presence of sodium amide according to the technique of A. G. CHIGAREV and D. V. IOFFE, Zh. Org. Khim. 3, 85-8 (1967), or in the presence of another very strong base such as sodium or potassium tert-butylate in liquid ammonia at -33° C. or in anhydrous dimethyl sulfoxide at room temperature. The yield of 3-cyano-3-(3,4-dichlorophenyl)propionic acid isolated is 74 to 78%, but it is even better if the product is not isolated, because it suffices to react it with D-(-)-N-methylglucamine, an inexpensive industrial product obtained from D-glucose and methylamine (KARRER, HERKENRATH--Helv. Chim. Acta, 20, 37 (1937)), in order to crystallize all the racemic cyanoacid (III) in the form of the salt of the levorotatory acid. The yield is excellent, being 190% based on the levorotatory enantiomer contained in the racemate (III). The crystallization solvent can be methanol, ethanol, Cellosolve® or any other suitable solvent. The resolution temperature is between the boiling point of the solvent and 0° C. The N-methylglucamine must be present in at least the stoichiometric amount. It is preferably used in slight excess.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (1.03 g, 3.81 mmol) in THF (70 mL), are added DCC (1.03 g, 4.91 mmol), HOBt (660 mg, 4.90 mmol) and 3(R)-quinuclidinol (1.18 g, 9.48 mmol) and the resulting mixture is stirred for 12 hours at RT under nitrogen flowstream (LC-MS monitoring: complete conversion). The solvent is evaporated and the residue is partitioned between EtOAc (100 mL) and 2M K2CO3 (50 mL); the organic layer is separated, washed with brine and dried over Na2SO4. The resulting crude is purified by flash chromatography (DCM/MeOH=95/5, 0.1% NH3 (aq.)) to obtain 1.12 g of I19 (80% yield).
Reaction SMILES: C[O:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[C:5]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[C:5]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)c(-c2ccc(C)cc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(O)ccc2C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)cc1
Temperature: 25 °C
Yield: 8.1 %

Procedure:
To a solution of 1-{4-[4-methoxy-2-(4-methylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (380 mg) in dichloromethane (15 ml) at -78° C. was added a solution of 1.0M boron tribromide in dichloromethane (2.4 ml). The resulting solution was allowed to warm to ambient temperature where it was maintained for 12 hours. The mixture was cooled to 0° C., and added water. The organic layer was washed with saturated sodium bicarbonate aqueous solution and filtered through a bed of celite, and concentrated. The residue was triturated with diethyl ether to give 1-{4-[4-hydroxy-2-(4-methylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (30 mg).
Reaction SMILES: [C:1]1(=[O:14])[C:9]2[C:8]3[CH:10]=[CH:11][CH2:12][O:13][C:7]=3[CH:6]=[CH:5][C:4]=2[CH2:3][NH:2]1.[H-].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([N:2]1[C:1](=[O:14])[C:9]2[C:8]3[CH:10]=[CH:11][CH2:12][O:13][C:7]=3[CH:6]=[CH:5][C:4]=2[CH2:3]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCc2ccc3c(c21)C=CCO3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1Cc2ccc3c(c2C1=O)C=CCO3
Reaction time: 0.67 h
Yield: 69 %

Procedure:
To a solution of 2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one (71) (500 mg, 2.67 mmol) in THF (35 ml) was added NaH (95%, 87 mg, 3.47 mmol) in portions. Resulting mixture was stirred for 40 min before adding MeSO2Cl by syringe. Stirring was continued for 1 hour. The solvent was removed in vacuo and the residue was portioned with CH2Cl2. The organic solution was washed with H2O, sat. NaCl and dried over Na2SO4. Concentration in vacuo gave the title compound (95) as a solid (490 mg, 69%). MS (ES) m/z 266.0.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Na].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyrazole (2.0 g, 29 mmol) in tetrahydrofuran (THF) is added dropwise to a suspension of 50% sodium hydride (1.4 g) in THF at RT, followed by stirring at RT for 2 hours. The resulting sodium salt of pyrazole is added to 4-fluoronitrobenzene (4.15 g) in THF at 0°, after which the mixture is heated under reflux for 15 hours. The reaction mixture is poured into saturated aq. ammonium chloride and extracted with ethyl acetate. The combined organic layers are washed with water and with brine and dried to give 1-(4-nitrophenyl)pyrazole.
Reaction SMILES: Br.[C:2]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CN(C)C=O>[C:2]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:10][CH2:9]1)(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CC(=O)N1CCNCC1
Reactant: C=C(C)C(=O)Cl
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)N1CCN(C(=O)CC(C)=O)CC1
Reaction time: 20 h
Yield: 56 %

Procedure:
Crude 1-acetoacetylpiperazine hydrobromide (50 g, 0.2 mole) was dissolved in N,N-dimethylformamide (300 ml) with AranoxTM (50 mg) (available from U.S. Rubber Co.). Triethylamine (50 g, 0.5 mole) was added at 0° C., followed immediately by the dropwise addition of methacryloyl chloride (20.8 g, 0.2 mole) at 0° C. The reaction solution was then allowed to reach 20° C. over a 20 hour period. The reaction solution was filtered and the solvent was removed at low vacuum. The residue was distilled to give 4-acetoacetyl-1-methacryloylpiperazine (b.p.=110°-129° C./10-8μ) at a yield of 56%.
Reaction SMILES: [CH:1]([O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]([CH2:21][C@H:22]([NH:38]C(OC(C)(C)C)=O)[C:23]([O:25][C@H:26]([CH3:37])[CH2:27][O:28][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[O:24])[CH:11]=[CH:12][C:13]=1[O:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[O:6])([CH3:3])[CH3:2].[ClH:46]>O1CCOCC1>[ClH:46].[NH2:38][C@@H:22]([CH2:21][C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[C:8]([O:7][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:9]=1)[C:23]([O:25][C@H:26]([CH3:37])[CH2:27][O:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30])=[O:24]
Reactant: CC(C)OC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H](C)COC(=O)c2ccccc2)cc1OC(=O)OC(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=O)Oc1ccc(C[C@H](N)C(=O)O[C@H](C)COC(=O)c2ccccc2)cc1OC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(1R)-1-Methyl-2-phenylcarbonyloxyethyl (2S)-3-[3,4-bis(isopropoxycarbonyloxy)phenyl]-2-[(tert-butoxy)carbonylamino]propanoate (9) (1.06 g, 1.63 mmol) was dissolved in 10 mL of 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 60 min. Dioxane was evaporated completely under reduced pressure. The resulting white solid was dissolved in water (15 mL) and washed with methyl tert-butyl ether. The aqueous phase was collected and mixed with acetonitrile (10 mL). Lyophilization gave the title compound (8) (0.926 g, 100% yield) as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.30 (3H, d, J=6.4 Hz), 1.35 (12H, d, J=6.4 Hz), 3.16 (1H, dd, J=14.4, 6.8 Hz), 3.23 (1H, dd, J=14.4, 6.4 Hz), 4.28 (1H, t, J=6.8 Hz), 4.31 (1H, dd, J=12.4, 6.4 Hz), 4.48 (1H, dd, J=12, 2.8 Hz), 5.33 (1H, m), 7.19 (1H, dd, J=8.2 Hz), 7.24 (1H, d, J=2 Hz), 7.25 (1H, d, J=8 Hz), 7.48 (2H, t, J=7.2 Hz), 7.60 (1H, t, J=7.2 Hz), 8.00 (2H, d, J=7.6 Hz). MS (ESI) m/z 532.21 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.8 %

Procedure:
To a solution of N-methylaniline (10.0 g) in DMF (100 ml) was added dropwise a solution of at room temperature N-bromosuccinimide (16.6 g) in DMF (100 ml), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was added to water, and the mixture was extracted with diethylether. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give pale yellow oil of 4-bromo-N-methylaniline (18.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
An ice-cooled solution of 4-bromophenol (69.2 g) and cinnamoyl chloride (66.8 g) in dichloromethane (150 ml) was treated with triethylamine (40.6 g). After stirring for 18 hrs at room temperature the mixture was washed with water (250 ml), 1 M aqueous HCl, and dried over anhydrous sodium sulphate. Evaporation in vacuum left solid 3-phenylacrylic acid 4-bromophenyl ester (121.0 g, 99.8% yield), m.p. 113.3° C., tlc: (1) 0.83. NMR (CDCl3): 116.85, 118.87, 123.49, 128.38, 129.06, 130.90, 132.49, 134.02, 147.07, 149.84, 165.06.