Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11]C)[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(Br)cc(O)c1O
Temperature: 25 °C
Yield: 90 %

Procedure:
To dichloromethane (400 mL) was added 5-bromo-2-hydroxy-3-methoxy-benzaldehyde (prepared per Synthetic Communications, 1991;21(8,9): 1091-5; 94.6 g, 409.4 mmol). To this was added with cooling to 10° C. a solution of boron tribromide (153.9 g, 614 mmol) in dichloromethane (400 mL) over 20 minutes, followed by warming to 25° C. overnight. The mixture was poured into 2 L of ice and extracted with chloroform. The chloroform solution was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and hexane was added giving a crystalline precipitate which was filtered, washed with hexane, and dried in vacuo to a solid, 80.0 g, 90% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cccc(OC(F)(F)F)c1
Product: CC(=O)Nc1nccc(C(=O)NC(C)c2cccc(OC(F)(F)F)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)pyrimidine-4-carboxamide (15 mg, 0.05 mmol, Step-1, single enantiomer) and acetyl chloride (4 mg, 0.05 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[C:17]([O:16][CH2:15][CH2:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCCc1nc(-c2ccc(Cl)cc2)co1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(OCCCc1nc(-c2ccc(Cl)cc2)co1)c1ccccc1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 3-[4-(4-chlorophenyl)-2-oxazolyl]propanol (0.5 g) in pyridine (2 ml) was added benzoyl chloride (0.29 ml), followed by stirring for an hour at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed succesively with an aqueous sodium hydrogen carbonate solution, 2N-HCl and water, dried over MgSO4 and distilled to remove the solvent. The precipitated crystals were collected by filtration to give 3-[4-(4-chlorophenyl)-2-oxazolyl]propyl benzoate (0.687 g, 96%). Recrystallization from ether-hexane gave colorless prism crystals of mp 47°-47.5° C.
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH2:26]Cl)=[CH:22][CH:21]=1>C(#N)C>[Cl:19][C:20]1[CH:29]=[CH:28][C:23](/[CH:24]=[CH:25]/[CH2:26][N:2]2[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4][CH2:3]2)=[CH:22][CH:21]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: O=C1CCCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.3 %

Procedure:
4-Perhydroazepinone hydrochloride (2.5 g, prepared according to Synth. Commun. 1992, 1249-1258) was suspended in acetonitrile (80 ml); diisopropylethylamine (4.4 ml) and 4-chlorocinnamyl chloride (2.7 g) were successively added at room temperature and the resulting reaction mixture was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (eluent cyclohexane:ethyl acetate 6:4) to afford 1-(trans-3-(4-chlorophenyl)allyl)-perhydroazepin-4-one (1.84 g) as a foam. MS (ES+) 264/266 (M+H+).
Reaction SMILES: C(OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[CH2:27]([S:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([N+:48]([O-])=O)[C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]([OH:38])=[O:37])[CH2:28][CH:29]([CH3:31])[CH3:30]>>[NH2:48][C:40]1[C:41]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[C:33]([S:32][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:34]=[C:35]([CH:39]=1)[C:36]([OH:38])=[O:37]
Reactant: CC(C)CCSc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Agent: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Product: CC(C)CCSc1cc(C(=O)O)cc(N)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 3-isopentylthio-5-nitro-4-phenylbenzoic acid, and following the procedure described, 5-amino-3-isopentylthio-4-phenylbenzoic acid is obtained crystallizing with 0.25 mole of water with a melting point of 124.5°-125.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[C:34]([NH2:38])(=[O:37])[CH2:35][CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:38][C:34](=[O:37])[CH2:35][CH3:36])=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: CCC(N)=O
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)CC)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and propanamide, the title compound was obtained as crystals.
Reaction SMILES: COC(O[CH:6]([CH3:14])/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>C(Cl)Cl.[Pd].CCCCCCC>[C:15]1(=[O:25])[N:19]([CH:6]([CH3:14])/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: CCOC(=O)/C=C/C(C)OC(=O)OC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(C)N1C(=O)c2ccccc2C1=O
Yield: 90 %

Procedure:
Reaction of 1 (rac-Ethyl (2E)-4-(methoxycarbonyloxy)pent-2-enoate) (104 mg, 0.50 mmol) with phthalimide (147 mg, 1.0 mmol), Cs2CO3 (40.7 mg, 0.125 mmol) and 5 mol % [Pd] in CH2Cl2 (10 ml) at room temperature according to Example 2. Flash chromatography (AcOEt:heptane fraction 25:75) yields 16 (rac-Ethyl (2E)-4-phthalimidopent-2-enoate) (124 mg, 90%) as a yellowish solid.
Reaction SMILES: Cl[CH2:2][C@@H:3]([NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]=[O:25]>>[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][O:25]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Reactant: CC(C)CN[C@H](CCl)CC(C)C
Product: Cc1cc([N+](=O)[O-])ccc1N=C1OC[C@H](CC(C)C)N1CC(C)C

Procedure:
(L)-Leucine methyl ester was reduced to (1S)-1-(hydroxymethyl)-3-methylbutylamine according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2-isopropyl-4-isobutyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (1S)-1-(hydroxymethyl)-N-isobutyl-3-methylbutylamine. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to give (1S)-1-(chloromethyl)-N-isobutyl-3-methylbutylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-oxazolidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B1OC(C)(C)C(C)(C)O1)[CH3:2].Br[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([NH2:32])[CH:26]=[CH:25]2.C([O-])(=O)C.[K+].CCO.O>>[NH2:32][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[C:22]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH:23]=2)[N:28]=1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ccc2cc(Br)ccc2n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccccc1-c1ccc2nc(N)ccc2c1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
To a microwave reaction vessel was added ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.7 g, 13 mmol), 6-bromoquinolin-2-amine (2.0 g, 9.0 mmol), PdCl2(PPh(t-Bu)2)2 (0.084 g, 0.13 mmol), potassium acetate (1.8 g, 18 mmol), EtOH (9.9 ml, 170 mmol) and water (2.4 ml, 134 mmol). The reaction mixture was heated at 85° C. for 8 h, and was then partitioned between EtOAc and water. The organic layer was washed with water and brine and allowed to stand for 72 h. The supernatant was decanted from the resulting precipitate and the precipitate was dried in vacuo to give ethyl 2-(2-aminoquinolin-6-yl)benzoate. Step 2 6-(2-Ethoxyphenyl)quinolin-2-amine (1.0 g, 3.8 mmol) was taken up in THF and then 5N NaOH was added and the solution was stirred for 72 h. DCM was added and the solid was filtered to give ethyl 2-(2-aminoquinolin-6-yl)benzoate. Step 3 A solution of 2-(2-aminoquinolin-6-yl)benzoic acid (50 mg, 0.19 mmol), 4-fluoropiperidine (25 mg, 0.24 mmol), HATU (91 mg, 0.24 mmol), DIEA (100 uL, 0.57 mmol), and DMF (1 mL) was heated in a shaker oven at 60° C. for 1 h. The resulting solution was purified by HPLC (CH3CN/water modified with 0.1% TFA) to give (2-(2-aminoquinolin-6-yl)phenyl)(4-fluoropiperidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 350 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:17]5[S:18][CH:19]=[CH:20][C:16]=5[C:15](=[O:21])[N:14]([CH3:22])[C:13]=34)[O:6][N:5]=2)CC1.CN1C(=O)C2C=CSC=2N2C=NC(C(OCC)=O)=C12.C1(C(=NO)N)CC1>>[CH3:22][N:14]1[C:15](=[O:21])[C:16]2[CH:20]=[CH:19][S:18][C:17]=2[N:12]2[CH:11]=[N:10][C:9]([C:7]3[O:6][N:5]=[C:4]([CH3:1])[N:8]=3)=[C:13]12
Reactant: Cn1c(=O)c2ccsc2n2cnc(-c3nc(C4CC4)no3)c12
Agent: CCOC(=O)c1ncn2c3sccc3c(=O)n(C)c12
Agent: NC(=NO)C1CC1
Product: Cc1noc(-c2ncn3c4sccc4c(=O)n(C)c23)n1

Procedure:
In the same manner 6-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-methyl-4-oxo-imidazo[1,5-a]thieno[3,2-e]pyrimidine, m.p. 218°-219° C., was prepared from ethyl 4,5-dihydro-5-methyl- 4-oxo-imidazo[1,5-a]thieno[3,2-e]pyrimidine-6-carboxylate and cyclopropan carboxamide oxime (Compound 18).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][C@H:12]([CH2:14]OS(C)(=O)=O)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Br-:21]>CC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][C@@H:12]([CH2:14][Br:21])[CH:11]=[CH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C=C[C@@H](COS(C)(=O)=O)C1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CBr)C1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A mixture of cis-methanesulfonic acid 4-tert-butoxycarbonylamino-cyclopent-2-enylmethyl ester (2.51 g, 8.6 mmol) and LiBr (2.24 g, 25.8 mmol) in dry acetone (20 mL) was refluxed overnight. The reaction mixture was allowed to cool to room temperature, filtered and concentrated. The residue was dissolved in CH2Cl2 and washed with water, dried and concentrated under reduced pressure to give of cis-(4bromomethyl-cyclopent-2-enyl)-carbamic acid tert-butyl ester (2.23 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.Cl[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]>CO>[CH2:18]([O:17][C:15]([NH:8][CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)[C:9]([OH:11])=[O:10])=[O:16])[CH:19]=[CH2:20]
Reactant: N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: C=CCOC(=O)Cl
Solvent: CO
Product: C=CCOC(=O)NC(Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The product is prepared by methods (ET3N, methanol) known from the literature starting from 10 g of 4-chlorophenylalanine and 8 ml of allyl chloroformate. MW=283.71 (calculated monoisotopic); measured value (M+H)+: 284.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.8 %

Procedure:
3-Nitro-5-trifluoromethylaniline (0.8 g; 4 mmol) was suspended in pyridine (5 mL), methanesulfonylchloride (0.6 mL; 8 mmol) was added at 0° C. and the mixture stirred for 5 hours at room temperature. A solution of sodium bicarbonate was then added to the reaction mixture and the precipitate obtained was washed with diluted hydrochloric acid and dried. 0.6 g (2.11; 52.8% yield) of N-(3-nitro-5-trifluoromethyl-phenyl)-methylsulfonamide were obtained as solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C@@H:8]2[CH2:11][CH2:10][C@H:9]2[C:12]([OH:14])=[O:13])=[O:7])=[CH:4][CH:3]=1.[CH3:17]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:11][CH2:10][C@H:9]2[C:12]([O:14][CH3:17])=[O:13])=[O:7])=[CH:15][CH:16]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H]1CC[C@H]1C(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.2 %

Procedure:
To a solution of trans-2-(4-bromobenzoyl)cyclobutanecarboxylic acid (8.2 g, 28.94 mmol) in MeOH (250 mL) was added 2,2-dimethoxypropane (3.65 g, 35.02 mmol) and HCl (4.0 M in dioxane) (2.0 mL). The resulting solution was stirred at rt for 3 days, and then evaporated to dryness. The resulting residue was purified with flash chromatography (Biotage Flash 40M) using 4 to 11% ethyl acetate in hexanes to afford methyl trans-2-(4-bromobenzoyl)cyclobutanecarboxylate (6.21 g, 78%). 1H NMR (400 MHz, CD2Cl2) δ 2.14–2.39 (m, 4H), 3.62 (m, 1H), 3.68 (s, 3H), 4.24 (m, 1H), 7.63 (m, 2H), 7.80 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C@H:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.[CH3:27][O:28][C:29](=[O:38])[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)Br>>[CH3:27][O:28][C:29](=[O:38])[CH:30]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@@H:9]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1cc2c(cc1OC)[C@H](CCc1ccc(C(F)(F)F)cc1)NCC2
Reactant: COC(=O)C(Br)c1ccccc1
Product: COC(=O)C(c1ccccc1)N1CCc2cc(OC)c(OC)cc2[C@@H]1CCc1ccc(C(F)(F)F)cc1

Procedure:
This compound is prepared by reaction of (1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,2,3,4-tetrahydroisoquinoline with α-bromo-phenyl-acetic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C@H:7]2[CH2:8][C@@H:9]3[O:21][CH:22]([O:23]C)[C@@:6]2([C@@H:11]2[CH2:12][CH2:13][C@H:14]4[C:17]([C:19](=[O:20])[C@@:10]32[C@@H:15]4[OH:16])=[CH2:18])[C@@H:5]([OH:25])[CH2:4][CH2:3]1>CCCCCC.C(OC(=O)C)C>[CH3:1][C:2]1([CH3:26])[C@H:7]2[CH2:8][C@@H:9]([OH:21])[C@@:10]34[C:19](=[O:20])[C:17](=[CH2:18])[C@@H:14]([C@H:15]3[OH:16])[CH2:13][CH2:12][C@H:11]4[C@:6]2([CH2:22][OH:23])[C@@H:5]([OH:25])[CH2:4][CH2:3]1
Reactant: C=C1C(=O)[C@@]23[C@@H]4C[C@@H]5C(C)(C)CC[C@H](O)[C@@]5(C(OC)O4)[C@@H]2CC[C@@H]1[C@H]3O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=C1C(=O)[C@@]23[C@H](O)C[C@@H]4C(C)(C)CC[C@H](O)[C@@]4(CO)[C@@H]2CC[C@@H]1[C@H]3O

Procedure:
The third fraction obtained by the first silica gel column chromatography was loaded on the third silica gel column chromatography, and four fractions, 3-A, 3-B, 3-C and 3-D, were obtained by elution with hexane-ethylacetate step gradient system. Kamebacetal A represented by Chemical Formula 2 was isolated from the 3-B fraction, and kamebakaurin represented by Chemical Formula 3 was isolated from the 3-C fraction.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.Br[C:17]1[CH:18]=[C:19]([CH2:23][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.[Pd].C(OCC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][P:4]([O:5][CH2:6][CH3:7])([C:21]1[CH:20]=[C:19]([CH2:23][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:18]=[CH:17][CH:22]=1)=[O:8])[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: COC(=O)CNCc1cccc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOP(=O)(OCC)c1cccc(CNCC(=O)OC)c1
Temperature: 25 °C

Procedure:
A solution of diethylphosphite (1 ml, 6.75 mmol) and triethylamine (5 ml) is stirred under a nitrogen atmosphere and then treated with tetrakis (triphenylphosphine) palladium (0) (0.4 g). A solution of methyl N-[(3-bromophenyl)methyl]glycinate (Example C) (1.62 g, 6.28 mmol) in toluene (10 ml) is degassed in vacuo, added to the palladium catalyst mixture, and the reaction vessel immersed in a 105° C. oil bath for 17 hours. The reaction mixture is cooled to room temperature and diluted with diethyl ether. An insoluble precipitate is removed by filtration and the filtrate evaporated to give a yellow residue. The product is purified by chromatography on silica gel (0-5% methanol in chloroform as eluant). 1H-NMR: 4H, m, 7.9-7.3 ppm; 4H, m, 4.25-3.95; 2H, s, 3.8; 3H, s, 3.7; 2H, s, 3.4; 6H, t, 1.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].[C:12](#[N:15])[CH:13]=[CH2:14]>C(O)(C)(C)C.CCOCC>[C:12]([CH2:13][CH2:14][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)#[N:15]
Reactant: COc1ccc(O)cc1
Reactant: C=CC#N
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COc1ccc(OCCC#N)cc1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
4-Methoxyphenol (248 g), KOH (5.6 g) and acrylo-nitrile (397 ml) were dissolved in 1 liter of t-butanol and heated with stirring at 75° C. for 5 hours. The mixture was then cooled to room temperature and stripped in vacuo to solid residue, which was repulped in ether and insolubles recovered by filtration. The latter were taken up in 2 liters of ethyl acetate, washed in sequence with 1 liter each of H2O, saturated NaHCO3 and saturated NaCl, dried over MgSo4 and restripped to yield purified title product, 199.4 g, m.p. 62-64° C.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:8]=2[C:9]([O:11]CC)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[OH-].[Na+].Cl.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C(O)C.[Cl-].[Na+].O>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([C:9]([C:8]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:7]=2[N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:11])[CH2:33][CH2:34]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1N1CCOCC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3N3CCOCC3)CC2)c(C)c1
Temperature: 50 °C
Yield: 62 %

Procedure:
To a mixture of ethyl 2-chloro-4-nitrobenzoate (1.5 g), palladium acetate (73.3 mg), 2-(dicyclohexylphosphino)biphenyl (229 mg), tripotassium phosphate (1.94 g) and morpholine (0.57 mL) was added 1,2-dimethoxyethane (23 mL), and the mixture was stirred with heating under reflux for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give ethyl 2-(morpholin-4-yl)-4-nitrobenzoate (220 mg). The obtained ethyl 2-(morpholin-4-yl)-4-nitrobenzoate (220 mg) and 1-(2,4-dimethylphenyl)piperazine (149 mg) were dissolved in ethanol (3.5 mL), 1N aqueous sodium hydroxide solution (1.1 mL) was added, and the mixture was stirred at 50° C. To the reaction mixture was added 1N hydrochloric acid (1.1 mL), 1-(2,4-dimethylphenyl)piperazine (149 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (218 mg) were added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, the obtained residue was purified by silica gel column chromatography to give [4-(2,4-dimethylphenyl)piperazin-1-yl][2-(morpholin-4-yl)-4-nitrophenyl]methanone (206 mg). Then, to a solution of ethanol (3 mL) and water (1 mL) were added ammonium chloride (294 mg) and iron (211 mg), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl][2-(morpholin-4-yl)-4-nitrophenyl]methanone (206 mg) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (188 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[N:10][N:11]=[C:12]3[CH2:19][C:20]2[C:25]([Cl:26])=[CH:24][N:23]=[CH:22][C:21]=2[Cl:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH:1]1([O:6][C:7]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[N+:10]([O-:36])[N:11]=[C:12]3[CH2:19][C:20]2[C:21]([Cl:27])=[CH:22][N:23]=[CH:24][C:25]=2[Cl:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OC1CCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[n+]([O-])cc2c1OC1CCCC1
Yield: 64.2 %

Procedure:
A solution under stirring of 5-cyclopentyloxy-1-(3,5-dichloropyridin-4-ylmethyl)-6-methoxy-phthalazine (0.1 g, 0.741 mmoles), obtained as described in example 8, in methylene chloride (2 ml), was added with 55% m-chloroperbenzoic acid (255.75 mg, 0.816 mmoles). The mixture was diluted with methylene chloride, washed with a solution of NaHCO3, anhydrified and dried. The residue was flash chromatographed over silica gel (eluent:methylene chloride/ethyl acetate 1:1) and the eluate taken up in ether to give 0.2 g of the title product (yield: 64%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:10][CH:9]1[CH2:24][OH:25])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:23][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=1)[O:13][CH:11]1[CH2:12][NH:8][CH:9]([CH2:24][OH:25])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(F)cc([N+](=O)[O-])c2)CC1CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(F)cc(OC2CNC(CO)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To 2.0 g of 4-(3-fluoro-5-nitro-phenoxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (6) in 5 mL of dichloromethane was added 10 mL of TFA. The mixture was stirred for 0.5 hours at room temperature and then solvents were removed in vacuo. The resulting residue was dissolved in 50 mL of EtOAc and washed with aq. NaOH (3×25 mL) and brine (25 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give 1.29 g (90%) of [4-(3-fluoro-5-nitro-phenoxy)-pyrrolidin-2-yl]-methanol as a thick yellow oil, which was used directly in the following reaction.