Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[N:11]3[C:15]([C:16](=O)[C:8]4[C:9]=2[C:4]([CH:5]=[CH:6][N:7]=4)=[CH:3][CH:2]=1)=[CH:14][CH:13]=[CH:12]3.Cl.[NH2:19][OH:20].O>N1C=CC=CC=1>[OH:20][N:19]=[C:16]1[C:8]2[C:9]3[C:4]([CH:5]=[CH:6][N:7]=2)=[CH:3][CH:2]=[CH:1][C:10]=3[N:11]2[C:15]1=[CH:14][CH:13]=[CH:12]2
Reactant: NO
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: ON=c1c2nccc3cccc(c32)n2cccc12
Yield: 90.9 %

Procedure:
A solution of 7H-indolizino[5,6,7-ij]isoquinolin-7-one (28 g.) and hydroxylamine hydrochloride (28 g.) in pyridine (560 cc.) is maintained at the boiling point, with stirring. The brown solution thus obtained is poured into water (3.92 liters). After stirring for 3 hours, the mustard yellow crystals obtained are filtered off and then washed copiously with water. After drying, 7-hydroxyimino-7H-indolizino[5,6,7-ij]isoquinoline (27.2 g.), melting at 254° C. with decomposition, is obtained. After recrystallisation from a mixture of water and pyridine (6- 5 by volume), the pure product melts at 258° C. with decomposition.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:9]=2)[CH2:4]1.[C:20](O)(=[O:29])[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].C(N(CC)CC)C.[Cl-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:15]([CH2:14][O:13][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH2:12][C@H:3]([NH:2][C:20](=[O:29])[C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])[CH2:4]2)=[CH:9][CH:8]=1)([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](N)CC2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NC(=O)[C@H](O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
To a suspension of 5.7 g of (S)-2-amino-7-carbethoxymethoxytetraline hydrochloride, 3 g of (R)-mandelic acid and 8 g of benzotriazolyl-N-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) in 100 ml of anhydrous methylene chloride, there is slowly added 5.6 ml of triethylamine, then the solution thus obtained is left under stirring at room temperature for 5 hours. After addition of 150 ml of a saturated solution of sodium chloride, the mixture is left under stirring for 30 minutes at room temperature, added with 500 ml of ethyl acetate. The organic phase is washed at first with a 1N solution of hydrochloric acid, then with a saturated solution of sodium bicarbonate and sodium chloride. The organic solution is dried on sodium sulfate, filtered and evaporated to dryness. The oil thus obtained is purified by flash chromatography by using a mixture of ethyl acetate/cyclohexane 55/45 as a solvent. The resulting solid is triturated in 20 ml of ethyl ether and the product thus obtained is crystallized from ethyl acetate to give N-[(2S)-7-carbethoxymethoxy-1,2,3,4 -tetrahydronaphth-2-yl]-(R)-mandelamide; m.p. 115°-117° C.; /alpha/=-98.3° (methanol, c=1%). Yield: 55%.
Reaction SMILES: C1(C[O:8][C:9](=[O:63])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:30])[CH:26]=[C:25]([C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:47])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1>[Pd].C(OCC)(=O)C.C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:30])[CH:26]=[C:25]([C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:47])[CH:24]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:63])=[O:8]
Reactant: CCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of 0.43 g of N-[3,5-bis[(tetradecyloxy)carbonyl]phenyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 0.2 g of 10% palladium on carbon in 30 ml of ethyl acetate and 20 ml of THF was shaken under an initial hydrogen pressure of 51 psi for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from methanol-water to give 0.28 g (82% yield, mp 84°-87°) of N-(carboxy-methyl)-N-[3,5-bis[(tetradecyloxy)carbonyl]phenyl]glycine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([OH:12])=[O:11])[C:7]1[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=1[S:5]2.[H-].[Na+].[CH2:19](I)[CH3:20]>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([O:12][CH2:19][CH3:20])=[O:11])[C:7]1[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=1[S:5]2
Reactant: CCI
Reactant: Cc1nc2sc3ccccc3n2c1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2sc3ccccc3n12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Subsequently, 6.0 g of 2-methylimidazo[2,1-b]benzothiazole-3-carboxylic acid was suspended in 100 ml of dry dimethylformamide. Under ice cooling, 1.5 g of 60% sodium hydride was added to the suspension. After stirring for 30 minutes, 6.0 g of ethyl iodide was added to the mixture followed by heating at 40° C. overnight. After completion of the reaction, the solvent was removed under reduced pressure. Ether and water were added to the residue, which was fractionated. The residue obtained from the ether phase was crystallized with n-hexane to give 4.0 g of ethyl 2-methylimidazo[2,1-b]benzothiazole-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:18])=[CH:7][CH:8]=2)[O:3]1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>>[O:24]1[CH2:23][CH:22]1[CH2:20][O:18][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:2]([CH3:19])([CH3:1])[O:3]2)=[CH:8][CH:7]=1
Reactant: ClCC1CO1
Reactant: CC1(C)C=C(c2ccccc2)c2ccc(O)cc2O1
Product: CC1(C)C=C(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Yield: 78 %

Procedure:
Reaction of 2,2-dimethyl-4-phenyl-2H-chromen-7-ol with epichlorohydrin, by an analogous process to that described in Example 1 gave 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenyl-2H-chromene (78%). Reaction of this epoxide with dimethylamine by an analogous process to that described in Example 2 gave 7-(2-hydroxy-3-dimethylaminopropoxy)-2,2-dimethyl-4-phenyl-2H-chromene isolated as its hydrochloride salt (48%), m.p. 208-209°.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[C:15]([CH3:22])=[C:16]([CH2:20][OH:21])[CH:17]=[CH:18][CH:19]=1.CCOCC.CCCCCC>ClCCl.C(OCC)C>[CH3:12][O:13][C:14]1[C:15]([CH3:22])=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH:20]=[O:21]
Reactant: COc1cccc(CO)c1C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cccc(C=O)c1C
Reaction time: 3.5 h
Yield: 97 %

Procedure:
A stirred suspension of pyridinium chlorochromate (19.2 g; 89.2 mmol) in dichloromethane at ambient temperature was treated with a solution of (3-methoxy-2-methylphenyl)methanol (9.05 g; 59.47 mmol) in dichloromethane. The reaction solution immediately turned a greenish-brown color. The reaction was stirred for 3.5 hr, diluted 50% with diethyl ether and decanted. The brown gummy residue was triturated twice more with diethyl ether (40 mL) and the ether extracts were combined and evaporated to yield a yellow oil. The oil was passed through a column of silica gel with an ether/hexane mixture to yield the title product, 8.74 g; 97% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([O:14][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([NH:23][CH3:22])[CH:25]=2)=[CH:3][CH:4]=1)[C:10]([O:12][CH3:13])=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cccc(-c2ccc(C[C@H](OCc3ccccc3)C(=O)OC)cc2)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
635 mg (0.55 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 4 g (11 mmol) of methyl (S)-3-(4-bromophenyl)-2-benzyloxypropionate and 4 g (17 mmol) of methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 25 ml of dimethylformamide. 10 ml of a 2M potassium phosphate solution are added and the reaction mixture is stirred at 70° C. for 1 hour. The reaction is halted by the addition of 50 ml of water and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 2.6 g of methyl (S)-2-benzyloxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate are obtained in the form of an oil. Yield=61%.
Reaction SMILES: [N+:1](=[CH:3][CH3:4])=[N-:2].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>CCOCC>[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[C:3](=[N+:1]=[N-:2])[CH3:4])[CH:18]=[CH:19][CH:20]=1
Reactant: CC=[N+]=[N-]
Reactant: O=C(Cl)c1cccc(Oc2ccccn2)c1
Solvent: CCOCC
Product: CC(=[N+]=[N-])C(=O)c1cccc(Oc2ccccn2)c1

Procedure:
To a solution of diazoethane (2.5 mol equivalent) in ether (150 ml), a solution of 3-(2-pyridyloxy)benzoyl chloride in anhydrous ether (90 ml) is added dropwise at -20° C for 40 minutes. The resultant mixture is stirred at -20° C for 20 minutes. The diazoethane is evaporated at -20° C under reduced pressure, and the ether is evaporated at -10° C to 0° C under reduced pressure. The residue is chromatographed on a column of silica gel, which is eluted with 20 % ether/benzene and 30 % ether/benzene to give 3-(2-pyridyloxy)-1-(2-diazopropionyl)benzene (2.87 g) as an oily substance. IR (CCl4): 2060, 1630 cm-1.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[N:24]1[CH:25]=[CH:26][C:21]([NH:20][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[O:7][C:6]4[CH2:17][CH2:18][CH:3]([N:2]([CH3:19])[CH3:1])[CH2:4][C:5]=4[C:9]=3[CH:10]=2)=[O:15])=[CH:22][CH:23]=1
Reactant: CN(C)C1CCc2oc3ccc(C(=O)Cl)cc3c2C1
Reactant: Nc1ccncc1
Product: CN(C)C1CCc2oc3ccc(C(=O)Nc4ccncc4)cc3c2C1
Yield: 38.8 %

Procedure:
Beginning with 0.011 gm (0.04 mMol) 2-dimethylamino-1,2,3,4-tetrahydrodibenzofuran-8-carbonyl chloride and 0.08 mMol 4-aminopyridine, 0.0052 gm (37%) of the title compound were recovered.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([SH:26])[CH:23]=[CH:24][CH:25]=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=2)=[CH:11][CH:12]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Reactant: COc1cccc(S)c1
Product: COc1cccc(SCC(=O)c2c(C)noc2-c2ccc(Br)cc2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and 3-methoxy-benzenethiol.
Reaction SMILES: [N:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Cl:20])=[CH:9][CH:8]=2)=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:20][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:21])[C:4]1[NH:1][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]2=1
Reactant: [N-]=[N+]=Nc1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2c2c1[nH]c1ccccc12

Procedure:
A suspension of 128 g. of 3-azido-6-chloro-4-phenylcarbostyril in 3 l. of toluene was heated to reflux for 5 hours. On cooling, 113 g. (98 percent) of analytically pure 2-chloro-7H-indolo[2,3-c]quinolin-6 (5H)-one crystallized from solution as colorless needles, having a melting point of 325°-327° (change in crystal form in the range of 270°-290°; melts with sublimation).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[C:18]([S:28]([CH3:31])(=[O:30])=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.O1CCCC1.[Fe]>[NH2:25][C:21]1[CH:20]=[C:19]([C:18](=[C:16]2[CH2:15][N:14]([CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:17]2)[S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc(N)c1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A mixture of 0.34 g of 1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methylene]azetidine, 16 cm3 of 1 N hydrochloric acid in 8 cm3 of ethanol and 16 cm3 of tetrahydrofuran is heated under reflux. 0.17 g of iron powder is added and the reflux is maintained for 3 hours. The mixture is then cooled to room temperature and the insoluble matter is filtered off. The solution is taken up in 10 cm3 of 1 N sodium hydroxide and 50 cm3 of a saturated aqueous sodium chloride solution. The aqueous phase is extracted with 3 times 40 cm3 of dichloromethane, the extracts are combined, dried over sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) as eluent, collecting 20 cm3 fractions. Fractions 13 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 15 cm3 of ethyl ether. 0.17 g of 3-[(3-aminophenyl)(methylsulfonyl)methylene]-1-benzhydrylazetidine is obtained melting at 197° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (250 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 5.25 (2H, s, NH2), 6.55 (3H, m, 3CH arom.), 7.05 (1H, t, J=7 Hz, CH arom.), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.)].
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[C:9]1([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23]CC)=O)[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[C:9]1([N:15]2[CH2:16][CH2:17][CH:18]([C:21](=[O:23])[CH2:2][C:1]#[N:3])[CH2:19][CH2:20]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC#N
Reactant: CCOC(=O)C1CCN(c2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCN(c2ccccc2)CC1
Yield: 23.8 %

Procedure:
To a solution of ethyl isonipecotate (8.9 g) in CH2Cl2 (500 mL) was added triphenyl bismus (25 g) and Copper(II)acetate (10.3 g) at room temperature, the mixture was stirred overnight. After filteration, the mixture was extracted with CH2Cl2. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) as colorless crystals. To a solution of acetonitrile (1.9 g) in THF (200 mL) was added n-BuLi (41 mmol) at −78° C. Further, ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-(1-phenylpiperidin-4-yl)-2-cyanoethan-1-one (2.0 g) as colorless crystals. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.2 g) and 1-(1-phenylpiperidin-4-yl)-2-cyanoethan-1-one (0.5 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[N:14][CH:15]([C:21]([CH2:23]Cl)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(=O)C.[K+]>C(O)C>[C:16]([C:15]1[C:21]([OH:22])=[CH:23][N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=2[Cl:12])[N:14]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(N=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1O
Reaction time: 1 h
Yield: 70.9 %

Procedure:
Ethyl 2-(2,6-dichloro-4-trifluoromethylphenylazo)-4-chloroacetoacetate (52.7 g) was dissolved in ethanol (650 ml) and heated to reflux. Potassium acetate (11.2 g) was added portionwise and the reaction mixture was boiled for 1 hour and allowed to cool, and the solvent was evaporated. The residue was dissolved in dichloromethane (500 ml), washed with water (2×150 ml), dried over magnesium sulfate, filtered and evaporated. The residue was triturated with hexane, filtered and dried to give 3-carboethoxy-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-hydroxypyrazole (34.0 g) as a light brown solid, m.p. 140°-143° C.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][C:24]=2[CH:34]=1.[CH3:35][CH2:36][CH:37](O)[CH2:38][CH3:39]>CN(C=O)C>[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:3]([O:5][CH:37]([CH2:38][CH3:39])[CH2:36][CH3:35])=[O:4])[CH2:32][CH2:33]3)=[N:25][C:24]=2[CH:34]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(O)CC
Reactant: Fc1cc(-n2cnnn2)ccc1-c1ccc2oc(C3CCNCC3)nc2c1
Solvent: CN(C)C=O
Product: CCC(CC)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
Tert-butyl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (250 mg, 0.54 mmol) dissolved in DCM (15 ml) and added Trifluoroacetic acid (1 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (260 mg). 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml) and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at rt for 1 h. To this mixture added 3-pentanol (46 mg, 0.63 mmol) and TEA (0.13 ml, 0.94 mmol) and stirred at 60° C. for overnight. Work up (EtOAc/H2O) and purification of the crude by combiflash with gradient mixture of ethyl acetate and petether (1:1) as eluent afforded the titled compound (20 mg) as an off-white solid. M.P.: 114-117° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m, 4H), 7.54-7.50 (m, 1H), 4.69 (quintet, J 6, 1H), 4.23 (d, J 13.5, 2H), 3.25-3.15 (m, 1H), 3.07 (t, J 11.9, 2H), 2.21-2.17 (m, 2H), 2.02-1.88 (m, 2H), 1.65-1.50 (m, 4H), 0.91 (t, J 7.4, 6H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[C:9]([O:13][CH3:14])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([OH:16])=[C:4]2[C:17](=[O:37])[C@:18]3([C:32]4[C:31]([OH:33])=[C:30]5[C:25]([CH:26]=[C:27]([CH:35]=O)[NH:28][C:29]5=[O:34])=[CH:24][C:23]=4[CH2:22][CH2:21]3)[C:19](=[O:20])[C:3]=12.[NH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1.C1C=CC(C[NH:53]C(CN2C3C(=CC=CC=3)C(C=O)=C2)=O)=CC=1>CN(C=O)C.FC(F)(F)C(O)=O>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([NH:38][N:53]=[CH:35][C:27]2[NH:28][C:29](=[O:34])[C:30]3[C:25]([CH:26]=2)=[CH:24][C:23]2[CH2:22][CH2:21][C:18]4([C:17](=[O:37])[C:4]5=[C:5]([OH:16])[C:6]6[C:7](=[O:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10](=[O:12])[C:11]=6[C:2]([OH:1])=[C:3]5[C:19]4=[O:20])[C:32]=2[C:31]=3[OH:33])[CH2:40][CH2:41]1
Reactant: CN1CCN(N)CC1
Reactant: O=Cc1cn(CC(=O)NCc2ccccc2)c2ccccc12
Reactant: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C=O)[nH]c(=O)c4c(O)c21)C3=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C1(CCc2cc4cc(C=NNN5CCN(C)CC5)[nH]c(=O)c4c(O)c21)C3=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Five (5) mg (9.42 μmol) fredericamycin aldehyde (4) are dissolved in 500 μl DMF and 25 μl trifluoracetic acid. At room temperature, 1.30 mg (11.3 μmol) 1-amino-4-methyl-piperazine is added. After stirring for 4.5 h at room temperature, 1 equivalent each of Wang aldehyde resin and sulfonohydrazide resin is added and stirred for 2 h.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.[C:15](Cl)(=O)[CH3:16].[CH2:19](O)[CH3:20]>>[C:1]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:19][CH3:20])=[O:9])[CH:2]=1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Reactant: CCO
Reactant: CC(=O)Cl
Product: CCOC(=O)Cc1cccc(CC(=O)OCC)c1

Procedure:
2,2′-(1,3-Phenylene)diacetic acid (10.0 g, 51 mmol) was dissolved in ethanol (100 mL) and the solution treated dropwise with catalytic acetyl chloride (2.5 mL). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated under reduced pressure. The residue was taken up in ethyl acetate (100 mL) and washed with sodium bicarbonate solution (3×50 mL) and brine (3×50 mL). The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was triturated with pentane to yield the title product, 11.8 g.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.Cl.[CH:20]1([NH:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C1C=CN=CC=1)C>[CH:20]1([N:26]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[F:8])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)cc1
Reactant: NNC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1ccc(-c2nn(C3CCCCC3)c3c(F)cccc23)cc1
Yield: 46.2 %

Procedure:
Prepared according to Method C step A (2,3-difluorophenyl)-(4-methoxyphenyl)-methanone (0.150 g, 0.6 mmol), cyclohexylhydrazine hydrochloride (0.90 g, 0.6 mmol) and DMAP (0.073 g, 0.6 mmol) to give 0.09 g of the title compound.