Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=O)([O-:19])=[O:18]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[N+:17]([O-:19])=[O:18])=[N:16][N:15]=1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2[N+](=O)[O-])o1
Yield: 79 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.12 mmol) was converted using 2-nitro-benzoic acid instead of o-toluic acid to the title compound (2.52 g, 79%) which was obtained as a light-brown solid. MS: m/e=349.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([OH:14])([CH2:12][CH3:13])[C:8]([F:11])([F:10])[F:9])=[N:4][N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([CH:32]=O)=[CH:29][CH:30]=3)[O:25][C:24](=[O:34])[CH:23]=2)=[CH:18][CH:17]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCO>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:32][NH:1][C:2]4[O:6][C:5]([C:7]([OH:14])([C:8]([F:11])([F:9])[F:10])[CH2:12][CH3:13])=[N:4][N:3]=4)=[CH:29][CH:30]=3)[O:25][C:24](=[O:34])[CH:23]=2)=[CH:18][CH:17]=1
Reactant: CCC(O)(c1nnc(N)o1)C(F)(F)F
Reactant: O=Cc1ccc2c(-c3ccc(F)cc3)cc(=O)oc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC(O)(c1nnc(NCc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)o1)C(F)(F)F
Reaction time: 8 h

Procedure:
A mixture of oxadiazole (14.41 g, 68.2 mmol) of step 3 and 4-(4-fluorophenyl)-2-oxo-2H-chromene-7-carbaldehyde (14.1 g, 52.5 mmol) in toluene (160 mL) with 10% of PPTS was brought to reflux and let go overnight. The system was equipped with a Dean-Stark trap to collect water. The solvent was removed and the crude oil (1H NMR (400 MHz, acetone-d6): δ 9.33 (1H, s, imine)) obtained was diluted in EtOH (ca. 75 mL) at 0° C. To this solution was added NaBH4 (1.9 g) portionwise and the reaction was quenched with a solution of NH4Cl after 45 min. The mixture was saturated with NaCl and extracted with EtOAc (3×200 mL). The organic phases were combined and dried over MgSO4. Purification over silica gel chromatography using toluene-EtOAc (55:45) gave the title compound. 1H NMR (400 MHz, acetone-d6): δ 7.65 (m, 2H), 7.50 (m, 3H), 7.38 (m, 3H), 6.35 (s, 1H), 6.06 (s, 1H), 4.70 (m, 2H), 2.21 (m, 1H), 2.11 (m, 1H) and 0.98 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([CH3:20])=[CH:14][C:15]=1[C:16]([O:18]C)=O.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([CH3:20])=[CH:14][C:15]=1[C:16]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:18]
Reactant: C=COCCON
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.500 g, 1.20 mmol) in THF (60 mL) was added O-(2-vinyloxy-ethyl)-hydroxylamine (0.149 g, 1.44 mmol). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (4.81 ml, 4.81 mmol) (1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 10 minutes the reaction mixture was quenched by the addition of 1 M HCl and partitioned between EtOAc and saturated NaCl. The layers were separated and the organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield a crude yellow solid that was used without purification in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15]([C:19]1[CH:20]=[C:21]2[C:26](=O)[O:25][C:23](=[O:24])[C:22]2=[CH:28][CH:29]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:20]=[C:21]2[C:22](=[CH:28][CH:29]=1)[C:23](=[O:24])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:26]2=[O:25])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Product: CCOC(=O)C(CN1C(=O)c2ccc(C(C)(C)C)cc2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(5-t-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.54 g, 35%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.80 g, 3.94 mmol) and 4-t-butylphthalic anhydride (0.88 g, 4.33 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[S:25][C:26]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[CH:27][CH:28]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:36])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[ClH:35].[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:25][C:24]([S:21]([N:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:16](=[O:36])[CH2:17]3)(=[O:23])=[O:22])=[CH:28][CH:27]=2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(-c4ccc(Cl)cc4)s3)CC2=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CCN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-2-piperazinone (115 mg) were added 4N hydrochloric acid in ethyl acetate (10 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give crude crystals of 4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride. A mixture of the obtained 4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride and chloropyridine hydrochloride (85 mg) was added to sodium bicarbonate solution, and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (10 ml), and the mixture was stirred at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=10:1) to give colorless solid of the title compound (42 mg).
Reaction SMILES: [OH:1][C@H:2]([CH3:22])[C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])[CH2:8][CH2:7]1)=[O:4].Cl.O1CCOCC1>ClCCl>[NH2:14][C@@H:12]([C@H:9]1[CH2:8][CH2:7][C@H:6]([NH:5][C:3](=[O:4])[C@H:2]([OH:1])[CH3:22])[CH2:11][CH2:10]1)[CH3:13]
Reactant: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trans-tert-butyl(R)-1-(4-((R)-2-hydroxypropanamido)cyclohexyl)ethylcarbamate (66 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL). A solution of HCl in dioxane (209.9 μL of 4 M, 0.84 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours. The crude mixture was concentrated in vacuo and coevaporated three times with diethylether. The residue was dissolved in methanol (10 mL), passed through a sodium bicarbonate cartridge and concentrated in vacuo to give the desired compound as a white solid (45 mg, quantitative yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].C(#N)C>C(OC)(C)(C)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C@:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19]
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Solvent: COC(C)(C)C
Solvent: CC#N
Product: COc1cc2c(cc1C)[C@@]1(CO2)C(=O)Nc2ccccc21

Procedure:
6-Methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (2.16 g, 0.10 g per run) was resolved on a semi-prep chiral IA column with 10% acetonitrile in tert-butyl methylether. (3S)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was isolated as a crystalline colorless solid (0.96 g, 89% recovery): ee>99% (analytical chiralpak IA, 1:1 acetonitrile/tert-butyl methylether); mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ10.57 (s, 1H), 7.23 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 7.07 (d, J=6.8 Hz, 1H), 6.99-6.89 (m, 1H), 6.61 (s, 1H), 6.45 (s, 1H), 4.81-4.74 (m, 1H), 4.64 (d, J=9.2 Hz, 1H), 3.77 (s, 1H), 1.95 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ179.2, 160.4, 158.9, 142.2, 133.4, 129.1, 124.4, 124.2, 122.7, 120.3, 118.4, 110.2, 94.3, 80.1, 58.0, 56.0, 16.0; MS (ES+) m/z 282.0 (M+1).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][OH:22])=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=1.C(N(CC)CC)C>ClCCl.O>[CH3:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=[O:22])=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:13]=1
Reactant: Cc1cn(CCCc2ccccc2)c2cc(CO)ccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cn(CCCc2ccccc2)c2cc(C=O)ccc12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 56.9 %

Procedure:
Dimethylsulphoxide (0.311 g) was added to a stirring solution of oxalyl chloride in dichloromethane (1 ml, 2M) in dichloromethane (25 ml) at −60° C. under argon and the mixture was stirred for 2 minutes. A solution of 3-methyl-1-{3-(phenyl)propyl}-1H-indole-6-methanol [0.501 g, Reference Example 22(c)] in dichloromethane (10 ml) was then added dropwise and the mixture stirred for 15 minutes at −60° C. Triethylamine (0.956 g) was then added and the solution warmed to room temperature and stirred for 1 hour. The mixture was poured into water (20 ml) and then extracted three times with dichloromethane (25 ml). The combined extracts were washed with brine (30 ml), then dried over sodium sulphate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v) to yield the title compound (0.283 g).
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:7]=1)=[O:5])C.[CH2:17]([CH:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21].C([Al](CC)CC)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:17]([CH:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)[N:7]=2)=[O:5])[CH2:26][CH2:27]1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)c1nc(-c2ccncc2)no1
Reactant: CCCCCC1CCC(N)CC1
Agent: CC[Al](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(NC(=O)c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-pyridin-4-yl-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (50.5 mg, 0.23 mmol) and 4-pentylcyclohexylamine (39 mg, 0.23 mmol) in anhydrous toluene (2 ml) was treated with triethylaluminium (345 μl of a 2M solution in hexanes, 0.69 mmol). After stirring at rt for 18 h, saturated aqueous NaHCO3 (2 ml) was added and the mixture diluted with CH2Cl2 (25 ml). The organic phase was separated, washed with brine (5 ml) and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to afford the title compound: RT=4.14 min; m/z (ES+)=343.2 [M+]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:26][CH:25]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(OC)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 45 %

Procedure:
A mixture of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.400 mmol), 4-methoxy-phenyl boronic acid (73 mg, 0.48 mmol), (Ph3P)2PdCl2 (28 mg, 0.040 mmol), and Na2CO3 (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N2 and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:2) to afford the title compound as a yellow solid (68 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:7]1([C:6]2[NH:5][N:4]=[C:3]([C:13]([F:16])([F:15])[F:14])[C:2]=2[NH:1][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1c(C(F)(F)F)n[nH]c1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1c(C(F)(F)F)n[nH]c1-c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.0 g of 4-amino-5-phenyl-3-trifluoromethyl-1H-pyrazole in 30 mL of dichloromethane was treated with 1.1 mL of pyridine followed by 0.57 mL of benzoyl chloride. The reaction mixture was stirred at RT for 5 hours and then concentrated. The residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by MPLC, eluting with 2/3 ethyl acetate/heptane, to give the title compound as a white solid, melting point 229–230° C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]#[C:4][C:5]1[C:6]([NH2:14])=[N:7][CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:2]([C:3]1[NH:14][C:6]2=[N:7][CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:5]2[CH:4]=1)([CH3:16])([CH3:15])[CH3:1]
Reactant: CC(C)(C)C#Cc1cc([N+](=O)[O-])cnc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Yield: 63.4 %

Procedure:
A solution of 3-(3,3-dimethylbut-1-ynyl)-5-nitropyridin-2-amine (0.4 g, 1.8 mmol) and TBAF (1.9 g, 7.3 mmol) in THF (10 mL) was heated at reflux overnight. The reaction mixture was concentrated to dryness under vacuum, and the residue was dissolved in ethyl acetate (20 mL). The organic layer was washed with water, brine, dried over Na2SO4 and concentrated under vacuum to afford 2-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.25 g, 63%). 1H-NMR (CDCl3, 400 MHz) δ 11.15 (brs, 1H), 9.20 (s, J=2.0 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H), 6.43 (d, J=1.6 Hz, 1H), 1.51 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([O-:21])=[O:20].N1C(C)=CC=CC=1C>C(OCC)(=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)#[N:13]
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: COCCOc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3)c2cc1C#N
Temperature: 155 °C
Reaction time: 1.5 h
Yield: 43.1 %

Procedure:
A mixture of 4-chloro-6-cyano-7-(2-methoxyethoxy)quinoline (3 g), 4-nitrophenol (3.17 g) and 2,6-lutidine (2.7 ml) was heated and stirred in an oil bath at 155° C. for 1.5 hours. After completion of the reaction, ethyl acetate was added, and the precipitated solid was filtered out. The solid was washed with 1N sodium hydroxide water and then with water and dried to obtain 1.8 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][CH:12]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]3)[N:14]=2)[CH:5]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[O:38]([CH2:45][C:46](Cl)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][CH:12]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:46](=[O:47])[CH2:45][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:14]=2)[CH:5]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: COC(=O)c1cccc(-c2nc([C@H]3CCCCN3)cs2)c1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2nc([C@H]3CCCCN3C(=O)COc3ccccc3)cs2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-((R)-4-piperidin-2-yl-thiazol-2-yl)-benzoic acid methyl ester (0.048 g, 0.16 mmol) in dry dichloromethane (2 mL) under argon was treated with triethylamine (0.064 g, 0.09 ml.), dimethylaminopyridine (0.002 g, 0.020 mmol) and phenoxyacetyl chloride (0.027 g, 0.16 mmol). The mixture was stirred at room temperature for 4 h. The mixture was washed with water and saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The residual oil was purified by preparative HPLC: Column: YMC-Pack Pro C18 RS, 20×50 mm, S-5 um, 8 nm, No200504707(W); Gradient: 0-0.4 min: 30% acetonitrile in (water+0.1% HCO2H), 0.4-2.4 min: increse of acetonitrile fraction from 30% to 95%, 2.4-4.7 min: 95% acetonitrile, 4.7-4.8 min: decrease of acetonitrile fraction from 95% to 30%; Program end at 4.87 min; Flow: 30 ml/min. 3-{4-[(R)-1-(2-Phenoxy-acetyl)-piperidin-2-yl]-thiazol-2-yl}-benzoic acid methyl ester was obtained after lyophilization as a light yellow oil (0.033 g, 48%), MS (ISP): 437.3 (M+H)+..
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:38])=[C:16]([S:18]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][C:25]=2[NH:33][CH2:34][C:35](O)=[O:36])(=[O:20])=[O:19])[CH:17]=1)#[N:11].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.C(N(CC)CC)C>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:38])=[C:16]([S:18]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][C:25]=2[NH:33][CH2:34][C:35]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:36])(=[O:19])=[O:20])[CH:17]=1)#[N:11]
Reactant: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(NCC(=O)O)c1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNC(=O)CNc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Reaction time: 0.08 h
Yield: 75.1 %

Procedure:
To a stirred solution of 0.11 g of ethyl 3-aminopropionate hydrochloride in 10 mL of N,N-dimethylformamide were added 0.072 ml of triethylamine, 0.30 g of [[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]amino]acetic acid, and 0.121 g of 1-hydroxybenzotriazole monohydrate under ice-cooling, and the mixture was stirred at 5minutes. To the mixture was added 0.140 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride under the same condition, and the mixture was stirred at room temperature for 7 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.278 g of ethyl 3-[2-[[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]amino]acetylamino]propionate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[OH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21](O)[CH:22]=2)[CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][C:22]1[C:23]3[C:18](=[CH:17][C:16]([OH:15])=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=1)=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Oc1cccc2cc(O)ccc12)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of 9.41 g (0.05 mol) of 6-hydroxy-2-naphthoic acid, 24.03 g (0.15 mol) of 2,6-dihydroxynaphthalene, 0.8 g of p-toluenesulfonic acid monohydrate and 3 drops of concentrated sulfuric acid in 100 ml of toluene was heated under reflux with occasional addition of concentrated sulfuric acid (3 drops every 3 h) for 12 h. The resulting suspension was cooled to room temperature and filtered. The filtercake was suspended in methanol, the suspension was stirred for 3 h and the solid was finally filtered off. 10.9 g of 6-hydroxynaphthyl 6-hydroxy-2-naphthoate (“NpNp”) were obtained as a brownish solid which was processed in the subsequent step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH3:17][C:18]1[NH:19][C:20]([CH3:44])=[C:21]([C:37]([O:39][CH2:40][CH2:41][CH2:42]Br)=[O:38])[CH:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:23]=1[C:24]([O:26][CH3:27])=[O:25].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:17][C:18]1[NH:19][C:20]([CH3:44])=[C:21]([C:37]([O:39][CH2:40][CH2:41][CH2:42][O:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:15][CH:14]=2)=[O:38])[CH:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCBr)C1c1cccc([N+](=O)[O-])c1
Reactant: Oc1ccc(CCOC2CCCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCOc2ccc(CCOC3CCCCO3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
4-(2-Tetrahydropyran-2-yloxyethyl)phenol (9, 72.1 g, 0.32 mol) was added to a solution of 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-bromopropoxycarbonyl)-1,4-dihydropyridine (12, 105 g, 0.23 mol) and K2CO3 (48 g, 0.35 mol) in acetone (700 mL), and the mixture heated at reflux overnight. After cooling, the solid was filtered, the solvent removed under reduced pressure, and the residue solubilised in CH2Cl2 (1 L). The organic layer was washed with 10% NaOH (2×100 mL) and water (2×100 mL) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to provide an oil which was purified by flash chromatography (EtOAc: CH2Cl2 --15:85) to yield 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-tetrahydropyran-2-yloxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (1, mp<50° C.).