Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCOCCO)O2
Yield: 82.5 %

Procedure:
Following the amide coupling procedure described in protocol A, 501 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 360 mg CDI (2.23 mmol) and 231 mg 2-(2-aminoethoxy)ethanol (2.19 mmol) produced 557 mg of 6-hydroxy-N-(2-(2-hydroxyethoxy)ethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as an amorphous white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[C:12]([N+:24]([O-])=O)[CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[NH2:24][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:27]
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of the product of Example 37B (116.6 mg, 0.2717 mmol) and iron powder (60.7 mg, 1.087 mmol) in acetic acid (2 mL) and ethanol (2 mL) was heated at reflux under a nitrogen atmosphere for 1 hour. The reaction was then cooled to room temperature. The mixture was diluted with water (20 mL), the pH adjusted to 6 with solid sodium carbonate, and the aqueous extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as a beige solid (100 mg, 92%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:20](O)=[O:21].Cl.[C:24]([S:43][CH2:44][CH2:45][NH2:46])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:20]([NH:46][CH2:45][CH2:44][S:43][C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:21]
Reactant: Cc1c(C(=O)O)[nH]c2c(NS(=O)(=O)c3cccs3)cccc12
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)[nH]c2c(NS(=O)(=O)c3cccs3)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a mixture of 3-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.70 g), 2-(tritylthio)ethylamine hydrochloride (0.82 g), 1H-1,2,3-benzotriazol-1-ol (0.34 g), triethylamine (0.35 mL) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.48 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.36 g, quantitative) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point>214° C. (decomposition).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:25][CH2:26][C:27]([NH:29][C:30]1[O:31][CH:32]=[CH:33][N:34]=1)=[O:28]>CC#N>[Br-:25].[O:31]1[CH:32]=[CH:33][N:34]=[C:30]1[NH:29][C:27]([CH2:26][N+:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2)=[O:28]
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: O=C(CBr)Nc1ncco1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ncco1
Product: [Br-]
Yield: 60.6 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (0.31 mmol) and 2-bromo-N-oxazol-2-yl-acetamide (Example 48a) (0.31 mmol) were stirred in anhydrous MeCN at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the yellow solid purified by flash silica gel column chromatography eluting with 0-15% MeOH/dichloromethane to give the title compound (100 mg) as a white solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[NH:29][C:13]3=[CH:14][C:15]4[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:19]=4[CH:20]=[C:12]3[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]([BH3-])#[N:31].[CH2:33]1COCC1>C(O)(=O)C>[CH3:33][N:31]([CH3:30])[C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[NH:29][C:13]3=[CH:14][C:15]4[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:19]=4[CH:20]=[C:12]3[N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: [BH3-]C#N
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(/C=C/c4cccc(N)c4)nc3cc21
Solvent: CC(=O)O
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(/C=C/c4cccc(N(C)C)c4)nc3cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution 2-[(E)-2-(3-amino-phenyl)-vinyl]-7,7-dimethyl-5-pentyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (170 mg) in dry THF (2.5 ml) and acetic acid (0.3 ml) is added p-formaldehyde (41.5 mg; 1,31 mmol) and resin-bound cyanoborohydride (MP-cyanoborohydride; Argonaut) (1.23 g; 2.50 mmol). The mixture is gently stirred under an inert atmosphere (Ar) at RT for 48 h. After completion of the reaction the mixture is filtered and concentrated in vacuo. The desired compound (43.0 mg) is obtained by preparative RP-HPLC.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[C:9]([CH:15]=O)=[CH:8][CH:7]=1.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:26]2[CH2:29][C@H:28]([NH2:30])[CH2:27]2)=[CH:21][C:20]=1[C:31]([F:34])([F:33])[F:32].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:26]2[CH2:29][C@H:28]([NH:30][CH2:15][C:9]3[C:10]4[N:11]([CH:12]=[CH:13][N:14]=4)[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=3)[CH2:27]2)=[CH:21][C:20]=1[C:31]([F:32])([F:33])[F:34]
Reactant: COCOCc1ccc(C=O)c2nccn12
Reactant: N[C@H]1C[C@H](Oc2ccc(F)c(C(F)(F)F)c2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCc1ccc(CN[C@H]2C[C@H](Oc3ccc(F)c(C(F)(F)F)c3)C2)c2nccn12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carbaldehyde (34 mg, 0.154 mmol) and trans-3-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}cyclobutanamine hydrochloride salt (44 mg, 0.154 mmol) in a mixture of DCM (1 mL) and methanol (1 mL) was added DIPEA (0.027 mL, 0.155 mmol) and sodium triacetoxyborohydride (98 mg, 0.463 mmol). The reaction was stirred at ambient temperature for 3.5 hours and then diluted with DCM (10 mL). The solution was then washed with saturated aqueous sodium bicarbonate (10 mL), dried (hydrophobic frit) and concentrated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (10 g) using a 0-10% methanol-DCM gradient over 40 min. The product containing fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (32 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:11]([CH3:12])[CH3:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1ccc(Cl)nc1

Procedure:
2-Chloro-5-(chloromethyl)pyridine (500 mg) was dissolved in ethanol (7.0 ml). dimethylamine (0.83 ml, 33% in ethanol) and potassium carbonate (641 mg) were added and the resulting mixture was refluxed for 1.5 hours. After evaboration of ethanol, water was added and the aqueous mixture was extracted with ethyl acetate. 1H NMR (400 MHz, d6-DMSO) δ: 8.31 (d, 1H, J 2.3 Hz), 7.77 (dd, 1H, J 8.2, 2.3 Hz), 7.47 (d, 1H, J 8.2 Hz), 3.41 (s, 2H), 2.14 (s, 6H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]#[N:12])=[CH:6][CH:5]=1.Cl.Cl[CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>CN(C)C=O>[NH:25]1[CH:26]=[C:22]([CH2:21][C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11]#[N:12])[N:23]=[CH:24]1
Reactant: ClCc1c[nH]cn1
Reactant: N#CC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
As described in Example 1, 2.04 g. of 50% sodium hydride, 10.12 g. of 2-(4-chlorophenyl)-2-phenylacetonitrile, and 3.06 g. of 4-chloromethylimidazole hydrochloride were reacted in 50 ml. of dimethylformamide. The reaction mixture was stirred for one hour at 60° C. and then for 20 hours at ambient temperature. Evaporation of the solvent and work up as described in Example 1 produced 5.3 g. of the product named above, which was converted to the maleate salt and crystallized from acetone/diethyl ether to obtain 6.29 g. of the maleate salt of the desired product, m.p. 135°-136° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][N:9]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][C:29]=1[O:38][CH3:39].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][N:9]=2)=[O:36])=[CH:30][C:29]=1[O:38][CH3:39]
Reactant: COC(=O)c1ccc(OCC2CCCN2)nc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
To a stirred mixture of methyl 2-(2-pyrrolidinyl)methoxypyridine-5-carboxylate (370 mg, 1.57 mmol), 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (525 mg, 1.57 mmol), 4-DMAP (230 mg, 1.88 mmol) in DMF (10 ml) was added EDC.HCl (360 mg, 1.88 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hr. The mixture was pored into ice-water. The solid was collected, washed with water and air-dried. The crude solid was purified by silica-gel (30 ml) column chromatography with CHCl3-EtOH (98:2, v/v) as eluent and crystallized with Et2O to give methyl 2-[1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenyl acetyl]-2-pyrrolidinylmethoxy]pyridine-5-carboxylate (600 mg, 69%) as an amorphous solid. 1H-NMR (CDCl3) δ 0.21 and 2.01 (each m, 4 H), 3.45–4.50 (series of s and m, 13 H which contains amide-isomers), 6.58–8.83 (series of s and m, 12 H which contains amide-isomers)
Reaction SMILES: Cl.[SH:2][C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.[CH3:10]OC(OC)N(C)C.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:10])[N:8]=1
Reactant: Cc1ccnc(S)n1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CSc1nccc(C)n1

Procedure:
2-Mercapto-4-methylpyrimidine hydrochloride (100 g, 617 mmol), dimethylformamide dimethylacetal (100 mL, 754 mmol), diisopropylethylamine (161 mL, 926 mmol) and toluene (200 mL) were combined under argon. The resulting solution was heated to reflux for 4 h. The solvent was removed in vacuo and water and sodium bisulfate were added. The resulting mixture was extracted with ether (3×100 mL). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford an oil. Vacuum distillation gave Compound 2 as a liquid: 70.5 g, (504 mmol, 82%)
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[NH2:15][CH:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].[OH-].[Na+]>CN(C=O)C>[OH:18][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]([N:15]1[CH2:9][CH2:10][CH2:11][C:12]1=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: NC(c1ccccn1)C(O)c1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCCN1C(c1ccccn1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
35 ml (252 mmol) of triethylamine and 11.3 ml (101 mmol) of 4-chlorobutyryl chloride were successively added dropwise to a solution of 21.6 g (101 mmol) of 2-amino-1-phenyl-2-pyridin-2-ylethanol in 50 ml of DMF at 50° C. After 1 h at room temperature, 48.4 g of sodium hydroxide were added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice-water and extracted with methylene chloride, and the organic phases were washed with water and sodium bicarbonate solution. Chromatography on silica gel with ethyl acetate/ethanol 20:1 resulted in isolation of 3.0 g each of the syn- and anti-diastereomer of 1-(2-hydroxy-2-phenyl-1-pyridin-2-ylethyl)pyrrolidin-2-one in pure form. The relative stereochemistry was assigned by X-ray spectroscopy.
Reaction SMILES: [CH2:1]([N:5]1[CH2:14][CH2:13][C:8]2([CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:15]([O:17][CH:18]([O:27][CH2:28][CH3:29])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.CN(C)C=O>[CH2:28]([O:27][CH:18]([O:17][CH2:15][CH3:16])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:11]2[CH2:10][CH2:9][C:8]3([CH2:7][CH2:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:14][CH2:13]3)[CH2:12]2)=[CH:21][CH:20]=1)[CH3:29]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: CC(C)CN1CCC2(CCNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CN2CCC3(CCN(CC(C)C)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.5 %

Procedure:
To a 10% acetic acid-dimethylformamide (10 mL) solution of 8-isobutyl-2,8-diazaspiro[4.5]decane (600 mg) and 4-(diethoxymethyl)benzaldehyde (661 mg), sodium triacetoxyborohydride (1.30 g) was added. The reaction solution was stirred at room temperature for 14 hours. To the reaction solution, an aqueous 5N sodium hydroxide solution (10 mL) was added. The aqueous layer was extracted twice with dichloromethane (20 mL). The combined organic layer was washed with saturated sodium chloride solution (20 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol: 28% aqueous ammonia=1:0:0→100:5:1→100:10:2) to obtain the title compound (730 mg) having the following physical properties.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:40][CH2:41][CH3:42])[C:34]=1[C:35]1[CH:36]=[N:37][NH:38][CH:39]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[O:44]=[C:45]1[O:49][N:48]=[C:47]([C:50]2[CH:51]=[C:52]3[C:62](=[CH:63][CH:64]=2)[O:61][C:55]2([CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:54][C:53]3=[O:65])[NH:46]1>O.CN(C=O)C.CCN(CC)CC>[CH2:41]([O:40][C:33]1[CH:32]=[C:28]([C:29]([N:58]2[CH2:59][CH2:60][C:55]3([CH2:54][C:53](=[O:65])[C:52]4[C:62](=[CH:63][CH:64]=[C:50]([C:47]5[NH:46][C:45](=[O:44])[O:49][N:48]=5)[CH:51]=4)[O:61]3)[CH2:56][CH2:57]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:36]=[N:37][NH:38][CH:39]=1)[CH3:42]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cn[nH]c1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3noc(=O)[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4noc(=O)[nH]4)ccc2O3)cc(OCC)c1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (83 μL), HOBT (46 mg) and WSC hydrochloride (58 mg) were added to a DMF (4 mL) solution of 3,5-diethoxy-4-(1H-pyrazol-4-yl)benzoic acid (101 mg) and 6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (70 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and the solid was washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 12.96 (1H, s), 8.21 (1H, d, J=4.0 Hz), 8.06 (2H, s), 8.00 (11, dd, J=8.0, 4.0 Hz), 7.30 (1H, d, J=8.0 Hz), 6.68 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.64-3.20 (3H, m), 2.97 (2H, s), 2.10-1.75 (4H, m), 1.37 (6H, t, J=8.0 Hz). MS [M+H]+=560.
Reaction SMILES: N1CCOCC1.C([Li])CCC.Br[C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:17][C:14]=1[CH:15]=[O:16].[F:34]NS(C1C=CC=CC=1)(=O)=O.Cl>C1COCC1.C(OCC)C>[F:34][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: COc1cc(Br)c(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: O=S(=O)(NF)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(F)c(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.01 ml of morpholine in 50 ml of THF there was added 8.69 ml of n-butyllithium (2.66 M, hexane solution) at −78° C. under a nitrogen atmosphere, and the mixture was stirred at −40° C. for 30 minutes. A solution of 2-bromo-4-methoxy-5-triisopropylsilanyloxybenzaldehyde in 15 ml of THF was then added dropwise at −78° C., and the mixture was further stirred at −78° C. for 40 minutes. After further adding 11.1 ml of n-butyllithium (2.66 M, hexane solution) at −78° C., the mixture was stirred at −78° C. for 40 minutes, and then a solution of 10.6 g of N-fluorobenzenesulfonamide in 40 ml of THF was added dropwise at −78° C. and the reaction mixture was stirred overnight while raising the temperature to room temperature. Dilute hydrochloric acid was added to the reaction mixture, and extraction was performed with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.96 g) as a light yellow solid.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[OH:14]>>[OH:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[NH:7][C:1](=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: NC1CCCCC1O
Reactant: CC(C)C(=O)O
Product: CC(C)C(=O)NC1CCCCC1O

Procedure:
Prepared as in Example 24a from isobutyric acid and 2-aminocyclohexanol as a colorless oil (53%). MS 186 (MH+).
Reaction SMILES: [N:1]1([C:11]2[C:12]([CH2:17][NH2:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[BH-](O[C:29]([CH3:31])=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC1C(C=O)=NC=C(C)C=1>[N:1]1([C:11]2[C:12]([CH2:17][NH:18][CH2:9][C:10]3[C:5]([CH3:6])=[CH:4][C:29]([CH3:31])=[CH:2][N:1]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ncccc1N1CCCc2ccccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1cnc(C=O)c(C)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNCc2ncccc2N2CCCc3ccccc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of C-[3-(3,4-dihydro-2H-quinoline-1-yl)pyridine-2-yl]methylamine in CH2Cl2 and 3,5-Dimethyl-pyridine-2-carbaldehyde with NaBH(OAc)3 gave [3-(3,4-Dihydro-2H-quinolin-1-yl)-pyridin-2-ylmethyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine.
Reaction SMILES: [CH2:1]1[S:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]([CH3:36])=[C:23]([CH2:25][O:26][C@@H:27]3[CH2:32][CH2:31][CH2:30][C@H:29](CC=O)[CH2:28]3)[N:24]=2)=[CH:16][CH:15]=1.Cl.[O:38]1CC[CH2:40][CH2:39]1>CCCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[O:21][C:22]([CH3:36])=[C:23]([CH2:25][O:26][C@@H:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([O:38][CH2:39][CH:40]=[C:1]4[S:7][C:5](=[O:6])[NH:4][C:2]4=[O:3])[CH2:28]3)[N:24]=2)=[CH:18][CH:19]=1
Reactant: C1CCOC1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](CC=O)C1
Reactant: O=C1CSC(=O)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OCC=C2SC(=O)NC2=O)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
66 mg of thiazolidinedione are dissolved in 10 ml of tetrahydrofuran and, at −78° C., 0.11 ml of a 2.7 M solution of n-butyllithium in n-hexane is added. The mixture is stirred at −78° C. for 30 minutes, and 150 mg of [cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl]acetaldehyde, dissolved in 5 ml of tetrahydrofuran, are then added. After 30 minutes of stirring at −78° C., the mixture is allowed to warm to room temperature. 5 ml of 1N hydrochloric acid are added, and the mixture is extracted three times with in each case 20 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 184 mg of 5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-oxy}ethylidene)thiazolidine-2,4-dione as a white solid. C22H23FN2O5S (446.01), MS (ESI): 447 (M+H+).
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=1>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:25]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)/C=C/c1ccc(N)cc1
Product: CCCCCCCCC#Cc1ccc(CNc2ccc(/C=C/C(=O)OCC)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-dec-1-ynyl-benzaldehyde and ethyl (2E)-3-(4-aminophenyl)acrylate. (purification by flash chromatography on SiO2, EtOAc/c-Hex 1/7 to 1/6 in about 30 min.) as a yellow solid (61%). 1H NMR (CDCl3) δ: 7.59 (d, J=15.8 Hz, 1H), 7.36 (m, 4H), 7.26 (m, 2H), 6.57 (d, J=8.7 Hz, 2H), 6.21 (d, J=15.8 Hz, 1H), 4.35 (s, 2H), 4.23 (dd, J1=7.2 Hz, J2=14.3 Hz, 2H), 2.39 (t, J=7.2 Hz, 2H), 1.66-1.52 (m, 2H), 1.50-1.39 (m, 2H), 1.38-1.24 (m, 11H), 0.87 (m, 3H). M+ (ESI): 418.1; M− (ESI): 416.2. HPLC, Rt: 6.1 min (purity: 98.7%).