Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[O:14][CH:15]=[CH:16][C:10]=2[CH2:9]1)C1C=CC=CC=1.[C:17]([O:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CO.C(O)(=O)C.ClCCl.[C].[Pd]>[C:28]([O:27][C:25]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][CH:15]=[CH:16][C:10]=2[CH2:9]1)=[O:26])([CH3:29])([CH3:30])[CH3:31].[C:25]([O:24][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26]
Reactant: c1ccc(CN2CCc3occc3C2)cc1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2occc2C1
Reaction time: 0.5 h

Procedure:
To a solution of 15.023 g (70.438 mmol) of 5-benzyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 100 ml of methanol, 2 ml of acetic acid was added, followed by hydrogenation over 5 g of 10% palladium-carbon (50% hydrated) at room temperature at atmospheric pressure for 8 hours. The mixture was filtered using Celite to remove the catalyst; the Celite was washed with methanol 3 times. The combined methanol solution was evaporated under reduced pressure. The resulting residue (crude 4,5,6,7-tetrahydrofuro[3,2-c]pyridine) was dissolved in 100 ml of dichloromethane. To this solution, a solution of 15.4 g (70.4 mmol) of di-tert-butyl dicarbonate in 50 ml of dichloromethane was added dropwise at room temperature, followed by stirring for 0.5 hours. The solvent was distilled off under reduced pressure; the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to yield 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine as a mixture with di-tert-butyl dicarbonate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:10])([F:20])[F:21])=[CH:14][CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: Fc1cnc(Cl)nc1Nc1ccc(OC(F)(F)F)cc1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-trifluoromethoxyaniline gave 2-chloro-5-fluoro-N4-(4-trifluoromethoxyphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.11 (d, 1H, J=2.1 Hz), 7.68 (dd, 2H, J=2.4 and 7.6 Hz), 7.26 (dd, 2H, J=3 and 8.7 Hz), 7.0 (bs, 1H); 19F NMR (CD3OD): δ−16517 and −44523; LCMS: purity: 94%; MS (m/e): 308 (MH+).
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[C:1]1([CH2:11][NH:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1cccc2ccccc12
Product: O=C(O)c1ccncc1NCc1cccc2ccccc12
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield from 1-naphthylmethylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.39 (br s, 1H), 8.25 (s, 1H), 8.15 (d, 1H, J=7.9 Hz), 7.98 (d, 1H, J=7.5 Hz), 7.84-7.89 (m, 2H), 7.45-7.62 (m, 5H), 5.03 (s, 2H). [M+H] calc'd for C17H14N2O2, 279. Found 279.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[CH3:16].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]([C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:5][C:6]1[C:7]([CH3:16])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][C:11]=1[CH3:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1Oc1ccccc1
Yield: 68.6 %

Procedure:
A solution of 4-(3-hydroxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene (150 mg), phenylboronic acid (190 mg), copper (II) acetate (189 mg) and TEA (0.22 mL) in dichloromethane (4 mL) was stirred for 6 h. The reaction was diluted into ethyl acetate, washed with 1N hydrochloric acid, dried over sodium sulfate and concentrated in vacuo. The resulting oil was flash chromatographed (10% DEE/petroleum ether) to afford 4-(3-phenoxy-4-methoxyphenoxy)-3,5-dimethyl-nitrobenzene (130 mg) as a colorless solid.
Reaction SMILES: [BrH:1].Br.Br.N1CCCC1=O.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].O>O1CCCC1>[Br:1][CH2:21][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:10]([CH3:13])([CH3:11])[CH3:12])=[CH:19][CH:18]=1)=[O:22]
Reactant: Br
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C1CCCN1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)CBr)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Pyrrolidone trihydrobromide (3.27 g, 10.0 mmol) was added to a solution of 1-(4-tert-butylphenyl)ethanone obtained (1.61 g, 9.13 mmol) in tetrahydrofuran (30 mL) and the mixture was heated to an external temperature of 60° C. and stirred for 30 min. After cooling, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=9:1) to afford the title compound as a colorless oil (472 mg).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.CN1CCNCC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][N:33]([CH3:32])[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CN1CCNCC1
Product: CN1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)CC1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-methylpiperazine and isolated as light-yellow solid (13.4 mg, 71%). MS (m/e): 400.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]C#N)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:21][N:20]=[C:17]3[CH:18]=[CH:19][C:14]([C:13]4[N:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[N:10]=[CH:11][CH:12]=4)=[CH:15][C:16]=23)=[CH:27][CH:26]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: COc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Product: COc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(OC)cc4)cc23)cc1

Procedure:
The title compound, yellow solid (7 mg, 5%), MS (ISP) m/z=398.2 [(M+H)+], mp 133° C., was prepared in accordance with the general method of example 1 from 1-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate G) (100 mg, 353 μmol) and commercially available 2-(4-methoxy-phenyl)-acetonitrile.
Reaction SMILES: [N:1]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:2]=1[CH2:3][C:4]([OH:6])=O.C1C(=O)N(O)C(=O)C1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:38][CH:39]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>C(OCC)(=O)C>[C:48]1([CH:39]([NH:38][C:4]([CH2:3][C:2]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:1]=2)=[O:6])[CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: O=C(O)Cc1ccc2ccccc2n1
Reactant: NC(CCN1CCCCC1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc2ccccc2n1)NC(CCN1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a suspension of 866 mg (5.0 mmol.) of quinaldinic acid and 576 mg (5.0 mmol.) of 1-hydroxysuccinimide in 20 ml of ethyl acetate was dropwise added over a period of 5-10 min. under chilling with ice a solution of 1.09 g (5.0 mmol.) of N,N'-dicyclohexylcarbodiimide. After the addition was complete, the mixture was stirred for 2 hours at room temperature. To this mixture was dropwise added a solution of 1.09 g (5.0 mmol.) of 1-(3-amino-3-phenylpropyl)piperidine in 5 ml of ethyl acetate. After the addition was complete, the mixture was stirred overnight at room temperature. Precipitated insolubles were filtered off and then the insolubles were washed with ethyl acetate. The filtrate and the washings were combined and washed twice with a saturated aqueous sodium hydrogencarbonate solution and once with a saturated aqueous sodium chloride solution. The mixture was then dried over sodium sulfate, and was evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (silica gel: 20 g, CHCl3 and CHCl3 /CH3OH (30:1)) to obtain 1.72 g (yield: 92%) of the subject compound as a pale yellow crystalline product.
Reaction SMILES: [CH:1]([CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH2:29][C:30]1[CH2:34][CH2:33][C:32](=[O:35])[CH:31]=1>C(OCC)C.CN(C)C=O>[CH2:7]([O:6][C:4]([C:3]1[CH:1]=[N:29][C:30]2[CH2:34][CH2:33][C:32](=[O:35])[C:31]=2[CH:9]=1)=[O:5])[CH3:8]
Reactant: NC1=CC(=O)CC1
Reactant: CCOC(=O)C(C=O)C=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 2-formyl-3-oxopropanoate (3.2 g, 22 mmol) in diethyl ether (25 mL) was teated with triethylamine (3.5 mL, 25 mmol) at about 0° C. The mixture was stirred at room temperature for about 1 h before the diethyl ether was removed in vacuo. To the residue was added a solution of p-toluenesulfonyl chloride (4.5 g, 23.6 mmol) in N,N-dimethylformamide (60 mL) at about 0° C. The mixture was stirred for about 5 h while being allowed to warm to room temperature. 3-Aminocyclopent-2-en-1-one (1.75 g, 18 mmol) was added and the mixture was heated to about 85-90° C. over night. The mixture was cooled to room temperature and was concentrated in vacuo. The residue was diluted with chloroform (200 mL), washed with sodium carbonate solution, filtered through Celite, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using dichloromethane/methanol/ammonium hydroxide (95:4.5:0.5) as the mobile phase to provide the title compound: 1H NMR (300 MHz, CDCL3): δ 1.42 (t, J=8.0 Hz, 3H), 2.82 (t, J=8.0 Hz, 2H), 3.38 (t, J=8.0 Hz, 2H), 4.42 (q, J=8.0 Hz, 3H), 8.60 (s, 1H), 9.40 (s, 1H).
Reaction SMILES: [CH2:1]([CH2:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:10].[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]2.[CH2:23]=O>C(O)C>[ClH:10].[CH2:1]([CH2:8][NH:9][CH2:23][CH:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([F:11])[CH:13]=2)[C:18]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: O=C1CCCc2cc(F)ccc21
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: O=C1c2ccc(F)cc2CCC1CNCCc1ccccc1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of N-benzylmethylamine (5.67 cm3) in ethyl alcohol (60 cm3) was added hydrochloric acid (5 M, 10 cm3). 6-Fluoro-3,4-dihydro-2H-naphthalene-1-one (6.00 g) and paraformaldehyde (1.32 g) were then added and the resulting mixture was stirred and heated to reflux for 4 h. Upon cooling, the alcohol was removed under reduced pressure and water (100 cm3) was added. The remaining tetralone was extracted into diethyl ether (100 cm3) and the aqueous mixture was then extracted further with dichloromethane (2×100 cm3). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. Trituration with diethyl ether and filtration provided the title compound (3.18 g) as a white solid.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[N:6]=[CH:7][N:8]=[N:9][C:10]=1[CH2:11][NH:12][C:13]([CH:15]1[CH2:18][C:17](=[O:19])[CH2:16]1)=O.CC#N.O=P(Cl)(Cl)Cl>CN(C=O)C>[CH3:3][O:4][C:5]1[C:10]2=[CH:11][N:12]=[C:13]([CH:15]3[CH2:18][C:17](=[O:19])[CH2:16]3)[N:9]2[N:8]=[CH:7][N:6]=1
Reactant: COc1ncnnc1CNC(=O)C1CC(=O)C1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ncnn2c(C3CC(=O)C3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In an oven-dried flask filled with N2 was added N-[(5-methoxy-1,2,4-triazin-6-yl)methyl]-3-oxocyclobutanecarboxamide (2.40 g, 0.00833 mol) followed by MeCN (200 mL) and DMF (40 mL). The reaction mixture was treated with POCl3 (3.1 mL, 0.033 mol) dropwise at 0° C. under N2 over 10 min. The reaction was stirred at rt overnight. The reaction mixture was concentrated and poured into ice, saturated aqueous NaHCO3 solution was added to adjust the pH to 7. The mixture was extracted with DCM (150×3). The organic extracts were combined, dried (Na2SO4) and concentrated under reduced pressure to give a crude residue, which was then purified by flash chromatography on silica gel using hexanes:EtOAc (1:1) as the eluent.
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])=[C:11]([F:29])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37]O)[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])=[C:11]([F:29])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:37][CH2:36][N:33]1[CH2:34][CH2:35][O:30][CH2:31][CH2:32]1)=[O:7]
Reactant: OCCN1CCOCC1
Reactant: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F)OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A mixture of 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetic acid (I(b)) (800 mg, 1.97 mmol, 1.0 eq), 2-morpholinoethanol (284 mg, 2.17 mmol, 1.1 eq), HATU (974 mg, 2.56 mmol, 1.3 eq), and TEA (598 mg, 5.91 mmol, 3 eq) in DCM (10 mL) and DMF (10 mL) was stirred at room temperature overnight under N2. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo and the residue purified by column chromatography, (MeOH:DCM 0:1 to 1:50) to give the title compound as a yellow oil (710 mg, 70%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([N:21]([CH3:31])[S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:24])=[O:23])[CH:20]=1)[NH:17][C:16]([C:32]1[S:33][CH:34]([CH2:37][C:38](O)=[O:39])[CH2:35][N:36]=1)=[CH:15]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[OH:6][CH:4]1[CH2:5][N:2]([C:38](=[O:39])[CH2:37][CH:34]2[S:33][C:32]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([O:11][CH2:10][CH2:9][O:8][CH3:7])=[CH:20][C:19]=4[N:21]([CH3:31])[S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:24])=[N:36][CH2:35]2)[CH2:3]1
Reactant: OC1CNC1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)N4CC(O)C4)S3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28.9 %

Procedure:
A mixture of azetidin-3-ol hydrochloride (80 mg), triethylamine (75 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 min. (2-{5-(2-Methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (250 mg), 1H-1,2,3-benzotriazol-1-ol (100 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (140 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-95:5, volume ratio) to give the title compound (80 mg, yield 29%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][NH2:15])=[CH:13][C:8]=2[CH2:7]1)=[O:5].[CH3:23][C:24]([CH3:26])=O>>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][N:15]=[C:24]([CH3:26])[CH3:23])=[CH:13][C:8]=2[CH2:7]1)=[O:5]
Reactant: CC(C)=O
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccc(Cl)cc1Cl)C2
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)c1ccc(Cl)cc1Cl)C2

Procedure:
A solution of 1.2 g of crude 6-(2,4-dichlorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido [4,3-c]pyridazine in 5 cc of acetone is heated on a water bath for 5 minutes. The title compound has a M.P. of 211°-214° (decomp., from methanol).
Reaction SMILES: C([O:4][C:5]1[CH:28]=[CH:27][C:8]([CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([O:23]C(=O)C)=[CH:14][C:15]=3[O:19]C(=O)C)[O:10]2)=[CH:7][CH:6]=1)(=O)C.C1(Cl)C(=O)C([Cl:37])=C(Cl)C(=O)C=1Cl.C(O)(=O)C.C=CN1C(=O)CCC1>Cl.CO.O>[CH:27]1[C:8]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([OH:23])=[CH:14][C:15]=3[OH:19])[O+:10]=2)=[CH:7][CH:6]=[C:5]([OH:4])[CH:28]=1.[Cl-:37]
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: CC(=O)Oc1ccc(C2CCc3c(OC(C)=O)cc(OC(C)=O)cc3O2)cc1
Agent: C=CN1CCCC1=O
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Oc1ccc(-c2ccc3c(O)cc(O)cc3[o+]2)cc1
Product: [Cl-]
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A mixture of 500 mg 4', 5,7-triacetoxyflavan, 750 mg chloranil, 25 ml acetic acid, 5 ml H2O and 1.5 ml 6 N HCl was heated with stirring at 100° for 1 hour. After cooling in ice, the solution was diluted to 250 ml with 0.01 N HCl in MeOH and passed through a 4.5 × 10 cm column of acid-treated POLYCAR AT[1] (slurry packed) (POLYCLAR AT is a trademark for polyvinylpyrollidine sold by G.A.F.). The column was washed with a second 250 ml of 0.01 N HCl in methanol and the combined eluants concentrated on a rotary evaporator to 25 ml. This solution was then freeze dried to give a red-orange solid. After washing twice with 10 ml ethyl acetate to remove unreacted chloranil, there was obtained 144 mg (36% yield) of crude apigeninidin chloride (E1% (476 nm) = 840). A sample of purified material recrystallized from EtOH-4 N CHl had E1% (476 nm) = 1010 and was identical by IR (KBr) and TLC (cellulose) comparison with an authentic sample prepared by Robinson's procedure [2] ; the yield of purified material was 30%.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[O:31])=[N:22][C:21]=1[CH3:32])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:26]2=[O:31])=[N:22][C:21]=1[CH3:32])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CCc1ccccc1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC(CCc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 24 %

Procedure:
Following the procedure as described in Example 3, making variations as required to use 2-phenylacetaldehyde in place of cyclopropanecarbaldehyde to react with N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 24% yield: mp 124-126° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.46-7.09 (m, 10H), 5.98 (t, J=5.4 Hz, 1H), 4.55 (d, J=5.4 Hz, 2H), 4.29-4.20 (m, 1H), 4.07-4.04 (m, 1H), 2.83-2.66 (m, 2H), 2.64 (s, 3H), 2.61-2.48 (m, 1H), 2.41-2.26 (m, 1H), 2.17-2.01 (m, 2H), 1.96-1.76 (m, 2H), 1.74-1.58 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 172.8, 162.7, 156.9, 152.2, 141.3, 137.9, 128.8, 128.5, 128.4, 127.9, 127.6, 126.1, 119.1, 47.9, 44.1, 41.4, 33.3, 33.0, 25.7, 21.3, 17.4; MS (ES+) m/z 434.1 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH3:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2[nH]cc(CCNC(=O)c3ccc(Cc4cccc(F)c4)cc3)c2c1
Yield: 41.9 %

Procedure:
4-(3-Fluorobenzyl)-N-(2-(5-methyl-1H-indol-3-yl)ethyl)benzamide was prepared according to method A with 2-(5-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.060 g; 0.284 mmol), 4-(3-fluorobenzyl)benzoic acid (0.079 g; 0.341 mmol), HATU (0.141 g; 0.370 mmol) and N,N-diisopropylethylamine 0.123 mL; 0.711 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.046 g (42%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([CH2:27][CH2:28][CH2:29][CH:30]([NH2:40])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:34]1([CH2:33][CH2:32][CH2:31][CH:30]([NH:40][C:16](=[O:18])[CH2:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:19])[CH2:29][CH2:28][CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)O)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-3-oxopropionic acid (36) (1.20 g; 4.41 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.61 g; 5.29 mmol), N,N-diisopropylethylamine (1.82 g; 14.1 mmol) and PyBOP (2.75 g; 5.29 mmol) are added sequentially. The reaction is stirred for 14 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (40%→70% ethyl acetate in hexanes) affording the desired product as a solid. ESMS: MH− 522.4