Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:11][CH3:12].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C(C)C)cc1OC
Reaction time: 3 h
Yield: 75.7 %

Procedure:
1.81 g of 4-amino-2-methoxy-benzoic acid methyl ester and 1.4 g of triethylamine were dissolved in 20 ml of dichloromethane. 1.23 g of isobutyryl chloride in 5 ml of dichloromethane was added dropwise at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 3 hours. The reaction mixture was washed with water, dried and the solvents were evaporated to yield 1.9 g of the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]([CH3:26])([O:14][C:15]([NH:17][C@@H:18]([CH2:23][C:24]#[CH:25])[C:19]([O:21][CH3:22])=[O:20])=[O:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.[Cu](I)I.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>[CH3:13][C:12]([CH3:26])([O:14][C:15]([NH:17][C@@H:18]([CH2:23][C:24]#[C:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:16])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC#Cc1ccc([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 64.3 %

Procedure:
A mixture of 2-bromo-5-nitropyridine (10.0 g; 49.0 mmol), methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pent-4-ynoate (13.34 g; 58.8 mmol), copper iodide (0.465 g; 2.5 mmol), potassium carbonate (13.6 g; 98.0 mmol) and dichlorobis(triphenylphosphine)palladium (1.7 g; 2.5 mmol) in 30 ml of anhydrous dimethylformamide (DMF) is heated for 4 hours at 60° C. under argon. The reaction mixture is taken up in 800 ml of ethyl acetate, washed with 2×400 ml of water, 400 ml of saturated hydrogen carbonate and 400 ml of brine, dried over sodium sulphate, filtered and then concentrated under reduced pressure. The residue obtained is purified on a column of silica, eluting with a cyclohexane/ethyl acetate gradient of from 0 to 20% ethyl acetate. 11 g of methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(5-nitropyrid-2-yl)pent-4-ynoate is isolated.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[Cl:24][C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH2:29])=[C:27]([F:33])[CH:26]=1>CC(O)CCC>[Cl:24][C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH:29][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[N:5][CH:4]=2)=[C:27]([F:33])[CH:26]=1
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)cnnc2cc1OCCCN1CCCC1

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline hydrochloride (0.1 g, 0.25 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline (57 mg, 0.35 mmol), (prepared as described in EP 061741 A2), in 2-pentanol (5 ml) was heated at 120° C. for 2.5 hours. The solid was filtered off, washed with isopropanol and then ether and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline as the hydrochloride salt (yellow solid, 94 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:19][C:15]1[CH:16]=[CH:17][C:18]2[C:7](=[O:9])[C:6]3[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH2:11][O:12][C:13]=2[CH:14]=1
Reactant: O=C(O)c1cc(F)ccc1COc1cccc(F)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1c2cc(F)ccc2COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.1 %

Procedure:
To 10 g of 5-fluoro-2-[(3-fluorophenyloxy)methyl]benzoic acid is added 50 g of thionyl chloride and the mixture is refluxed with heating for 1 hour. After cooling the reaction mixture to room temperature, dry toluene is added and the solvent is distilled off under reduced pressure. The residue is added with dichloromethane and cooled to 0° C. Thereto 10 g of powdery anhydrous aluminum chloride is added and the mixture is stirred for 15 minutes. The reaction mixture is added with ice-water and extracted with toluene. After the extract is dried over magnesium fulfate, the solvent is distilled off under reduced pressure and the residue is subjected to silica-gel chromatography, followed by elution with toluene to give 4.3 g of 3,9-difluoro-6,11-dihydrodibenz[b,e]oxepin-11-one (oil). Mass spectrum m/z: 246(M+).
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][N:15]=[N+]=[N-])[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.Cl>[Pt]>[Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][NH2:15])[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=NCC1Cc2c(Cl)cc3c(c2O1)CCC3
Agent: [Pt]
Agent: Cl
Product: NCC1Cc2c(Cl)cc3c(c2O1)CCC3
Yield: 76 %

Procedure:
Treatment of (±)-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl 4-methylbenzenesulfonate (4.0 g, 10.6 mmol) with sodium azide (2.75 g, 42.2 mmol) generally according to the procedure described for Intermediate 24 gave (±)-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl azide. Treatment of the azide with sulfided platinum on carbon (5 wt. %, 0.63 g) followed by hydrogen chloride (3 mL, 4 M in isopropanol) generally according to the procedure described for Example 2 provided 2.1 g (76%) of (±)-1-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp 251-254° C.; Anal. calcd. for C12H14ClNOHCl: C, 55.40; H, 5.81; N, 5.38. Found: C, 55.10; H, 5.68; N, 5.29.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][N:7]=1)(=O)C.[OH-].[Na+].O1CCCC1>CO>[C:12]1([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[N:7][CH:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OCc1ccc(-c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccccc2)cn1
Yield: 94.7 %

Procedure:
A mixture of 5-phenyl-2-pyridylmethyl acetate (3.68 g), a 1N aqueous sodium hydroxide solution (30 ml), tetrahydrofuran (30 ml) and methanol (300 ml) was stirred at room temperature for 3 hours, which was concentrated. The residue was dissolved in ethyl acetate, and then the solution was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residual colorless crystals were collected by filtration to obtain 5-phenyl-2-pyridylmethanol (2.84 g, yield 95%). This was recrystallized from ethyl acetate-hexane. Melting point: 86–87° C.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:51]=[CH:50][C:31]([O:32][CH2:33][CH2:34][N:35]2[C:39](=[O:40])[N:38]([C:41]3[S:42][C:43]([C:47](O)=[O:48])=[C:44]([CH3:46])[N:45]=3)[CH:37]=[N:36]2)=[CH:30][CH:29]=1.[N:52]1[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58][NH2:59])[CH:53]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[C:39](=[O:40])[N:38]([C:41]3[S:42][C:43]([C:47]([NH:59][CH2:58][C:54]4[CH:53]=[N:52][CH:57]=[CH:56][CH:55]=4)=[O:48])=[C:44]([CH3:46])[N:45]=3)[CH:37]=[N:36]2)=[CH:50][CH:51]=1
Reactant: Cc1nc(-n2cnn(CCOc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(CCOc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 45 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(2-(4-fluorophenoxy)ethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 45% yield: mp 154-155° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.58 (br s, 1H), 8.53-8.45 (m, 1H), 8.26 (s, 1H), 7.72-7.65 (m, 1H), 7.30-7.21 (m, 1H), 6.98-6.86 (m, 2H), 6.85-6.75 (m, 2H), 6.61 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 4.28-4.15 (m, 4H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 157.6, 154.2, 153.4, 151.0, 149.3, 149.1, 135.8, 133.6, 131.0, 123.7, 121.6, 116.0, 115.9, 115.8, 65.5, 45.3, 41.6, 17.2; MS (ES+) m/z 455.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([NH2:13])=[O:12].[Cl:14][CH2:15][C:16]([CH2:18]Cl)=O>>[Cl:14][CH2:15][C:16]1[N:13]=[C:11](/[CH:10]=[CH:9]/[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[O:12][CH:18]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)/C=C/c1ccc(F)cc1F
Product: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Yield: 49.4 %

Procedure:
Using (E)-3-(2,4-difluorophenyl)-2-propenamide (9.16 g) and 1,3-dichloroacetone (7.62 g), the same reaction as Reference Example 1-(ii) was carried out to yield the titled compound (6.31 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:20][OH:21])[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=[O:21])[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1
Reactant: C[C@@H]1CN(c2c(CO)cc3c(N)noc3c2F)C[C@H](C)O1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@H]1CN(c2c(C=O)cc3c(N)noc3c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of {3-amino-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzisoxazol-5-yl}methanol (Intermediate 7, 200 mg, 0.67 mmol) in CH2Cl2/CH3CN mixture (4 mL, 1:1 v/v) was added NMO (119 mg, 1.0 mmol) followed TPAP (23 mg, 0.06 mmol) and mixture stirred for 2 h at room temperature. The reaction mixture filtered thorough a silica gel bed and washed with EtOAc. The organic phase concentrated under reduced pressure to give the title compound as a yellow solid. Yield: 100 mg, (50%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)CCC.C([Sn](Cl)(CCCC)CCCC)CCC.C[Sn](Cl)(C)C.Br[C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH:45]=[O:46]>C1(C)C(C)=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH:45]=[O:46]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2o1
Reactant: O=Cc1ccccc1Br
Agent: [Pd]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Sn](C)(C)Cl
Solvent: Cc1ccccc1C
Product: O=Cc1ccccc1-c1nc2ccccc2o1
Temperature: 115 °C
Yield: 84.9 %

Procedure:
A mixture of 12.5 g of 2-tributylstannylbenzoxazole (prepared by the method of P. Jutzi and W. Gilge, J. Organometallic Chem. 1983, 246, 159, using tributyltin chloride as a less toxic replacement for trimethyltin chloride) 5.66 g 2-bromobenzaldehyde, and 0.46 g tetrakis(triphenylphosphine)-palladium (0) in 300 ml of anhydrous xylene under a nitrogen atmosphere was heated to 115° C. for 12 h. The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. The resulting oil was purified by chromatography on silica eluting with ethyl acetate-heptane (1:5) to afford 5.8 g of 2-(benzoxazol-2-yl)benzaldehyde, GC-M.S. (E.I.) (M/Z): 223 [M+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH:12]([CH3:13])[CH2:11][CH2:10][C:9]2=[O:14])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:28][CH3:29].[Cl-].[NH4+]>O1CCCC1>[CH2:28]([CH:10]1[CH2:11][CH:12]([CH3:13])[N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:14])[CH3:29]
Reactant: CCI
Reactant: COc1ccc(CN2C(=O)CCC2C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1CC(C)N(Cc2ccc(OC)cc2)C1=O
Reaction time: 1 h

Procedure:
To a solution of 1-(4-methoxybenzyl)-5-methylpyrrolidin-2-one (3.0 g) obtained in Step A in tetrahydrofuran (25 mL) was added sodium bis(trimethylsilyl)amide (1.9M tetrahydrofuran solution, 11 mL) at −78° C. under nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hr. Iodoethane (2.2 mL) was added thereto, and the mixture was stirred overnight while it was allowed to be warmed. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.5 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([I:23])=[C:19]([CH:22]=1)[CH:20]=O>COCCOC>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([I:23])=[C:19]([CH:20]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:22]=1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: O=Cc1cc(Br)ccc1I
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2I)C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (0.388 g, 2.73 mmoles) in anhydrous 1,2-dimethoxyethane (5 ml) is added sodium methoxide (0.177 g, 3.27 mmoles) in one portion. The reaction mixture is stirred for 5 minutes at this temperature, followed by the dropwise addition of 5-bromo-2-iodo-benzaldehyde (0.850 g, 2.73 mmoles) as a solution in 1,2-dimethoxyethane (5 ml). The reaction mixture is further stirred at 0° C. for 30 minutes, then at ambient temperature for a 1 hour. After partitioning between 1M hydrochloric acid and dichloromethane, the organic phase is separated, and the aqueous phase is extracted again with additional dichloromethane. All organics are combined then concentrated in vacuo to afford 4-[1-(5-bromo-2-iodophenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (1.18 g) as a yellow gum.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH:14]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3)c2c1
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A solution of tert-butyl 4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.8 g, 2.330 mmol) in CH2Cl2 (16 mL) was treated with TFA (4 mL) at 0° C. and the resulting mixture was stirred at same temperature for 3 h. The reaction was evaporated and crude was basified with 1 N NaOH solution (pH ˜14). The solid was filtered off, washed with water (2×10 mL). The crude was dried under vacuum and treated with 10% ethyl acetate in hexanes (20 mL). The solid was filtered and washed with hexanes (2×5 mL). The yellow solid was dried under vacuum to obtain 5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.56 g, 99%). 1H NMR (DMSO-d6) δ 8.69 (d, 1H, J=2.1 Hz), 8.00 (dd, 1H, J=2.1, 9.0 Hz), 7.63 (s, 1H), 7.55 (d, 1H, J=9.0 Hz), 6.21 (s, 1H), 3.42-3.30 (m, 2H, merged with DMSO-peak), 2.93 (t, 2H, J=5.4 Hz), 2.40-2.30 (m, 2H); ESI-MS (m/z, %): 244 (MH+, 77), 215 (100).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8]([C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:7]=[C:2]1[NH:3][C:4](=[O:6])[C:5](=[CH:8][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[S:1]1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(OCCCC(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CCCOc1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 32.3 %

Procedure:
Thiazolidine-2,4-dione (3.55 g, 27.6 mmol), 4-(4-formylphenoxy)butyric acid (5.74 g, 27.6 mmol), anhydrous sodium acetate (11.3 g, 138 mmol) and acetic acid (100 mL) was refluxed for 16 h. After cooling, the mixture was filtered and washed with acetic acid and water. Drying in vacuo afforded 2.74 g (32%) of 4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[N:49]1([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([N:58]2[CH2:59][CH2:60][CH:55]([N:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)[CH2:56][CH2:57]2)=[O:24])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Reactant: C1CCN(C2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(OCC(=O)N4CCC(N5CCCCC5)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenoxy}acetic acid (100 mg), WSC.HCl (81 mg), and HOBT.H2O (57 mg) were dissolved in chloroform (3 ml) to prepare a solution. 4-Piperidinopiperidine (57 mg) was then added to the solution, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (34 mg, yield 24%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[Cl:18].C(O[C:22](=[NH:24])[CH3:23])C.[C:25]([OH:28])(=[O:27])[CH3:26]>C(#N)C>[C:25]([OH:28])(=[O:27])[CH3:26].[NH:24]=[CH:22][CH2:23][NH:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[Cl:18]
Reactant: CCOC(C)=N
Reactant: CCOc1cc(Cl)c(-c2c(C)n[nH]c2N)c(Cl)c1
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOc1cc(Cl)c(-c2c(C)n[nH]c2NCC=N)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 5-amino-4-(4-ethoxy-2,6-dichlorophenyl)-3-methylpyrazole (4.8 g) in acetonitrile (50 mL) add ethylacetimidate (free base, 2.3 mL) followed by acetic acid (0.96 mL). Collect the precipitate that formed upon stirring overnight by filtration. Wash the solid with dry ether and dry to afford 5.02 g of (iminoethyl)[4-(4-ethoxy-2,6-dichlorophenyl)-3-methylpyrazol-5-yl]amine acetate salt as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:5].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][N:20]=1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:1]=[C:23]2[C:22]2[CH:21]=[N:20][C:19]([Cl:18])=[CH:26][CH:25]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2nc(-c2ccc(Cl)nc2)n1-c1ccc(Cl)cc1
Temperature: 150 °C
Yield: 4 %

Procedure:
2-Amino-N-(4-chlorophenyl)benzamide (0.500 g, 2.03 mmol) and 6-chloronicotinaldehyde (2.23 mmol), NaHSO3 (0.253 g, 2.44 mmol) and p-TsOH (0.039 g, 0.20 mmol) were dissolved in DMA (20 mL) and heated at 150° C. for 21 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (2×200 mL), dried (Na2SO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 30% ethyl acetate/heptane to 70% ethyl acetate/heptane, afforded the title compound as a white solid (4%). 1H-NMR (300 MHz, DMSO-6): δ 8.46 (d, J=2.1 Hz, 1H), 8.23 (d, J=8.1 Hz, 1H), 7.92-7.97 (m, 1H), 7.80-7.86 (m, 2H), 7.63-7.68 (m, 1H), 7.47-7.50 (m, 5H). MS (APCI) m/z: 368 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:17]2[C:18]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Brc1cccc(I)c1
Product: Brc1cccc(-c2cccc3ccccc23)c1

Procedure:
1-(3-Bromophenyl)naphthalene was synthesized by the same method, except that in Synthetic Example 1, 3-bromoiodobenzene was used in place of 4-bromoiodobenzene and that 1-naphthaleneboronic acid was used in place of 2-naphthaleneboronic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][C:8]([CH:10]=O)=[CH:7][CH:6]=1)[CH3:3].N1CCCCC1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21]>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:9][C:8]([CH:10]=[CH:19][C:20]([OH:22])=[O:21])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(C=O)s1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CN(C)Cc1ccc(C=CC(=O)O)s1
Yield: 54.8 %

Procedure:
5-(Dimethylaminomethyl)thiophene-2-carboxaldehyde (40.09 g) and piperidine (3 ml) were added to a solution of malonic acid (24.65 g) in pyridine (150 ml). The mixture was stirred under reflux for 7 hours. During the reaction a solid precipitated and slowly re-dissolved. The solution was allowed to cool and was then poured on to 2 M hydrochloric acid (150 ml). The volume of the solution was reduced to about 120 ml by evaporation at reduced pressure and extracted with diethyl ether. The ether extracts were washed with water. The aqueous phase was cooled and the solid, which precipitated out, was filtered off and washed with water-isopropanol. More solid was obtained by evaporating the filtrate to about 100 ml and adding isopropanol and cooling the mixture in ice for about 15 minutes. This solid was filtered off, and washed with isopropanol. The solids were combined and recrystallised from isopropanol-water to give 3-(5-dimethylaminomethyl-2-thienyl)acrylic acid (27.45 g) m.p. 223.5°-225° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Br:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].ON1[C:20]2C=CC=C[C:19]=2N=N1.CN(C1C=CC=CN=1)C.Cl.CN(C)CCCC(N=C=N)C>ClCCl.C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Br:14])=[C:9]([CH:13]=1)[C:10]([O:12][CH2:19][CH3:20])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)c1
Reactant: On1nnc2ccccc21
Agent: CC(CCCN(C)C)N=C=N
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(NC(C)=O)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A mixture of 5-(acetylamino)-2-bromobenzoic acid (2.58 g, 10 mmol), 1-hydroxybenzotriazole (1.68 g, 11 mmol), dimethylaminopyridine (1.22 g, 10 mmol) and 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (2.20 g, 11.5 mmol) in dichloromethane/ethanol (5:1, 30 ml) was stirred at room temperature for 2 hours then washed with saturated sodium bicarbonate solution, dried (magnesium sulphate) and chromatographed on silica eluting with ethyl acetate/iso-hexane (2:3) to give 2.18 g of white solid.