Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([O:20][CH2:21][CH3:22])[CH:12]=2)[CH2:7][C:8]([NH2:10])=O)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.CN1CCOCC1.S(Cl)(Cl)=O.CC#N.OP(O)(O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:4]1(=[O:23])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([O:20][CH2:21][CH3:22])[CH:12]=2)[CH2:7][C:8]#[N:10])[C:1](=[O:28])[C:2]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:3]12
Reactant: CCOc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1OCC
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(C(CC#N)N2C(=O)c3ccccc3C2=O)cc1OCC
Temperature: 0 °C
Yield: 54.9 %

Procedure:
To an ice bath cooled stirred suspension of 3-phthalimido-3-(3,4-diethoxyphenyl)propionamide (0.96 g, 2.5 mmol) and 4-methylmorpholine (0.66 mL, 6 mmol) in DMF (9 mL) under nitrogen, was added thionyl chloride (0.35 mL, 4.8 mmol) dropwise. There was a slight exotherm after which the mixture was stirred at 0°-5° C. for 30 minutes and at room temperature for 2 hours. The reaction was monitored by HPLC (Waters Nova-Pak/C-18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 50/50 CH3CN/H3PO4 0.1% (aq)). The reaction mixture was poured into a mixture of NaHCO3 (8.5 mL) and ice (40 g) and stirred until the ice had melted. The mixture was filtered and the solid was washed with copious amounts of H2O. The wet solid was dissolved in CH2Cl2 (25 mL) and the organic layer was separated and dried over MgSO4 and concentrated in vacuo to a sticky semi-solid. The solid was purified twice by flash column chromatography (silica gel, 3 % ethyl acetate/methylene chloride) to afford a solid which was dried in vacuo (50° C., <1 mm) to afford 0.5 g (55%) of product as a pale yellow solid; 1H NMR (CDCl3) δ7.91-7.65(m, 4H), 7.12-6.98(m, 2H), 6.90-6.78(m, 1H), 5.61(dd, J=6.4, 10.3 Hz, 1H), 4.19-3.96(m, 4H), 3.83(dd, J=10.3, 16.8 Hz, 1H), 3.26(dd, J=6.4, 16.8 Hz, 1H), 1.55-1.30(m, 6H); 13C NMR (CDCl3)δ167.7, 149.2, 148.9, 134.3, 131.5, 129.1, 123.6, 120.2, 116.9, 113.2, 112.9, 64.7, 64.5, 51.1, 21.1, 14.7; HPLC 98.4%. Anal. Calcd for C21H20N2 O4. Theoretical: C, 69.22; H,5.53; N,7.69. Found: C, 69.06; H, 5.48; N, 7.58.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[CH:8]=2)[N:3]=1.P(Br)(Br)([Br:16])=O.[OH-].[Na+]>P(Br)(Br)Br>[NH2:1][C:2]1[CH:11]=[C:10]([Br:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[CH:8]=2)[N:3]=1
Reactant: Nc1cc(O)c2cc(F)ccc2n1
Reactant: O=P(Br)(Br)Br
Agent: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Br)c2cc(F)ccc2n1
Yield: 56.5 %

Procedure:
1 (7.2 g) was heated with POBr3 (22.0 g) in PBr3 (20 ml) at 140-160° C. under N2 for 19 hours. The reaction was cooled, carefully basified with 2 M NaOH (250 mL) and thrice extracted with CHCl3 (30 mL). The organic layer was concentrated, and the residue purified by silica gel chromatography using CHCl3/acetone/Et3N (75:25:1) to afford the product that was re-crystallized from benzene/CH2Cl2/hexane to furnish off-white crystals (5.5 g, 57% yield): 1H NMR (CDCl3) δ 4.70 (bs, 2 H, NH2), 7.10 (s, 1 H), 7.37 (m, 1 H), 7.66 (m, 2 H); HRMS-FAB (M+) calculated for 239.9698, found 239.9707.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][N:12]([CH3:16])[C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClC=C(Cl)Cl>[CH3:11][N:12]([CH3:16])[C:13]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:14]
Reactant: Nc1nc2ccccc2s1
Reactant: CN(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=C(Cl)Cl
Product: CN(C)C(=O)Nc1nc2ccccc2s1
Reaction time: 40 h
Yield: 97.7 %

Procedure:
Using 2-aminobenzothiazole (1.50 g), N,N-dimethylcarbamoyl chloride (1.29 g), aluminum chloride (1.60 g), and trichloroethylene (40 ml), the reaction is effected as in Example 1, except that the reflux is carried out for 40 hours. Thus, 1,1-dimethyl-3-(2-benzothiazolyl)urea (2.16 g) is obtained. Yield is 97.7%. Melting point is higher than 300° C. (after recrystallization from ethanol).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[NH:21][C:20]3[CH:22]=[C:23]([N:27]4[CH2:31][CH2:30][CH2:29][CH:28]4[CH2:32][N:33]([CH3:35])[CH3:34])[C:24]([Cl:26])=[CH:25][C:19]=3[N:18]=2)[CH:10]=1)(C)(C)C.Cl>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH2:7])=[CH:10][C:11]=1[NH:16][C:17]1[NH:21][C:20]2[CH:22]=[C:23]([N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH2:32][N:33]([CH3:35])[CH3:34])[C:24]([Cl:26])=[CH:25][C:19]=2[N:18]=1
Reactant: CN(C)CC1CCCN1c1cc2[nH]c(Nc3cc(CNC(=O)OC(C)(C)C)ccc3Cl)nc2cc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CC1CCCN1c1cc2[nH]c(Nc3cc(CN)ccc3Cl)nc2cc1Cl

Procedure:
The sub-title compound was prepared from {4-chloro-3-[5-chloro-6-(2-dimethylaminomethyl-pyrrolidin-1-yl)-1H-benzimidazol-2-ylamino]-benzyl}-carbamic acid tert-butyl ester (20 mg, 0.04 mmol) and 6 M aq. HCl-solution (1.0 ml) in THF (2 mL) in analogy to example 3 step (d).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.O>C1COCC1>[CH:1]1([N:4]2[C:5]3=[N:6][CH:7]=[CH:8][N:9]=[C:10]3[NH:11][C:17]2=[O:18])[CH2:3][CH2:2]1
Reactant: Nc1nccnc1NC1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2nccnc2n1C1CC1
Yield: 71.2 %

Procedure:
To a solution of N2-cyclopropylpyrazine-2,3-diamine (0.6690 g, 4.45 mmol) in THF (22.27 ml) at 50° C. was added CDI (2.89 g, 17.82 mmol, Fluka). The reaction was allowed to stir for 1½ h. The reaction flask was place in an ice bath until the temperature reached 0° C. The flask was raised and water (5 mL) was added dropwise to quench. (Note: if exothermic reaction was detected then flask was placed back into ice bath until it stopped.) The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 1% to 8% MeOH in CH2Cl2, to provide 1 the title compound (0.5578 g, 3.17 mmol, 71.1% yield). LCMS showed product peak at 0.999 min (m+1=177.1). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.07 (m, 4 H) 2.87-3.00 (m, 1 H) 7.84-7.89 (m, 1 H) 7.89-7.94 (m, 1 H) 11.87 (s, 1 H)
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1.C(N(C(C)C)CC)(C)C.CO>C(O)(=O)C.CCCCCC>[Cl:8][C:9]1[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[C:12]([O:16][CH3:1])=[CH:13][C:14]=1[CH3:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 13.3 mL, 26.6 mmol) was added to a mixture of 4-chloro-5-methyl-2-nitro-phenol (1.0 g, 5.33 mmol) and diisopropylethylamine (1.04 mL, 6.13 mmol) in a mixture of anhydrous methanol and anhydrous acetonitrile (1/1, 50 mL) and the reaction mixture was stirred for 1 hour. Glacial acetic acid (5 drops) was then added and the resulting mixture was evaporated under reduced pressure. The residue was partitioned between diethyl ether (100 mL) and water (50 mL); the organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 1.07 g of 1-chloro-4-methoxy-2-methyl-5-nitro-benzene as a light orange solid without further purifications.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[C:8]2[C:13]([C:14]=1[C:15](=[O:19])[C:16](O)=[O:17])=[CH:12][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[CH:10][CH:9]=2)(=O)C.[OH-].[K+].Cl>>[CH3:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=4)=[CH:10][CH:9]=3)[C:14]3[C:15](=[O:19])[C:16](=[O:17])[O:4][CH2:5][C:6]2=3)=[CH:29][CH:30]=1
Reactant: CC(=O)OCc1c(C(=O)C(=O)O)c2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(Cn2c3c(c4cc(-c5cccc(C)c5)ccc42)C(=O)C(=O)OC3)cc1

Procedure:
The title compound was prepared from [2-[(acetyloxy)methyl]-1-(4-methylbenzyl)-5-(3-methylphenyl)-1H-indol-3-yl](oxo)acetic acid and aqueous potassium hydroxide in substantially the same manner, as described in step 6 of Example 1 followed by the treatment with aqueous HCl in substantially the same manner, as described in step 7 of Example 1. The product was obtained as a white solid; mp: 216-217° C. Mass spectrum (ESI, [M+H]+) m/z 396. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.71 (d, 1H, J=8.56 Hz), 7.64 (dd, 1H, J=8.75 and 1.28 Hz), 7.49 (s, 1H), 7.46 (d, 1H, J=8.09 Hz), 7.36 (t, 1H, J=7.63 Hz), 7.19-7.14 (m, 5H,), 5.91 (s, 2H), and 5.49 (s, 2H), 2.39 (s, 3H), 2.26 ppm (s, 3H),
Reaction SMILES: [CH:1]([N:4]([CH:15]([CH3:17])[CH3:16])[C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].B(O)O.[Br-].[K+].[O:23]1[CH2:28][CH2:27]OCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([N:4]([CH:15]([CH3:17])[CH3:16])[C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:27]([CH:28]=[O:23])=[CH:5][CH:6]=2)=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: CC(C)N(C(=O)Cc1ccc(Br)cc1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [Br-]
Product: CC(C)N(C(=O)Cc1ccc(-c2ccc(C=O)cc2)cc1)C(C)C

Procedure:
A mixture of 3 g of the product of Stage A, 1.66 g of boronic acid (Preparation 5), 3.5 g of monohydrated potassium phosphate, 1.32 g of potassium bromide and 300 mg of Pd(PPh3)4 (palladium tetrakis) in 50 ml of dioxane was refluxed for 12 hours. After pouring the reaction medium into a water-ice mixture, and carrying out extraction with ethyl acetate, the organic phase was dried, filtered and evaporated under reduced pressure. The crude product was purified by chromatography, eluting with a cyclohexane/ethyl acetate mixture (85/15) to obtain 1.95 g of the expected product with a Rf=0.05 (cyclohexane/ethyl acetate 85/15).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH:22]([CH3:27])[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:34](Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.O.C(OCC)(=O)C>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C@@H:21]([O:28][Si:34]([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:22]([CH3:27])[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCCCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(C)[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (3aR,4R,5R,6aS)-5-(benzoyloxy)hexahydro-4-[(1E,3S)-3-hydroxy-4-methyl-1-octenyl]-2H-cyclopenta[b]furan-2-one (3.8 g, 9.8 mmol) in DMF (177 mL) was treated with imidazole (1.34 g, 19.66 mmol) and tert-butyldiphenylsilyl chloride (5.1 mL, 19.7 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with water and Ethyl acetate. The combined organic layers were washed with water and brine, dried, concentrated. Purification by normal phase chromatography eluting with a gradient of ethyl acetate in hexane gave (3aR,4R,5R,6aS)-5-(benzoyloxy)-4-[(1E,3S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-one as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:12])=[O:11]>ClCCl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CS(=O)(=O)c1cc(CO)ccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(C=O)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Chloro-3-(methylsulfonyl)benzyl alcohol (1.0 g) was dissolved in dichloromethane (20 mL) and then active manganese(IV) oxide (4.2 g) was added and the mixture was stirred for 15 min at 22-28° C. The solid was removed by filtration and the filtrate was evaporated to dryness (yield 0.76 g). 1H-NMR (400 MHz, DMSO-d6) d=3.44 (s, 3H), 8.00 (d, J=8.2 Hz, 1H), 8.23 (dd, J=8.2 Hz, 2.2 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 10.12 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:7][C:8]1[O:9][C:10]([C:13](=[O:21])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[CH:4]([OH:6])[CH3:5].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[Si:27]([O:1][CH2:2][CH:3]([CH2:7][C:8]1[O:9][C:10]([C:13](=[O:21])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[CH:4]([OH:6])[CH3:5])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)C(CO)Cc1ccc(C(=O)Nc2ccccc2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(O)C(CO[Si](C)(C)C(C)(C)C)Cc1ccc(C(=O)Nc2ccccc2)o1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
645 mg of (2RS,3SR)-3-(hydroxymethyl)-4-{5-(phenylcarbamoyl)-2-furyl}butan-2-ol in 12 ml of dimethylformamide was mixed with 305 mg of imidazole and 372 mg of tert-butyldimethylsilyl chloride under cooling with ice and stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=3/1] to give 805 mg of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:24])[CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: Cc1cc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)ccn1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.45 min; Mass spectrum (ESI+): m/z=396 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](\[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:34]CCl>C(O)C>[ClH:34].[F:30][C:26]1[CH:25]=[C:24](/[C:16](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:15]\[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(\c2cccc(F)c2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1/C(=C/OCCN1CCC[C@@H](C(=O)O)C1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20 %

Procedure:
Z or E-(R)-1-[2-[[2-(3-Fluorophenyl)-2-(2-methylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.50 g, 0.22123 mol) (prepared as described in Method A) (opposite geometric isomer of example 9) was dissolved in ethanol (5 ml) and 12 N sodium hydroxide solution (0.3 ml) was introduced. After stirring the solution at room temperature for 5 h, 37% hydrochloric acid solution was added until the pH was measured as ca. 1. Dichloromethane (250 ml) was introduced, and the resultant precipitate was dissolved by addition of ice with vigorous stirring. The organic phase was separated, dried (Na2SO4) and evaporated to a residue, which was co-evaporated with acetone. Recrystallization from acetone provided the title compound (0.10 g, 20%) as a white solid, m.p. 193°-195°
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH:15]=2)[C:10](=[O:28])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29]>O1CCOCC1>[ClH:29].[NH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:28])[NH:9][CH:8]2[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(Cc1ccccc1)NC2=O
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1ccc2c(c1)C(Cc1ccccc1)NC2=O
Reaction time: 3 h

Procedure:
To tert-butyl 2-(3-benzyl-1-oxoisoindolin-5-yloxy)ethylcarbamate (426 mg, 1.11 mmol) was added 3 mL of dioxane and 3 mL of 4N HCl in dioxane at room temperature, this was stirred for 3 hours, then concentrated down to give 5-(2-aminoethoxy)-3-benzylisoindolin-1-one hydrochloride as HCl salt (355 mg, 100%).
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([OH:27])[C:18]=2[CH2:28][CH2:29][CH3:30])=[CH:8][CH:7]=1)C.[OH-].[Na+]>CO>[OH:27][C:19]1[C:18]([CH2:28][CH2:29][CH3:30])=[C:17]([CH:22]=[CH:21][C:20]=1[C:23]([O:25][CH3:26])=[O:24])[O:16][CH2:15][CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:5](=[O:31])[C:4]([OH:32])=[O:3])=[CH:11][CH:10]=1
Reactant: CCCc1c(OCCCOc2ccc(C(=O)C(=O)OCC)cc2)ccc(C(=O)OC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)C(=O)O)cc2)ccc(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
As in Example 19, a solution of 4-[3-[3-hydroxy-4-(methoxycarbonyl)-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.3 g) in methanol (30 mL) was treated with 4N sodium hydroxide (0.53 mL) and then was stirred at room temperature for 1 hour. Most of the solvents were removed in vacuo, then the mixture was acidified with 3N hydrochloric acid and extracted with ethyl acetate. The dried (MgSO4) extracts were evaporated and the crude acid was crystallized from a carbon tetrachloride-hexane mixture containing a small amount of dichloromethane to yield 0.164 g of 4-[3-[3-hydroxy-4-(methoxycarbonyl)-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid, as a colorless solid, mp 86°-87° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.[CH3:20][CH:21]([CH2:26][C:27](=O)[CH2:28][CH3:29])[CH2:22][C:23]([OH:25])=[O:24]>C(O)(C)C>[CH3:20][CH:21]([CH2:26][C:27]1[N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[C:12]2[C:17]([C:28]=1[CH3:29])=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCC(=O)CC(C)CC(=O)O
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)CC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the method of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphenyl)hydrazine hydrochloride and 3-methyl-5-oxoheptanoic acid as the starting materials and isopropanol as the solvent, the title compound was prepared.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Na+].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:20][C:19]3[CH:22]=[CH:23][C:16]([Br:15])=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(CN2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 29.8 %

Procedure:
A solution of N-(4-pyridyl)piperazine (0.33 g) in dry dimethylformamide (15 ml) was treated with sodium hydride (0.14 g) (45-55% dispersion in oil). The reaction mixture was then stirred for 45 minutes at ambient temperature under argon. 4-Bromobenzyl bromide (0.58 g) was added and the mixture heated slowly to 60° C. and then maintained at this temperature for 2 hours. The resulting mixture was then poured into water, basified with aq.NaHCO3 solution and then extracted with diethyl ether. The organic extracts were then washed with aq.NaHCO3, water, brine, dried (Na2SO4) and evaporated. The residue was recrystallised from acetonitrile to give 1-(4-pyridyl)-4-(4-bromobenzyl)piperazine (0.2 g) as a solid, m.p. 140-141° C.; microanalysis, found: C,55.3; H,5.2; N,12.0%; C16H18N3Br requires: C,55.4; H,5.7; N,12.1%; NMR: (CDCl3) 2.54(t,4H); 3.2(t,4H); 3.51(s,2H); 6.66(d,2H); 7.23(d,2H); 7.46(d,2H); 8.29(d,2H); MS: m/z 332 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1c(Cl)cccc1Cl
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1c(Cl)cccc1Cl
Yield: 40.4 %

Procedure:
1.12 g (4.42 mmol) of 2,6-dichlorobenzenesulfonylisocyanate and 882 mg (4.42 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 725 mg of the above-identified compound (yield 40.5%). Properties: colorless crystal, Melting point: 260°-261° C., PMR (δppm, DMSO-d6):7.18 (1H,s), 7.22 (1H,br), 7.63 (3H,br), 7.88 (1H,d), 11.83 (1H,br).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[O:30]1[C:35]2[CH:36]=[CH:37][C:38]([CH:40]=O)=[CH:39][C:34]=2[O:33][CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:40]([C:38]3[CH:37]=[CH:36][C:35]4[O:30][CH2:31][CH2:32][O:33][C:34]=4[CH:39]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc5c(c4)OCCO5)nc23)CC1)Nc1nccs1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.024 g, 0.06 mmol) and EtOH (3.0 ml) was added 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.017 g, 0.10 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.35 ml, 0.35 mmol). The reaction mixture was stirred at 80° C. for 22 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with 2% methanol in ethyl acetate/dichloromethane (v:v; 1:1) afforded a pale yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.007 g, 23%); 1H-NMR (500 MHz, DMSO-d6) 2.77 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CON), 3.73 (br s, 4H, piperazine N(CH2)2), 4.31 (s, 4H, OCH2CH2O), 7.01 (d, J=8.2 Hz, 2H, PhH), 7.24 (d, J=3.5 Hz, 1H, thiazole H), 7.48 (d, J=3.5 Hz, 1H, thiazole H), 7.69 (m, 3H, PhH)), 8.08 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.87 (s, 1H, CONH), 13.30 (br s, 1H, imidazo[4,5-b]pyridine N—H);