Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][Cl:24].[Cl-].[NH4+]>CN(C)C=O>[Cl:24][CH2:23][CH2:22][CH2:21][N:6]1[C:7](=[O:17])[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: ClCCCBr
Reactant: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c(=O)n(CCCCl)c2ccccc12
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
To a solution of 5H-dibenz[b,e]azepine-6,11-dione (3.0 g, 0.013 mol) in dry N,N-dimethylformamide (25 ml) kept under an atmosphere of nitrogen, sodium hydride (0.7 g, 0.027 mol, 60% dispersion in mineral oil) was added in portions and the reaction mixture was stirred for 1.5 hour. 1-Bromo-3-chloropropane (5.0 g, 0.031 mol) dissolved in N,N-dimethylformamide was slowly added and the mixture was stirred overnight. Ammonium chloride (2.0 g, 0.04 mol) was added and stirring was continued for 30 minutes. The solution was poured onto water (300 ml) and the mixture was extracted with dichloromethane (2×200 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (150 g) using a mixture of heptane and ethyl acetate (4:1) as eluent to give 3.1 g (79%) of 5-(3-chloropropyl)-5H-dibenz[b,e]azepine-6,11-dione as an oil.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]([C:26]([C:28]([C:44](=[O:72])[C@H:45]([CH2:53][C:54]1[CH:61]=[C:59]([I:60])[C:58]([O:62][C:63]2[CH:70]=[C:68]([I:69])[C:67]([OH:71])=[C:65]([I:66])[CH:64]=2)=[C:56]([I:57])[CH:55]=1)[NH:46]C(=O)C(F)(F)F)([CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][C:41]([NH2:43])=[O:42])[C:29]([NH2:31])=[O:30])=[O:27])[CH2:7][C:8]1[CH:15]=[C:13]([I:14])[C:12]([O:16][C:17]2[CH:24]=[C:22]([I:23])[C:21]([OH:25])=[C:19]([I:20])[CH:18]=2)=[C:10]([I:11])[CH:9]=1)=O.[OH-].[Na+].[ClH:77]>CO.C(O)C>[ClH:77].[ClH:77].[NH2:5][C@H:6]([C:26]([C:28]([C:44](=[O:72])[C@H:45]([CH2:53][C:54]1[CH:55]=[C:56]([I:57])[C:58]([O:62][C:63]2[CH:64]=[C:65]([I:66])[C:67]([OH:71])=[C:68]([I:69])[CH:70]=2)=[C:59]([I:60])[CH:61]=1)[NH2:46])([CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][C:41]([NH2:43])=[O:42])[C:29]([NH2:31])=[O:30])=[O:27])[CH2:7][C:8]1[CH:9]=[C:10]([I:11])[C:12]([O:16][C:17]2[CH:18]=[C:19]([I:20])[C:21]([OH:25])=[C:22]([I:23])[CH:24]=2)=[C:13]([I:14])[CH:15]=1
Reactant: NC(=O)CCOCCCCOCC(C(N)=O)(C(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)C(F)(F)F)C(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: NC(=O)CCOCCCCOCC(C(N)=O)(C(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 40 h

Procedure:
Bis-(trifluoroacetyl-L-thyroxyl)-4,9-dioxadodecane-1,12-diamide (example 8A), 0.34 g, was dissolved in 3ml methanol. 1M sodium hydroxide was added with stirring and the reaction was allowed to go at room temperature for 40 hours. The reaction mixture was diluted into 20 ml of cold 1M hydrochloric acid to give a fine suspension of product. The suspension was centrifuged and the pellet was dissolved in ethanol. The ethanol solution was evaporated to a solid residue of crude product. The product was recrystallized from methanol/ether to obtain 0.18 g of bis-(L-thyroxyl)-4,9-dioxa-1,12-dodecanediamide, dihydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1>C(O)(=O)C.[Pt]=O>[F:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: Fc1ccc(F)c(Cc2ccncc2)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Fc1ccc(F)c(CC2CCNCC2)c1
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A mixture of platinum oxide (0.5 g) and 4-(2,5-difluorobenzyl)pyridine from above in acetic acid (100 ml) was hydrogenated for 3 hr. The catalyst was removed and the solution concentrated in vacuo. The residue was dissolved in water and the solution basified with sodium hydroxide. The basic mixture was extracted with ether and the extracts concentrated in vacuo. The crude oil was vacuum distilled to give the product (5.1 g, 72.9%, bp: 110° C.). A sample of the hydrochloride was prepared in ether (mp: 182°-183° C.). Calc'd. for C12H15F2N.HCl: C, 58.19%; H, 6.52%; N, 5.66%. Found: C, 58.14%; H, 6.56%; N, 5.59%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([C:31]1[S:35][C:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:33][CH:32]=1)(=[O:30])=[O:29]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:39]2[CH2:38][CH2:37][N:36]([C:34]3[S:35][C:31]([S:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)(=[O:30])=[O:29])=[CH:32][N:33]=3)[CH2:41][CH2:40]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: O=S(=O)(c1ccccn1)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccn3)s2)CC1)C(F)(F)F
Yield: 68 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 45(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 68%). MS (m/e): 605.0 (M+H+, 100%).
Reaction SMILES: [CH:1]1([N:7]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=[O:17])=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO>[CH:1]1([N:7]([C@H:18]2[CH2:19][CH2:20][C@H:21]([CH3:24])[CH2:22][CH2:23]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][OH:17])=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(C=O)s2)C2CCCCC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(CO)s2)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-urea (175 mg, 0.5 mmol) in MeOH (5 mL) was added sodium borohydride (38 mg, 1 mmol). The mixture was stirred at rt for 10 min and the solution was poured into water (25 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layer was washed with water (2×20 mL), brine (1×20 mL), dried (anhydrous Na2SO4) and concentrated to get trans-1-cyclohexyl-3-(5-hydroxymethyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea in (90%, 158 mg) yield.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH:36]=[O:37])=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>ClCCl.CO>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH:36]=[O:37])=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3C=O)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3C=O)cc2)cc1)C(=O)O
Yield: 51.3 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(2′-formylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (314 mg), which is the product of Example 46, was reacted with aqueous sodium hydroxide solution (1N, 2.50 ml) and the reaction mixture was treated to afford the crude free acid which was subjected to chromatography on a silica gel thin layer plate using dichloromethane/methanol=10/1 as the eluant to give the title compound (152 mg) as a mass of foam.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc(Sc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: The solution of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid in 50 ml of water containing 0.4 g of sodium hydroxide is adjusted to pH = 7.4 by the addition of 4N aqueous sodium hydroxide whereupon 1.3 g of benzylchloride are added while stirring under nitrogen. As soon as the pH remains constant the mixture is filtered and the filtrate acidified with glacial acetic acid to a pH of 4-5. The precipitate formed is recrystallized from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-benzylamino-5-sulfamoylbenzoic acid melting at 255°-258°.
Reaction SMILES: C([O:8][C:9]1[CH:40]=[CH:39][C:12]([C:13]([NH:15][C:16]([CH3:38])([CH3:37])[C:17](=[O:36])[N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:20][CH2:19]2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[Pd].C(OCC)(=O)C>[CH3:38][C:16]([NH:15][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:40][CH:39]=1)([CH3:37])[C:17](=[O:36])[N:18]1[CH2:19][CH2:20][N:21]([C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:32])([F:34])[F:33])[CH2:22][CH2:23]1
Reactant: CC(C)(NC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1ccc(O)cc1)C(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Pd/c (20 mg) was added to a stirred solution of 4-benzyloxy-N-{1,1-dimethyl-2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide (70 mg, 0.12 mmol) in a mixture methanol (2 mL) and ethyl acetate (5 ml) and stirring was continued at room temperature under hydrogen atmosphere for 2 hrs. The mixture was filtered over a bed of celite. The celite was washed with methanol and the filtrate was concentrated under reduced pressure to afford 50 mg (86.2% yield) of N-{1,1-dimethyl-2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-hydroxy-benzamide. LCMS Purity: 95.26%. 1H NMR (DMSO): δ 8.2-8.3 (bs, 1H), 7.5-7.9 (m, 6H), 7.4 (d, 2H), 6.8 (d, 2H), 3.5 (m, 6H), 3 (m, 2H), 1.4 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH:5]2[N:4]=[C:3]1[C:17]([F:20])([F:19])[F:18].Cl>CO.C(OCC)(=O)C>[CH3:1][N:2]1[C:6]2[CH2:7][NH:8][CH2:9][C:5]=2[N:4]=[C:3]1[C:17]([F:19])([F:18])[F:20]
Reactant: CN1C(C(F)(F)F)=NC2CN(C(=O)OC(C)(C)C)CC21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1c(C(F)(F)F)nc2c1CNC2
Reaction time: 2 h

Procedure:
To the product from Step A in 2 mL of methanol was added 2 mL of saturated hydrochloric acid in ethyl acetate. After stirring for 2 h the reaction was concentrated in vacuo and the residue purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (20% methanol/ethyl acetate, 2% ammonium hydroxide) to give the title compound as a white solid. LC/MS 192.2 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:13]1([CH2:12][O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][O:1][C:5]=3[CH:6]=2)[CH2:15][CH2:14]1
Reactant: Oc1ccc2ncoc2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1nc2ccc(OCC3CC3)cc2o1
Temperature: 60 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A mixture of 1,3-benzoxazol-6-ol (2.31 g), (bromomethyl)cyclopropane (3.46 g), potassium carbonate (3.54 g) and DMF (25 mL) was stirred at 60° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined 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 (2.88 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][S:8]([C:11]2[C:12](=[O:25])[O:13][C:14]3[C:19]([CH:20]=2)=[C:18](OC)[CH:17]=[C:16](OC)[CH:15]=3)(=[O:10])=[O:9])=[CH:5][CH:4]=1.COC1C=CC(CS(C2C(=O)OC3C(C=2)=CC([N+]([O-])=O)=CC=3[N+]([O-])=O)(=O)=O)=CC=1.ClC1C=CC(CS(C2C(=O)OC3C(C=2)=CC=CC=3)(=O)=O)=CC=1.ClC1C=C(Cl)C=CC=1CS(C1C(=O)OC2C(C=1)=CC=CC=2)(=O)=O.COC1C=CC(CS(C2C(=O)OC3C(C=2)=CC(Br)=CC=3)(=O)=O)=CC=1.COC1C=CC(CS(C2C(=O)OC3C(C=2)=CC(Cl)=CC=3)(=O)=O)=CC=1.COC1C=CC(CS(C2C(=O)OC3C(C=2)=CC=C(OC)C=3)(=O)=O)=CC=1.COC1C=CC(CS(C2C(=O)OC3C(C=2)=CC=C(O)C=3)(=O)=O)=CC=1.COC1C=CC(CS(C2C(=O)OC3C(C=2)=C(OC)C=C(OC)C=3)(=O)=O)=CC=1[N+]([O-])=O.COC1C=CC(CS(C2C(=O)OC3C(C=2)=CC=C(OC)C=3)(=O)=O)=CC=1[N+]([O-])=O.COC1C=CC(CS(C2C(=O)OC3C(C=2)=CC=C(O)C=3)(=O)=O)=CC=1[N+]([O-])=O.ClC1C=CC(CS(C2C(=O)OC3C(C=2)=CC(Cl)=CC=3)(=O)=O)=CC=1[N+]([O-])=O.ClC1C=CC(CS(C2C(=O)OC3C(C=2)=CC(Cl)=CC=3)(=O)=O)=CC=1N>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8]([C:11]2[C:12](=[O:25])[O:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:10])=[O:9])=[CH:26][CH:27]=1
Reactant: COc1ccc(CS(=O)(=O)c2cc3c(OC)cc(OC)cc3oc2=O)cc1
Agent: COc1cc(OC)c2cc(S(=O)(=O)Cc3ccc(OC)c([N+](=O)[O-])c3)c(=O)oc2c1
Agent: COc1ccc(CS(=O)(=O)c2cc3cc(Br)ccc3oc2=O)cc1
Agent: COc1ccc(CS(=O)(=O)c2cc3cc(Cl)ccc3oc2=O)cc1
Product: COc1ccc(CS(=O)(=O)c2cc3ccccc3oc2=O)cc1

Procedure:
3-(4-methoxybenzylsulfonyl)-5,7-dimethoxy-2H-chromen-2-one; 3-(4-methoxybenzylsulfonyl)-6,8-dinitro-2H-chromen-2-one; 3-(4-chlorobenzylsulfonyl)-2H-chromen-2-one; 3-(2,4-dichlorobenzylsulfonyl)-2H-chromen-2-one; 3-(4-methoxybenzylsulfonyl)-6-bromo-2H-chromen-2-one; 3-(4-methoxybenzylsulfonyl)-6-chloro-2H-chromen-2-one; 3-(4-methoxybenzylsulfonyl)-7-methoxy-2H-chromen-2-one; 3-(4-methoxybenzylsulfonyl)-7-hydroxy-2H-chromen-2-one; 3-(4-methoxy-3-nitrobenzylsulfonyl)-5,7-dimethoxy-2H-chromen-2-one; 3-(4-methoxy-3-nitrobenzylsulfonyl)-7-methoxy-2H-chromen-2-one; 3-(4-methoxy-3-nitrobenzylsulfonyl)-7-hydroxy-2H-chromen-2-one; 3-(4-chloro-3-nitrobenzylsulfonyl)-6-chloro-2H-chromen-2-one; 3-(4-chloro-3-aminobenzylsulfonyl)-6-chloro-2H-chromen-2-one; mixtures thereof; and salts thereof.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[O:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1.C(OCC)C>O1CCOCC1.O>[CH3:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:15]=[C:14]2[CH2:13][CH2:12][OH:11]
Reactant: C1=COCC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc2[nH]cc(CCO)c2c1
Temperature: 95 °C
Yield: 17.6 %

Procedure:
To a suspension of 4-methylphenylhydrazine hydrochloride (2.50 g, 15.7 mmol) in 1,4-dioxane (25 mL) and water (1.5 mL) was dropped neat 2,3-dihydrofuran (1.66 g, 23.6 mmol). After the addition, the mixture was heated at 95° C. for 4 hours. After cooling to room temperature, it was poured into ethyl ether, dried over magnesium sulfate, evaporated to dryness. Flash chromatography on silica gel provided 0.485 g (18%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 7.95 (br, 1H), 7.41 (s, 1H), 7.27 (d, 1H), 7.05 (m, 2H), 3.90 (dd, 2H), 3.01 (t, 2H), 2.46 (s, 3H), 1.50 (t, br, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:36]=[CH:35][CH:34]=[CH:33][C:15]=2[O:16][CH:17]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18]2=[O:32])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37].C=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].O1CCCC1>[ClH:37].[CH3:6][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:36]=[CH:35][CH:34]=[CH:33][C:15]=2[O:16][CH:17]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=3)[C:18]2=[O:32])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCN(c3ccc(C(F)(F)F)cc3)C2=O)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN(c2ccccc2OC2CCN(c3ccc(C(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 50 mL round-bottomed flask equipped with N2 inlet were added 320 mg (0.634 mmol) 3-[2-(4-t-butoxycarbonyl-piperazin-1-yl)-phenoxy]-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one and 15 mL dry ethyl acetate. The reaction was saturated with dry HCl and stirred at room temperature for 2 hours. The reaction was evaporated and azeotroped with ether to afford a solid residue that was used directly as follows: To the residue in a 50 mL round-bottomed flask equipped with N2 inlet were added 10 mL dry tetrahydrofuran, 0.109 mL (1.45 mmol) of a 37% solution of formaldehyde in water, 0.041 mL (0.723 mmol) acetic acid, and 306 mg (1.45 mmol) sodium triacetoxyborohydride. The reaction was stirred at room temperature overnight, then diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated. The residue was dissolved in ethyl acetate and the product extracted into 1N aqueous HCl; then the aqueous layer, after washing 2 times with ethyl acetate, was basified with solid potassium carbonate and extracted 3 times with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The resulting oil was dissolved in ethyl acetate and treated with 2 mL of a solution of ethyl acetate saturated with HCl, then evaporated to a solid, 37 mg (13%), mp 137–162° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][N:33]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 50.2 %

Procedure:
The compound was prepared from tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.548 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (129 mg, 0.548 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (143 mg, 50%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=8.0 Hz, 1H), 7.43-7.29 (m, 6H), 7.01 (d, J=7.9 Hz, 1H), 6.05-6.02 (m, 2H), 5.02 (s, 2H), 4.64 (br s, 2H), 3.84 (br s, 2H), 3.63 (s, 3H), 2.82 (br s, 2H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:12])[C:5]([O:7][CH3:8])=[O:6].[C:13](O)(=[O:17])[C:14]([CH3:16])=[CH2:15].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>ClCCl.CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([I:12])=[C:2]([NH:1][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])[CH:3]=1
Reactant: C=C(C)C(=O)O
Reactant: COC(=O)c1ccc(I)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)C(=O)Nc1cc(C(=O)OC)ccc1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred suspension of Methyl 3-amino-4-iodobenzoate (1.67 g, 6 mmol) and Methacrylic acid (568 mg, 6.6 mmol) in dichloromethane (60 mL) and DMF (60 mL) were added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HAM) (2.5 g, 6.6 mmol) and then a solution of N,N-diisopropylethylamine (1.16 g, 1560 μL, 9 mmol) in DMF (20 mL). The reaction mixture was stirred at ambient temperature for 24 h. The reaction medium was acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), and concentrated to give the amide which was purified by flash chromatography (AcOEt/heptane: 5/5).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16](C)(C)[O:17][SiH2]C(C)(C)C)[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].O[Li].O>O>[OH:17][CH2:16][C:10]1[CH:9]=[C:8]([C:5]2([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COC(=O)C1(c2ccc(OC)c(C(C)(C)O[SiH2]C(C)(C)C)c2)CC1
Agent: [Li]O
Solvent: O
Product: COc1ccc(C2(C(=O)O)CC2)cc1CO
Temperature: 40 °C
Reaction time: 8 h
Yield: 132.5 %

Procedure:
To a solution of 1-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenyl]-cyclopropane carboxylic acid methyl ester (6.2 g, 18 mmol) in Me (75 mL) was added a solution of LiOH.H2O (1.5 g, 36 mmol) in water (10 mL) at 0° C. The reaction mixture was stirred overnight at 40° C. MeOH was removed by evaporation under vacuum. AcOH (1 mol/L, 40 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to provide 1-(3-hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid (5.3 g).
Reaction SMILES: O[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1.O=P(Cl)(Cl)[Cl:23]>C(N(CC)CC)C>[Cl:23][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ccc(-c2c(-c3ccccc3)noc2O)cc1
Solvent: CCN(CC)CC
Product: CSc1ccc(-c2c(-c3ccccc3)noc2Cl)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-hydroxy-4(4-methylsulfanylphenyl)-3-phenyl isoxazole (Compound prepared in step 1) (0.6 g) and triethyamine (0.43 mL) was added POCl3 (10 mL) under stirring and the reaction mixture was heated to 70° C. for 4 h. Solvents were evaporated and the crude product was chromatographed over silicagel using petroleum ether as eluent to yield 310 mg of product as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[NH:9][C:8](=[O:15])[C:7](=[O:16])[NH:6]2)[CH3:2].FC(F)(F)C(O)=O.[N+:24]([O-])([O-:26])=[O:25].[K+]>O>[N+:24]([C:11]1[C:12]([CH2:13][CH3:14])=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]2[C:10]=1[NH:9][C:8](=[O:15])[C:7](=[O:16])[NH:6]2)([O-:26])=[O:25]
Reactant: CCc1cc2[nH]c(=O)c(=O)[nH]c2cc1CC
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1CC
Yield: 69.1 %

Procedure:
6,7-Diethyl-2,3-quinoxalinedione 25 (218 mg, 1.0 mmol) was added to trifluoroacetic acid (8 mL; Sigma). To this suspension was added potassium nitrate (121.2 mg, 1.2 mmol; Baker) in one portion with stirring under N2. The reaction was stirred at room temperature for 48 h. Trifluoroacetic acid was evaporated in vacuo to give a residue. Water (10 mL) was added to this residue with vigorous stirring. A yellow solid precipitated, which was collected by suction filtration and dried in vacuo to give 182 mg (69%) of the title compound 26 as a yellow solid; mp 270-272° C. (dec.); 1H NMR (DMSO-d6, 300 MHz) δ 1.137 (m, 6H), 2.622 (m, 4H), 7.088 (s, 1H), 11.762 (s, 1H), 12.028 (s, 11H). EIMS m/e 263 (100, M+). (HPLC purity 100%).