Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][C:14]2[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[C:9]([F:12])([F:11])[F:10])=[CH:4][N+:3]=1[O-].O.C(=O)([O-])[O-:34].[K+].[K+]>C(OC(=O)C)(=O)C>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:4]=[N:3][C:2]([CH2:1][OH:34])=[CH:7][CH:6]=1)[O:13][C:14]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[N:22][C:21]2[C:16]([N:15]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: O=C([O-])[O-]
Reactant: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccc(C)[n+]([O-])c1)C(F)(F)F
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccc(CO)nc1)C(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 29.9 %

Procedure:
Compound B2 (103 mg, 0.226 mmol) obtained in Step 2 was suspended in acetic anhydride (1.0 mL) and the suspension was stirred at 100° C. for 1.5 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in methanol (2.0 mL). Potassium carbonate (93.7 mg, 0.678 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and a saturated aqueous ammonium chloride solution and water were added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) and further purified by preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to give Compound 31 (30.8 mg, 30% yield).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10](Br)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:27])=[C:23]([CH:26]=1)[CH:24]=[O:25].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:27])=[C:23]([CH:24]([C:10]2[CH:9]=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=2)[OH:25])[CH:26]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: Brc1cnn(-c2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1cnn(-c2ccccc2)c1)c1cc(Br)ccc1Cl
Reaction time: 5 h

Procedure:
A solution of 1-phenyl-4-bromopyrazole (see M. A. Khan, et al., Can. J. Chem., (1963) 41 1540) (2.23 g) in diethyl ether (30 ml) wad cooled to −78° C. under argon atmosphere, and added dropwise thereto was n-butyl lithium (1.59 M hexane solution, 6.9 ml). The mixture was stirred at −20° C. to −10° C. for 5 hours, and added dropwise thereto at the same temperature was a solution of 5-bromo-2-chlorobenzaldehyde (2.19 g) obtained in Reference Example 16-(1) in diethyl ether (30 ml). The mixture was stirred at the same temperature for 30 minutes, and added thereto was tetrahydrofuran (30 ml), and the mixture was stirred at 0° C. for further 30 minutes. A saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=83:17-80:20) to give 5-bromo-2-chlorophenyl-1-phenyl-4-pyrazolylmethanol (831 mg) as yellow oil. APCI-Mass m/Z 363/365 (M+H). (2) The above 5-bromo-2-chlorophenyl-1-phenyl-4-pyrazolylmethanol was treated in a manner similar to Reference Example 120-(2) to give the desired 5-bromo-2-chloro-1-(1-phenyl-4-pyrazolylmethyl)benzene as colorless powder. APCI-Mass m/Z 347/349 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]1.[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:5]1)[CH:19]=[CH2:18]
Reactant: O[C@@H]1CCC[C@H](OCc2ccccc2)C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1CCC[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under an atmosphere of argon, 12 g of sodium hydride (55-65%) are initially charged in 200 ml of abs. DMF, and the mixture is stirred at RT for 10 min. With ice-cooling, 54 g of benzyl (1S,3R)-3-hydroxycyclohex-1-yl ether in 70 ml of DMF are added dropwise. The mixture is stirred at RT for 90 min. With ice-cooling, 50 g of allyl bromide are slowly added dropwise. After the addition has ended, the mixture is stirred at 45° C. for 1 h. According to TLC, the reaction is complete. The reaction solution is quenched with 15 ml of iPrOH, diluted with water and sat. NaCl solution and extracted with MTBE. The combined organic phases are washed with water and NaCl solution, dried over MgSO4 and concentrated. This gives 60 g of benzyl (1S,3R)-3-allyloxycyclohex-1-yl ether as a light-beige oil. C16H22O2 (246.35), MS (ESI): 247 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])(=[O:20])=[O:19])[CH2:9][CH2:8]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:28](=[O:30])[CH3:29])(=[O:20])=[O:19])[CH2:11][CH2:12]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1
Product: CC(=O)Nc1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mol of N-(4-(4-(2-pyrimidinyl)-1-piperazin- yl)butyl)-2-aminobenzenesulphonamide and 0.5 mol of acetic anhydride are stirred at room temperature for 2 hours. The mixture is evaporated to dryness, concentrated aqueous ammonia solution is poured onto the residue and the base is extracted by shaking with methylene chloride. Purification is carried out by chromatography on silica gel; the eluting agent is CH2Cl2 /CH3OH (9:1). The substance is recrystallised from isopropanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.NC1C=CC=CC=1.C1(=O)OC(=O)CCC1.C(Cl)(=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:20])[CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[CH2:12][C:13]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(CC(=O)Nc1ccc(Br)cc1)C(F)(F)F
Agent: O=C1CCCC(=O)O1
Solvent: Nc1ccccc1
Solvent: CC(=O)Cl
Product: O=C1CC(C(F)(F)F)CC(=O)N1c1ccc(Br)cc1
Yield: 78.5 %

Procedure:
Into a 50 ml 1-necked, round-bottomed flask containing a stir bar were placed 2.50 g (7.96 mmol) N-(4'-bromophenyl)-3-(trifluoromethyl)glutaramic acid (prepared as described in Example 1 from the appropriate aniline and glutaric anhydride) and acetyl chloride (15 ml). The mixture was heated to reflux for 6 hours resulting in a clear, light grey solution. The acetyl chloride was removed via atmospheric distillation through a short path distillation head. The resulting light grey crystalline solid was triturated with hexanes, filtered and washed with hexanes to yield an off-white crystalline solid which was dried in vacuo at 50° C. to yield 2.10 g (89% yield) of product, m.p. 163°-4° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(N(C(C)C)CC)(C)C>CC#N>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3ccccc3o2)c1
Temperature: 25 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone (40 mg, 122 μmol), 2-chlorobenzoxazole (38 mg, 245 μmol) and diisopropylethyl amine (DIPEA; 43 μL, 245 μmol) in CH3CN (2 mL) was heated at reflux overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHCO3, brine, and dried (MgSO4). The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 442 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)([CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:32][OH:33]>>[OH:33][NH:32][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:10])=[O:11])([CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCC#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Product: CCCCCC#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 67 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide was prepared according to the procedure outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid (0.71 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.48 g of the product was isolated. Yield 67%; off-white solid; mp 65° C.; MS: 445.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ0.84 (t, J=6.8 Hz, 3H), 1.10-1.40 (m, 6H), 1.85-2.00 (m, 2H), 2.79 (d, J=17.9 Hz, 1H), 2.90 (d, J=17.9 Hz, 1H), 3.50 (d, J=13.7 Hz, 1H), 3.74 (d, J=13.7 Hz, 1H), 3.89 (s, 3H), 7.19 (d, J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.85-7.89 (m, 1H), 8.37-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm−1): 3157m, 3095m, 2954s, 2932s, 2858m, 1671m, 1593s; Anal. Calc'd for C23H28N2O5S.HCl.0.9H2O: C, 55.56; H, 6.24; N, 5.63. Found: C, 55.84; H, 6.19; N, 5.59.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:12]1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(Ethoxycarbonylmethyl)piperazine (5.1 g) was dissolved in tetrahydrofuran (300 ml) under a nitrogen atmosphere, and then triethylamine (8.25 ml) and benzoyl chloride (3.44 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 4 hrs. The reaction mixture was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (100 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml), water (100 ml), brine (100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to provide the titled compound (8.19 g, quant.) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:9])=[C:6]([S:11][C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step G, using equimolar amounts of 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylthio)benzoic acid, 4-nitrophenol, and dicyclohexylcarbodiimide in methylene chloride, yielding 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylthio)benzoate.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:16][CH2:1][CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCCCCCCCCC=CCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCCCCCCCC=CCCCOS(C)(=O)=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,14-pentadecadien-1-ol (15.0 g) and triethylamine (14 ml.) in dry methylene chloride (320 ml.) at -8° C. is added methanesulfonylchloride (5.73 ml.), dropwise. The reaction mixture is stirred at -10° C. for 30 minutes and then diluted with methylene chloride, extracted with ice-water (250 ml.), followed by cold 10% HCl (200 ml.); cold saturated sodium bicarbonate (200 ml.) and cold brine (200 ml.). The organic phase is dried (MgSO4) and the solvent removed in vacuo to provide 4,14-pentadecadien-1-yl methanesulfonate as a clear oil.
Reaction SMILES: [C:1]([C:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([S:24]([NH:9][C:3]2([C:1]#[CH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: C#CC1(N)CCCCC1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC1(NS(=O)(=O)c2cccc(Cl)c2)CCCCC1
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of 1-ethynylcyclohexanamine (40 mg, 0.32 mmol) in CH2Cl2, was added triethylamine (68 mL, 0.48 mmol), followed by 3-chlorobenzenesulfonyl chloride (68.2 mg, 0.32 mmol). After 30 min, the mixture was partitioned between ethyl acetate and 3N aq. HCl. The organic layer was washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated in vacuuo to give the title compound as a white solid (90 mg, 93% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:4]=1.Cl.[N:37]1([C:42]([NH2:44])=O)C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:5]2[N:4]=[C:3]([CH2:2][NH:1][C:42]([NH2:44])=[NH:37])[CH:7]=[N:6]2)=[O:30])[N:17]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CN)n1)c1csc(N)n1)C(=O)O
Reactant: NC(=O)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CNC(=N)N)n1)c1csc(N)n1)C(=O)O
Reaction time: 16 h
Yield: 14.7 %

Procedure:
To a solution of 2-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (60 mg, 0.089 mmol) and pyrazole-1-carboxamide hydrochloride (16 mg, 0.11 mmol) in DMF (3 mL) was added DIPEA (45 μL, 0.27 mmol). After stirring for 16 h, the solution was concentrated and washed with ether. The crude residue was purified by reverse phase prep HPLC (XBridge, 30×150 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (7.5 mg, 15%) as a white solid. LCMS: m/z=571.9 (M−1); 1H NMR (400 MHz, D2O): δ 7.55 (s, 1H), 6.78 (s, 1H), 5.38 (d, J=5.2 Hz, 1H), 4.82-4.76 (m, 1H assumed; obscured by solvent residual peak), 4.76-4.72 (m, 2H assumed; obscured by solvent residual peak), 4.32 (s, 2H), 1.15 (s, 3H), 1.14 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:6]2=O)[CH3:2].O.[NH2:27][NH2:28]>C(O)C>[CH2:1]([C:3]1[C:12]([OH:13])=[CH:11][C:10]([OH:9])=[C:5]([C:6]2[C:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[C:8]([C:14]([OH:16])=[O:15])[NH:27][N:28]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)c(-c3ccc(OC)cc3)c(C(=O)O)oc2cc1O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1cc(-c2n[nH]c(C(=O)O)c2-c2ccc(OC)cc2)c(O)cc1O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
6-Ethyl-7-hydroxy-3-(4-methoxyphenyl)-4-oxo-chromene-2-carboxylic acid (13.6 g, 41.73 mmol) and hydrazine monohydrate (6.1 ml, 125.19 mmol) were suspended in ethanol (200 ml) at room temperature. The mixture was then heated slowly to 70° C. and stirred at this temperature for 4 hours. The mixture was cooled to room temperature and all volatile components were removed in vacuum. The residue was partitioned between water (11) and Ethyl acetate (1.41). Then the aqueous phase was separated. The organic phase yielded some product. The remainder of the product was extracted from the aqueous phase with Ethyl acetate (4×500 ml). The combined organic extracts were dried over Magnesium sulfate and evaporated to dryness under vacuum resulting in a further quantity of the desired product. The combined isolated product portions yielded 6.99 g (51%) of a light brown solid. 1H NMR Spectrum: δH (400 MHz, DMSO-6d) 0.84 (3H t, J=7.5 Hz), 2.23 (2H q, J=7.5 Hz), 3.38 (1H s, br), 3.74 (3H, s), 6.36 (1H, s), 6.56 (1H, s), 6.85 (2H d, J=8.7 Hz), 7.13 (2H d, J=8.7 Hz), 9.3 (1H s, br), 9.4 (1H s, br), 12.8 (1H s, br); Mass Spectrum: (M+H+) 355.04, (M+H−) 353.09.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C@H:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1.[H][H].[ClH:26]>C(O)C.[Pd].CCOCC>[ClH:26].[ClH:26].[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C@H:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C@H:4]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: CN1CC[C@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CN1CC[C@H](Oc2ccc(N)cc2)[C@H](c2ccccc2)C1
Reaction time: 48 h

Procedure:
A solution of 3.7 g of the free base of cis-1-methyl-4-(4-nitrophenoxy)-3-phenylpiperidine, of Example 7, in 100 ml of absolute ethanol is hydrogenated over 0.37 g of 10% Pd on carbon catalyst at 45 psi of hydrogen and room temperature. Uptake stops after 48 hours. The catalyst is filtered off and the filtrate is concentrated in vacuo to a gum. This material is chromatographed on silica gel using acetone and then 25% methanol/acetone as solvent. A purified free base is obtained and a portion of this material is dissolved in ether and is then added dropwise to a solution of dry HCl in ether. The resulting precipitate is filtered, washed with ether, and is then immediately suspended in boiling ether. Absolute ethanol is added until the mixture grows clear. Scratching of the cold solution causes crystallization to occur. The recrystallized solid is filtered, washed with cold acetone, then ether, and dried to afford a solid (m.p. 226°-227° C. dec.) of cis-4-(4-aminophenoxy)-1-methyl-3-phenylpiperidine dihydrochloride.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:10]([O:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[C:1](=[O:3])[NH2:2])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Solvent: c1ccncc1
Product: NC(=O)c1[nH]cnc1OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
To a suspension of 455 mg of 4-carbamoylimidazolium-5-olate in 5 ml of dry pyridine was added 1.02 g of benzoyl chloride at a temperature below 5° C. After addition was over, the mixture was stirred under ice cooling for 2 hours. Then separated crystals were filtered off, washed with water and ether, dried to give 5-carbamoyl-1H-imidazol-4-yl benzoate, m.p. 204° C. (dec.).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([O:23][CH3:24])[CH:16]=2)[C@H:10]1[CH2:25][CH3:26])(C(C)(C)C)(C)C.C(O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:25]([C@H:10]1[C@H:9]([OH:8])[CH2:13][C:12](=[O:14])[N:11]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([O:23][CH3:24])[CH:16]=1)[CH3:26]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-methoxybenzonitrile (1.04 g) in tetrahydrofuran (30 mL)-ethanol (15 mL) was added 6 mol/L hydrochloric acid (15 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=5/1→0/1) to give the title compound as a colorless solid (yield: 528.3 mg, 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[NH2:19])([O-:3])=[O:2].Br[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=1[F:31].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[F:31][C:22]1[C:21]([C:8]2[CH:7]=[CH:6][C:5]([NH2:19])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=2)=[C:26]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:24][CH:23]=1
Reactant: Fc1cccc(C(F)(F)F)c1Br
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 2-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (264 mg, 1.00 mmol, as prepared in Example 17, step A) and 2-bromo-1-fluoro-3-trifluoromethyl-benzene (243 mg, 1.00 mmol) in DME (5 mL) and 2 M aqueous Na2CO3 (4 mL, 8 mmol) was degassed via sonication, placed under argon and treated with Pd (PPh3)4 (115 mg, 0.100 mmol). The resulting mixture was heated at 80° C. for 16 h and allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (10 mL) and washed twice with water (10 mL). The aqueous layer was extracted with additional EtOAc (10 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica (EtOAc/hexanes, 0:100 to 50:50, v/v) to yield 6′-fluoro-3-nitro-2′-trifluoromethyl-biphenyl-4-yl-amine.