Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([NH:16][C@@H:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:18]3[CH:23]=[CH:22][C:21]([P:24]([CH3:29])(=[O:28])[O:25]CC)=[CH:20][CH:19]=3)=[O:15])=[CH:9][N:8]=2)[CH:6]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[C:11]([OH:13])[C:10]([C:14]([NH:16][C@@H:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:18]3[CH:19]=[CH:20][C:21]([P:24]([CH3:29])(=[O:25])[OH:28])=[CH:22][CH:23]=3)=[O:15])=[CH:9][N:8]=2)[CH:6]=1
Reactant: CCOP(C)(=O)c1ccc([C@@H](NC(=O)c2cnc(-n3cc(F)cn3)nc2O)c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc([C@@H](NC(=O)c2cnc(-n3cc(F)cn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 39 %

Procedure:
A solution of 28-h (3.8 g, 7.4 mmol) in 25 ml of dioxane was treated with 7.2 ml of 3N NaOH and heated at 80° C. for one hour. The mixture was cooled to room temperature and then concentrated under vacuum and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with conc. HCl to pH=1 and the resulting solid was collected via filtration to give compound 28-1 (1.4 g of crude), which was further purified via prep-HPLC (150 mg, 4%). 1H NMR (300 MHz, CD3OD): δ 8.72 (s, 1H), 8.17 (s, 1H), 7.81 (m, 3H), 7.43 (m, 2H), 7.20 (m, 2H), 7.11 (m, 2H), 6.71 (s, 1H), 1.65 (d, 3H). (M+H)+=486.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[N:12][CH:11]=[C:10]([CH:9]=2)[C:20]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: COc1cc(CN)on1
Agent: Cl
Product: COc1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-82-5) and 3-methoxy-5-isoxazolemethanamine hydrochloride as starting materials, LC-MS (UV peak area/ESI) 100%, 442.079 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:7][CH2:8][CH2:9][CH2:10][C:11]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: c1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCCl)c1ccccc1
Yield: 881 %

Procedure:
Benzene (0.5 mg), 4-chlorobutyryl chloride (141 mg), and aluminium chloride (170 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (10.3 mg).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:34])[C:23]([C:31]([OH:33])=[O:32])=[CH:24][N:25]4[CH:28]4[CH2:30][CH2:29]4)=[CH:20][C:19]=3[F:35])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2)=O)(C)(C)C.[ClH:36]>>[ClH:36].[NH2:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:34])[C:23]([C:31]([OH:33])=[O:32])=[CH:24][N:25]4[CH:28]4[CH2:29][CH2:30]4)=[CH:20][C:19]=3[F:35])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2
Reactant: CC(C)(C)OC(=O)NCC12CN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)CC1CCO2
Agent: Cl
Product: NCC12CN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)CC1CCO2

Procedure:
In an analogous manner to Example 1B, the product from step A is reacted with half-concentrated hydrochloric acid to give 7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]-oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride with a melting point of 223°-226° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C(C1C=CC(S([N:36]=[N+:37]=[N-:38])(=O)=O)=CC=1)CCCCCCCCCCC.[NH4+].[Cl-]>O1CCCC1>[N:36]([C:4]1[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[N+:37]=[N-:38]
Reactant: CC(C)(C)C(=O)Nc1ccc(F)cn1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc(F)cc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
To a −78° C. solution of N-(5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (1.34 g, 6.83 mmol) in tetrahydrofuran (25 mL) was added tert-butyl]ithium (1.31 mL of a 1.7 M solution, 20.5 mmol) drop wise. After 3 h at −78° C., 4-dodecylbenzenesulfonyl azide (3.60 g, 10.2 mmol) was added at the reaction was allowed to warm to room temperature. After 1 h, saturated aqueous NH4Cl was added, and the tetrahydrofuran was removed via rotary evaporator. Dichloromethane was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by two successive silica gel chromatographies (10%→80% EtOAc/hexanes, then 5%→42% EtOAc/hexanes) to give the title compound (0.275 g). MS 234.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.CC(C)([O-])C.[K+].C[N:18](C)C=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH2:18]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Nc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 1 h

Procedure:
1-chloro-3-nitrobenzene (3.1 g, 0.0197 mol) and o-methoxylamine hydrochloride (2.02 g, 0.0236 mol) were dissolved in N,N-dimethylformamide (15 mL). The solution was added drop wise in 15 min to a suspension of cuprous chloride and potassium tert-butoxide (11.07 g, 0.965 mol) in N,N-dimethylformamide (15 mL) cooled in a 15° C. bath. The cold bath was removed; the mixture was allowed to come to RT and stirred for 1 h. The reaction was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (4×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, concentrated under vacuum and purified by silica gel column chromatography to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 8.020-7.994 (dd, J=8.8 Hz, 10.4 Hz, 1H), 7.696-7.674 (dd, J=7.2 Hz, 8.8 Hz, 1H), 7.229 (bs, 1H), 6.705-6.664 (t, J=8.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](OC(=O)CC)(=O)[CH2:14][CH3:15].[OH-].[Na+]>Cl>[CH2:14]([C:15]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:13]
Reactant: Nc1cnc2ccccc2c1S
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc2cnc3ccccc3c2s1
Yield: 90 %

Procedure:
A mixture of 17.62 g (0.1 mole) of 3-amino-4-mercapto-quinoline and 85 ml of propionic anhydride is first slowly heated to boiling and then refluxed for one hour and a half. The reaction mixture is added dropwise to 800 ml of 1% aqueous hydrochloric acid under vigorous stirring. The homogenous solution is made alkaline to pH 10 by adding sodium hydroxide solution and extracted three times with 200 ml of benzene each. The benzene solution is evaporated. Thus 19.26 g of 2-ethylthiazolo[4,5-c]quinoline are obtained, yield 90%, m.p.: 48°-49° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[N:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1cncc(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cncc(CO)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
5-Amino-nicotinic acid methyl ester (5.7 g, 30.2 mmol) was dissolved in THF (150 ml) and LiAlH4 (1M in THF solution 133 ml, 133 mmol) added slowly at 0° C. The reaction mixture was stirred at room temperature for 21 h. The reaction mixture was quenched and acidified to pH 3 using dilute HCl, and basified (pH 8) using solid Na2CO3. Solvents were removed under reduced pressure. The residue was filtered through silica gel using 20% MeOH/DCM yielding the product 3.8 g, (100%) with LCMS purity 97%, m/z 125 [M++H]+, by ELS.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[CH:4]=[C:3]1[C:10]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:11].[CH3:21][N:22]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]1[C:30](Cl)=[O:31]>CO.C(Cl)Cl.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:30]([C:23]2[N:22]([CH3:21])[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=2)=[O:31])[CH:4]=[C:3]1[C:10]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:11]
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)NCCN1CCOCC1
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)NCCN1CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-Methyl-N-[2-(4-morpholinyl)ethyl]-4-nitro-1H-pyrrole-2-carboxamide (1.42 g, 3.41 mmol; see step (iii) above) was dissolved in methanol (10 mL) and cooled to 0° C., Pd/C (0.055 g) was then added in small portions and the solution stirred under H2 for 3 h. The solution was then filtered and the solvent removed under reduced pressure. A solution of 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (0.642 g, 3.42 mmol) in DCM (10 mL) was added and the mixture allowed to stir for 1 h at RT. The solvent was then removed under reduced pressure and the crude product was separated on basified silica using a 1:1 solution of methanol ethyl acetate to yield the sub-title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>>[I:25][C:26]1[CH:27]=[C:28]([NH:29][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4cccc(I)c4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 3-iodoaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 535 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.F[C:25]1[C:30]([CH:31]2[CH2:35][CH2:34][C:33]([CH3:37])([OH:36])[CH2:32]2)=[CH:29][CH:28]=[CH:27][N:26]=1>CN1C(=O)CCC1.O>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:25]2[C:30]([CH:31]3[CH2:35][CH2:34][C:33]([CH3:37])([OH:36])[CH2:32]3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: CC1(O)CCC(c2cccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(O)CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Temperature: 180 °C

Procedure:
To a 20 mL microwave vial was added cesium carbonate (1460 mg, 4.48 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (565 mg, 2.331 mmol), and 3-(2-fluoropyridin-3-yl)-1-methylcyclopentanol (350 mg, 1.793 mmol) as a solution in NMP (3585 μL). The reaction mixture was heated to 180° C. for 3 h with microwave irradiation. The reaction was diluted with water and extracted with ethyl acetate before drying over magnesium sulfate, filtering, and concentrating under reduced pressure to a dark brown oil. Three purifications of the diastereomeric mixture by SFC gave four compounds. MS (ESI, pos. ion) m/z: 418.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[C:26]([C:28]3[O:32][N:31]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]=3[C:39]([F:42])([F:41])[F:40])[O:25][N:24]=2)=[CH:19][CH:18]=1)[C:3]([NH:5][CH:6]1[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:4].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[NH:8]1[CH2:7][CH:6]([NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[C:26]([C:28]4[O:32][N:31]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:29]=4[C:39]([F:42])([F:40])[F:41])[O:25][N:24]=3)=[CH:19][CH:18]=2)[CH2:9]1.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CNC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 22.6 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 90 mg, 0.209 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (115 μL, 1.043 mmol), 3-amino-azetidine-1-carboxylic acid tert-butyl ester (53.9 mg, 0.313 mmol), and BOP (166 mg, 0.376 mmol). This was stirred overnight before EtOAc was added. The solution was washed with brine, 1N HCl, and sat. NaHCO3 solution. The organic layer was dried and concentrated to give single enantiomer tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)azetidine-1-carboxylate (120.6 mg, 0.206 mmol, 99% yield): LCMS=586.4 [M+H]+. A portion of this tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)azetidine-1-carboxylate (118 mg, 0.202 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (2 mL). This was stirred for 1 h and then concentrated. The resulting residue was purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B% over 10 min, product retention time=10.5 min, 20 mL/min, 220 nM) to give single enantiomer N-(azetidin-3-yl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide-TFA (30 mg, 0.046 mmol, 22.60% yield): LCMS=486.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.25 (2 H, m), 7.65-7.78 (4 H, m), 7.54-7.65 (3 H, m), 5.18 (1 H, s), 4.71 (1 H, t, J=7.81 Hz), 4.16-4.32 (4 H, m). HPLC Peak RT=8.3 min (Analytical Method A).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.C([C:24]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:25]1[C:26](Cl)=[O:27])(=O)C>C(Cl)Cl>[OH:33][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:27]
Reactant: CC(=O)C1(O)C=CC=CC1C(=O)Cl
Reactant: NCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCSc1cccc2nccn12)c1ccccc1O
Yield: 56 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (3.87 g, 20 mmoles) and triethylamine (5.58 ml, 40 mmoles) in methylene chloride (200 ml) was added o-acetylsalicyloyl chloride (4.77 g, 24 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off, ethanol (60 ml) and 1N NaOH (40 ml) were added to the residue, followed by stirring for 1 hour. 1N HCl (40 ml) was added and ethanol was distilled off, and then the residue was extracted with chloroform and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to obtain 3.51 g of the desired product (56.0%, colorless solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[C:14](=O)([O:23]C1C=CC([N+]([O-])=O)=CC=1)[O:15][C:16]([O:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17]>CN(C)C=O.O>[C:20]([O:19][C:16]([O:15][C:14]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:23])([CH3:18])[CH3:17])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)OC(C)(C)OC(C)=O)cc1OC

Procedure:
A solution of 3,4-dimethoxyphenethylamine (110 mg) and acetoxyisopropyl p-nitrophenyl carbonate (0.18 g) in dimethylformamide (3 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate. The ethyl acetate extract was washed with water, ice cold 1% aqueous sodium hydroxide, 1N HCl, water and brine. The organic extract was dried over sodium sulfate and evaporated. The residue (0.11 g) was purified by preparative thin layer chromatography on silica gel plates. The title compound (75 mg) was eluted with ethyl acetate-chloroform (5:95). 1H NMR (CDCl3) δ 1.81 (6H, s), 2.05 (3H, s), 2.75 (2H, t), 3.36 (2H, m), 4.85 (1H, br, t), 6.71-6.84 (3H, m); 13C NMR (CDCl3) δ 22.05, 25.9, 35.45, 41.91, 55.76, 55.83, 105.07, 111.29, 111.87, 120.61, 131.09, 147.59, 148.91, 153.36 and 168.79; 1R (film) 3370, 2941, 1748, 1718, 1517, 1464, 1370, 1261, 1238, 1140, 1027 cm-1 ; HRMS (e/m) calculated for C16H23NO6, 325.1525; found, 325.1512.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:2]([OH:1])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OCc2ccccc2)ccc1O

Procedure:
In 100 ml of acetone is dissolved 15 g (0.0824 moles) of ethyl 2,5-dihydroxybenzoate, 13.9 g (0.110 mole) benzyl chloride and 34.1 g (0.247 mole) potassium carbonate. The mixture is heated to its reflux temperature and maintained at reflux for 22 hours. The solution is filtered and the residue is washed with acetone. The filtrate and washings are concentrated, and the residue is dissolved in diethyl ether. The ether extracts are washed twice with water then with saturated sodium chloride solution and finally dried over magnesium sulfate. The magnesium sulfate is removed by filtration and the solution is evaporated to provide a suspension of product which is triturated with hexane and dried to provide a solid. The solid is recrystallized from hexane to provide ethyl 5-benzyloxy-2-hydroxybenzoate, m.p. 71.5°-73° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:34][CH:35]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(N2CCCCC2)cc1

Procedure:
The title compound, off-white solid (95 mg, 72%), MS (ISP) m/z=514.4 [(M+H)+], mp 221° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-piperidin-1-yl-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[CH2:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:12]#[CH:13].CCN(CC)CC>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.CC#N>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]#[C:12][CH2:11][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: C#CCNS(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCNS(C)(=O)=O)s1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic acid methyl ester (1.66 g, 8.0 mmol), N-prop-2-ynyl-methanesulfonamide (1.09 g, 8.2 mmol), Et3N (1.7 mL, 12.1 mmol), and CH3CN (30 mL) was added Pd(PPh3)4 (462 mg, 0.4 mmol) followed by Cul (76 mg, 0.4 mmol). The reaction was heated at reflux for 24 h and was cooled to room temperature. The volatiles were removed in vacuo and the residue was purified via flash chromatography (20% EtOAc in hexanes to 33% EtOAc in hexanes) to yield 5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acid methyl ester as a pale yellow solid (1.1 g). 1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H), 7.14 (d, 1H), 4.60 (m, 1H), 4.22 (d, 2H), 3.88 (s, 3H), 3.10 (s, 3H); MS 274 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:13]1[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([Cl:18])[C:12]=1[Cl:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cc(Cl)cc(Cl)c1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 54.3 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 500 mg, 3.4 mmol), 2,3,5-trichlorophenylboronic acid (Aldrich; 751 mg, 3.35 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-methyl-N′-(2,3,5-trichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (592 mg, 53%) as a colorless oil that solidified on standing.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:12][C:7]1[CH:6]=[C:3]([C:2]([OH:1])=[CH:9][C:8]=1[O:10][CH3:11])[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
A mixture of 2-hydroxy-4-methoxy-benzaldehyde (3.64 g, 20 mmol) and tetrabutylammonium tribromide (6.40 g, 20 mmol) in anhydrous dichloromethane (200 mL) was stirred at room temperature for 24 hours. The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography, using a Biotage 40M cartridge; eluting with 5% ethyl acetate/95% hexane to give 3-bromo-6-hydroxy-4-methoxy-benzaldehyde as a white solid (3.50 g, 76%).