Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[C:3]1([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[NH3:12].[Br:1][C:6]1[CH:7]=[CH:8][C:3]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:4][CH:5]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: BrBr
Product: Brc1ccc(C2CCNCC2)cc1
Product: N
Temperature: 25 °C
Reaction time: 2 h
Yield: 127 %

Procedure:
A solid mixture comprised of 2.65 g (16.4 mmol) of bromine adsorbed onto 5 g of Al2O3 was combined with a solid mixture of 1.05 g (6.56 mmol) of 4-phenylpiperidine adsorbed onto 5 g of Al2O3 and the combined mixture was stirred at rt for 2 h. The mixture was then put into a filter funnel and was eluted with CH2Cl2: EtOAc, 1:1 then CH2Cl2: MeOH:(2N NH3 in MeOH), 100:4:2 to give 1.0 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=4[NH:16][C:15]3=[O:27])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:28]([C:30]1[CH:39]=[C:38]([CH3:40])[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)=[O:29].CCN(C(C)C)C(C)C.CO.C[C:53](C)([O-:55])C.[K+]>C(O)(=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:17]2[NH:16][C:15](=[O:27])[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:6]=[N:7][C:2]([O:55][CH3:53])=[C:3]([C:28]([C:30]5[CH:39]=[C:38]([CH3:40])[C:33]6[NH:34][C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)=[O:29])[CH:4]=4)[CH2:9][CH2:10]3)[CH2:20][CH2:19][C:18]=2[CH:21]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c(Cl)nn3)CC1)C(=O)N2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c(OC)nn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.13 g (0.11 mmol) (purity 50%) 3-{1-[6-chloro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]-diazepin-2-one and 0.050 mL (0.29 mmol) DIPEA were heated with 1 mL MeOH in a microwave container for 2 h at 125° C. Then potassium-tert-butoxide was added and the mixture was stirred for 48 h at RT. Next, the reaction mixture was heated for a further 6 h and then it was neutralised with acetic acid and purified by preparative HPLC-MS.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[Si](C=[N+]=[N-])(C)(C)[CH3:12].CO>C(OCC)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:12])=[O:9])[CH2:3]1
Reactant: O=C1CCCC(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1CCCC(=O)C1
Temperature: 25 °C

Procedure:
To a solution of 3-oxocyclohexanecarboxylic acid (1.0 g, 7.0 mmol) in diethyl ether (28 mL) was added dropwise TMS-diazomethane (3.5 mL, 7.0 mmol, 2.0 mL in diethyl ether). MeOH (30 mL) was added and the mixture was maintained at ambient temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was purified by MPLC on silica gel (using a gradient elution of 0-45% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[C:9]([NH:12][C@H:13]([C:21](O)=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:11])[CH3:10].CN1CCOCC1>ClCCl>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][C:21](=[O:22])[C@H:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:12][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: -10 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
0.1 g of L-alanine methyl ester hydrochloride (0.7 mmol), 0.2 g of N-acetyl-L-phenylalanine (1 mmol) and 0.55 ml of N-methylmorpholine (5 mmol) are dissolved in 50 ml of dichloromethane and cooled to −10° C. 0.5 g of CPA from example 1 (50% in CH2Cl2; 0.8 mmol) is added slowly, and the mixture is stirred under cold conditions for 3 h and at room temperature for 72 h. The solution is concentrated by evaporation and extracted with ethyl acetate and 1 N HCl solution, sat. NaHCO3, sat. NaCl and dist. water. The organic phase is dried over magnesium sulfate, filtered off and concentrated by evaporation. 0.18 g of the white N-acetyl-L-phenylalaninyl-L-alanine methyl ester is obtained (88%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])[CH:15]=1.C([O-])(O)=O.[Na+]>CN1CCCC1=O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)[CH:21]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: Nc1cccc(-c2cccnc2)c1
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(Nc2cccc(-c3cccnc3)c2)c([N+](=O)[O-])c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A mixture of 4-Fluoro-3-nitroacetophenone (5 g, 27.3 mmol) and 3-(3-pyridyl)aniline (4.62 g, 27.2 mmol) in dry 1-methyl-2-pyrrolidone (10 ml) is stirred at 40-50° C. overnight. The resulting solid reaction mixture is suspended in ice water (50 ml) and made alkaline by addition of 1 M NaHCO3. The product is filtered off, washed with water and dried to yield 7.68 g 4-acetyl-2-nitro-N-(3-(3-pyridyl)phenyl)aniline (85%).
Reaction SMILES: [C:1]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](O)=[O:10].[BH4-].[Na+].[H][H].[B-](F)(F)(F)[O+](C)C>O1CCCC1.O>[OH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: O=C(O)CCCCCCCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: C[O+](C)[B-](F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCCCCCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product from 11a (12.9 g; 46.3 mmol) was added in portions to a stirred mixture of sodium borohydride (1.70 g; 45.0 mmol) in dry tetrahydrofuran (25 mL). After the evolution of hydrogen subsided, a solution of boron trifluoride dimethyl etherate (4.6 mL; 5.7 g; 50 mmol) in dry tetrahydrofuran (15 mL) was added drop-wise. The exothermic reaction was moderated with a cold water bath. After stirring 4 h at ambient temperature, the reaction mixture was hydrolyzed with cold water (20 mL). The mixture was separated and the organic phase was evaporated; the residue was mixed with water (20 mL) and dichloromethane (70 mL) to give an emulsion that separated on standing overnight. The organic layer was washed with water (4×15 mL) until the washings were neutral to pH paper. Following drying (Na2SO4), filtration, and evaporation 11.95 g (98%) product was obtained (oil).
Reaction SMILES: [Br:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:3]1=[O:12].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br-:1].[O:12]=[C:3]1[CH:2]([P+:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:6][CH2:5][N:4]1[CH2:7][C:8]([F:11])([F:10])[F:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1C(Br)CCN1CC(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1C([P+](c2ccccc2)(c2ccccc2)c2ccccc2)CCN1CC(F)(F)F
Product: [Br-]
Temperature: 5 °C

Procedure:
189 g (0.77 Mol) rac-3-Bromo-1-(2,2,2-trifluoroethyl)-2-pyrrolidone were dissolved in 1 l toluene, and 222 g (0.85 Mol) triphenylphosphine were added. The mixture was refluxed over-night in an argon atmosphere, the product starting to precipitate. The mixture was then cooled to 5° C. and the slightly brownish crystals were filtered off. They were stirred twice in 1 l THF, filtered and dried in a vacuum at 50° C. Yield: 308 g (79%) colorless crystals 1H-NMR (3): δ[ppm]2.17 (m, 1 H); 3.2-3.5 (m, 3 H); 3.93 (dd, 1H); 4.24 m, 1H); 6.91 (m, 1H); 7.60-8.03 (arom., m, 15H). IR (KBr): 1690 cm-1 MS(ISP): 428.3 (M+)
Reaction SMILES: Cl.[CH2:2]([NH:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[P:13]([O-:18])([O:16][CH3:17])[O:14][CH3:15].[C:19](=O)(O)[O-].[Na+]>C1COCC1>[CH2:2]([N:9]([CH2:19][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15])[OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: COP([O-])OC
Reactant: ONCc1ccccc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COP(=O)(CN(O)Cc1ccccc1)OC
Temperature: 55 °C
Yield: 82.9 %

Procedure:
Using the procedure of Example 1, the above-named compound is prepared from 5.0 g (31 mmol) of N-benzylhydroxylamine hydrochloride, 1.8 g (60 mmol) of paraformaldehyde, 3.7 ml (40 mmol) of dimethyl phosphite, 2.5 g (30 mmol) of sodium bicarbonate and 350 ml of THF by heating at 55° C. for seven hours. The residue is purified by column chromatography (silica gel, methylene chloride: ethyl acetate eluent) to give 6.1 g (80% yield) of a viscous colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:26][CH:25]=1)(=[O:23])=[O:22].[OH-].[Li+].O1CCCC1.O>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCNS(=O)(=O)c3ccc(CCC(=O)OC)cc3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCNS(=O)(=O)c3ccc(CCC(=O)O)cc3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound obtained in Example 2-11 (100 mg) and lithium hydroxide (17 mg) were added to tetrahydrofuran (4 ml) and water (2 ml) and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added acetic acid (2 ml) and the mixture was concentrated under reduced pressure. The residue was purified by RPHPLC and appropriate fractions were concentrated under reduced pressure to give the titled compound as a white solid. Yield: 40 mg (41%); mp 210-211° C., MS APCI+ve 507 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Yield: 53.3 %

Procedure:
To a solution of (2R)-2-methyl-piperazine (4.5 g, 45 mmol) in ethanol (80 mL) was added 4-fluorobenzyl chloride (5.38 mL, 45.0 mmol) and sodium hydrogen carbonate (11.3 g, 135 mmol). The reaction was refluxed overnight, cooled and concentrated. The remaining residue was diluted with dichloromethane and washed with water. The organic layer was separated and concentrated to give a clear oil. Chromatography on silica gel gave the title compound (5.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:16](O)[CH2:17][OH:18].Cl>O>[OH:18][CH2:17][CH2:16][O:11][C:10](=[O:12])[CH:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[CH3:13]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: OCCO
Agent: Cl
Solvent: O
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCO
Yield: 56.8 %

Procedure:
To a mixture of 2-(4-Nitro-phenoxy)-propionic acid 47 (45 g, 213 mol) and ethylene glycol (135 ml) was passed dry HCl gas for 1½ hours. During HCl gas bubbling the temp. rose to 60° C. The crude reaction mass was poured onto cold water (600 ml). Crude 48 was extracted into chloroform, dried over Na2SO4, distilled and purified by column chromatography on silica gel using hexane as eluant to give pure 48 (28 g, 56.8%) as a syrup.
Reaction SMILES: [CH3:1][S:2]([C:5](C(OC)=O)([CH2:16][CH2:17][CH2:18][CH:19]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:4])=[O:3].[Cl-].[Na+].CN(C)C=O>O>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:4])=[O:3]
Reactant: COC(=O)CCCCCCC(CCCC(COc1ccc(F)cc1)OCc1ccccc1)(C(=O)OC)S(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCCC(CCCC(COc1ccc(F)cc1)OCc1ccccc1)S(C)(=O)=O
Temperature: 160 °C

Procedure:
A mixture of methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyloxy-13-(4-fluorophenoxy)tridecanoate (2.60 g., 4.5 mmoles), sodium chloride (0.5 g., 8.5 mmoles), dimethylformamide (8 ml.) and water (0.2 ml.) is heated with an oil bath at 160° C. overnight (ca. 15 hours). The reaction mixture is allowed to cool to room temperature, quenched with cold water, and then extracted with chloroform three times. The combined extracts are washed with brine and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation in vacuo leaving the desired product as a viscous oil residue (2.30 g., 4.4 mmoles, 98%). ir (neat) 3.40, 5.72, 6.20, 6.62, 6.87, 7.71, 8.00, 8.28, 8.90, 12.04, 13.17, 14.37μ; pmr CCl4)δ1.0-2.9 (22H, m, containing a methyl singlet at 2.60δ), 3.54 (3H, s); 3.5-4.1 (3H, m), 4.47 (1H, d, J=12Hz), 4.70 (1H, d, J=12Hz), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4].[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+]>CO>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]([CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH2:25][CH2:24][C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:8]1)[C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C(N(CC1CCNC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)CCN1CCC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.2 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-(pyrrolidin-3-ylmethyl)acetamide (165 mg, 0.528 mmol) in methanol (3 mL) were added tert-butyl acrylate (0.103 mL, 0.703 mmol) and potassium carbonate (110 mg, 0.792 mmol), and the mixture was stirred at room temperature for 4 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes and then 10% MeOH/EtOAc) to give 68 mg of product as colorless oil. MS: (M+H)+=441.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.36-1.69 (m, 11H), 1.89-2.08 (m, 1H), 2.21-2.88 (m, 10H), 3.10-3.21 (m, 1H), 3.47-3.75 (m, 2H), 7.05-7.40 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.O>C1COCC1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cc1nc(-c2ccc(C#N)cc2)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(CN)cc2)cs1
Temperature: 0 °C
Yield: 38.6 %

Procedure:
Dissolve 4-(2-methylthiazol-4-yl)-benzonitrile (305 mg, 1.52 mmol) in anhydrous THF (50 mL). Add a 1M solution of lithium aluminum hydride in THF (3.05 mL, 3.05 mmol). Heat the mixture overnight under reflux. Cool the reaction mixture with ice/water and work-up sequentially with EtOAc and water. Filter the mixture over Celite®. Separate the organic phase, and extract the aqueous phase with chloroform. Dry the combined organic extracts over Na2SO4, filter and concentrate to obtain the title compound as an oil (120 mg) that was used without further purification. GC-MS m/z: 204 (M+).
Reaction SMILES: CS[C:3]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(OCC)C>C(O)(=O)C.S([O-])([O-])(=O)=O.[Cu+2].[Zn]>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(SC)c1cccs1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C(C)c1cccs1
Yield: 0.1 %

Procedure:
Methyl α-methylthio-α-(2-thienyl)propionate (432 g) was dissolved in 4 ml of acetic acid, and 32 mg of anhydrous copper sulfate and 400 mg of zinc powder were added. With stirring, the mixture was heated under reflux for 3.5 hours. After cooling, 30 ml of diethyl ether was added, and the insoluble matter was separated by filtration, followed by washing with 10 ml of diethyl ether. The filtrate and the washing were combined, and washed with 10 ml of water. After 20 ml of water was further added, sodium carbonate was gradually added to neutralize the acetic acid present. The organic layer was then separated, washed with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to short-path distillation (bath temperature 100°-110° C./8 mmHg) to afford 297 mg of methyl α-(2-thienyl)propionate as a colorless oil in a yield of 87%.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[H-].[Na+].C1(=O)O[CH2:18][CH2:17][O:16]1>CN(C=O)C.O>[CH3:1][C:2]1[N:3]([CH2:18][CH2:17][OH:16])[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=1
Reactant: O=C1OCCO1
Reactant: Cc1cc(-c2ccccc2)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccccc2)nn1CCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
A solution of 497 mg (3.14 mmol) of 3-methyl-5-phenylpyrazole in 12.6 mL of DMF at 0° C. was treated with 138 mg (3.45 mmol, 60% in oil) of NaH. After stirring for 15 min, 1.38 g (15.7 mmol) of ethylene carbonate was added, and the reaction was warmed to 25° C. and stirred overnight. The reaction was diluted with H2O and the product was extracted with hexanes/EtOAc (1:1). The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexanes/EtOAc (1:3) as eluent to give 305 mg (48%) of title compound: low resolution MS (ES) m/e 225 (MNa+), 203 (MH+).
Reaction SMILES: [OH-].[K+].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[CH2:15][C:16]([OH:18])=[O:17]>O>[C:3]1([O:13][CH2:15][C:16]([OH:18])=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCl
Reactant: Oc1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1cccc2ccccc12
Yield: 64.2 %

Procedure:
To a solution of potassium hydroxide (2.98 g, 52.1 mmol) in H2O (35 mL) was added 1-naphthol (3.08 g, 21.4 mmol), followed by 2-chloroacetic acid (2.32 g, 24.7 mmol). The resulting mixture was heated at reflux for 3 h, then allowed to cool and extracted with EtOAc. The aqueous phase was made acidic by the addition of 3N HCl and extracted with EtOAc. The organic phase from the acidic extraction was washed with saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (2.78 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21].Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.N1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=1)[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)=[O:21]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(Cl)ccc2OC)cc1
Yield: 70.6 %

Procedure:
8.9 g Ethyl 4-aminophenylacetate are suspended in 200 ml. toluene. After the addition of 4 ml pyridine, a solution of 10.2 g 5-chloro-2-methoxybenzoyl chloride in 10 ml toluene is added dropwise thereto and the reaction mixture heated under reflux for 2 hours. After cooling, the toluene phase is successively shaken out with dilute hydrochloric acid, aqueous sodium bicarbonate solution and water and thereafter dried and evaporated. The evaporation residue is then recrystallized twice from ethanol to give 12.2 g (70% of theory) ethyl 4-(5-chloro-2-methoxybenzamido)-phenylacetate; m.p. 104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:42]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[S:42])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=S)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 93.2 %

Procedure:
In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.21 mmol) prepared in example 36b was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.2 g, 0.49 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one as a white solid (Yield 0.095 g, 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(Cl)([Cl:18])=[O:17].[CH2:20]([N:22](CC)CC)[CH3:21]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([Cl:18])=[O:8])([O-:3])=[O:2].[NH2:22][CH2:20][C:21]([O:9][CH2:7][C:6]1[CH:5]=[CH:4][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Product: NCC(=O)OCc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
As shown in scheme C, reaction of 3,4-dinitrobenzoic acid with thionyl chloride gave 3,4-dinitrobenzoyl chloride, which on further treatment with benzyl glycinate in the presence of triethylamine gave benzyl 2-(3,4-dinitrobenzamido)acetate (intermediate 3). The intermediate 3 is treated either with K18F or K19F in the presence of a catalyst such as kryptofix [2.2.2] or 18-crown-6 to yield benzyl 2-(4-fluoro-3-nitrobenzamido)acetate, which on reduction with hydrogen gas or hydrogen source in the presence of Pd/C gave 2-(3-amino-4-fluorobenzamido)acetic acid (compound 3). In an analogous manner, 2-(5-amino-2-chloro-4-fluorobenzamido)acetic acid (compound 4) is synthesized starting from 2-chloro-4,5-dinitrobenzoic acid.