Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[CH3:16].[C:17](OCC)(=[O:22])[CH2:18][C:19]([CH3:21])=O>C(O)(=O)C>[OH:22][C:17]1[N:6]2[N:5]=[C:4]([CH3:7])[C:3]([C:8]3[C:13]([CH3:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=3[CH3:16])=[C:2]2[N:1]=[C:19]([CH3:21])[CH:18]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(Cl)cc(C)c1-c1c(C)n[nH]c1N
Solvent: CC(=O)O
Product: Cc1cc(O)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
Dissolve 5-amino-4-(4-chloro-2,6-dimethylphenyl)-3-methylpyrazole in 20 mL glacial acetic acid at ambient temperature, and add ethyl acetoacetate (2.0 mL, 1.99 g). Heat to reflux (130° C.) under N2 overnight. Evaporate down to concentrate and add 200 mL Et2O to precipitate out product. Stir at ambient temperature for 1 hour, then filter and wash the resulting white solid (1.25 g) with copious amounts of Et2O. LCMS=302.2 (MH+); 300.2 (M−).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:26])([F:27])[F:1])[CH:4]=2)=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 105 %

Procedure:
As in Example 115, (E)-5,5-bis[3-(trifluoromethyl)phenyl]2,4-pentadienoic acid (5.8 g) and 4-nitrophenol (2.5 g) in dichloromethane (50 mL) was treated with 1,3-dicyclohexylcarbodiimide (3.1 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 2 hours. The usual work up furnished 8 g of (E)-5,5-bis[3-(trifluoromethyl)phenyl]-2,4-pentadienoic acid 4-nitrophenyl ester as an oil essentially homogeneous by tlc. This material was used without further purification in subsequent reactions.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[C:10]([C:30]([F:33])([F:32])[F:31])=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19](O)=[O:20])=[C:14]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:13]=[CH:12]2.Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][NH:39][CH3:40].C(N(CC)CC)C.OP(O)(O)=O>C(Cl)Cl>[CH3:35][O:36][C:37](=[O:41])[CH2:38][N:39]([C:19]([C:15]1[C:16]2[C:11](=[C:10]([C:30]([F:33])([F:31])[F:32])[C:9]([O:8][CH3:7])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH3:40]
Reactant: CNCC(=O)OC
Reactant: COc1ccc2c(C(=O)O)c(OCc3ccccc3)ccc2c1C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=P(O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)c1c(OCc2ccccc2)ccc2c(C(F)(F)F)c(OC)ccc12
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
A solution of oxalyl chloride (0.51 mL, 5.8 mmol) in CH2Cl2 (6 mL) was added dropwise to a suspension of 6-methoxy-2-(phenylmethoxy)-5-(trifluoromethyl)-1-naphthalenecarboxylic acid (2.00 g, 5.3 mmol, described in Example 8) in 50 mL of CH2Cl2 under a nitrogen atmosphere. The suspension became homogeneous upon stirring for 1.5 hours. The mixture was then placed under mild vacuum for about 5 minutes to remove the dissolved gases and then was transfered via syringe to a flask containing a suspension of N-methylglycine methyl ester hydrochloride (1.11 g, 8.0 mmol) and triethylamine (3.7 mL, 27 mmol) in 50 mL of CH2Cl2. The suspension was stirred for 20 hours then was poured into additional CH2Cl2 and 1M H3PO4. The organic phase was separated and washed successively with 1M H3PO4, water, saturated NaCl and then dried over Na 2 SO4. After filtration, concentration and silica gel chromatography with 20:1 CH2Cl2 :ethyl acetate as eluent, the residue was recrystallized from ethanol to give 1.51 g (62% yield) of the title compound as a white powder, m.p. 95°-98° C.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[O:2].[C:6](OCC)(=[O:9])[CH2:7][CH3:8].CC(C)([O-])C.[K+:18]>O1CCCC1>[CH2:4]([O:3][C:1]([C:7]([CH3:8])=[CH:6][O-:9])=[O:2])[CH3:5].[K+:18]
Reactant: CCOC(=O)CC
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C[O-]

Procedure:
To a solution of ethyl formate (117.5 g) and ethyl propionate (54.0 g) in 40 ml of tetrahydrofuran (THF) was added, drop-wise, potassium t-butoxide (502 ml of a 1.0 molar solution in THF) at ambient temperature over approximately 0.5 hour. A white precipitate began to form along with some bubbling. After another 7.5 hours the reaction was filtered, the solid was washed with diethyl ether and then dried under vacuum at 40° C. for 16 hours to give potassium 2-ethoxycarbonyl-propen-1-olate as a grey powder (23.5 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: C1CNCCNC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(N2CCCNCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine (362 mg, 1.99 mmol) and [1,4]-diazepane (1000 mg, 9.98 mmol) in DMF (6.0 mL) is stirred for 2 hours at room temperature followed by evaporation of the solvent DMF under vacuo. The residue is distributed between ethyl acetate (30 mL) and water (40 mL). The aqueous phase is extracted once with ethyl acetate (20 m) and the combined organic phases are dried with Na2SO4. Evaporation gives an oily residue (crude 1-(5-trifluoromethyl-pyridin-2-yl)-[1,4]-diazepane) which is used directly for reductive amination in the last step.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[C:16]3[CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH:6]1([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[CH:17]=[C:16]3[CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(OC3CCCCC3)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1Cc1cn(S(=O)(=O)c2ccccc2)c2ccc(OC3CCCCC3)cc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 16.9 %

Procedure:
n-Butyllithium (0.19 mL, 1.45M in hexane, 0.28 mmol) was added to a solution of (R)-5-cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (Example 3g, 77.1 mg, 0.25 mmol) in THF (1 mL) at -78° C.; the temperature was raised to 0 ° C. and the mixture was stirred for 40 min. After recooling to -78° C., phenylsulfonyl chloride (60 μL, 0.47 mmol) was added and the mixture was allowed to warm to room temperature slowly (overnight). The mixture was quenched with water (5 mL) and extracted into dichloromethane. The organic layer was washed sequentially with water and brine, and dried over sodium sulfate. Purification by flash chromatography (silica gel, 1-4% 2M methanolic ammonia in chloroform) yielded (R)-5-cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1-phenylsulfonylindole (19.1 mg, 17%, HRMS-FAB+ for C26H32N2O3S: calculated MH+ :453.22119; found MH+ :453.22550).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:20])[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[NH:18][CH3:19].O>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([OH:20])[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[NH:18][CH3:19]
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc(Cl)cc1C(O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a suspension of sodium borohydride (1.2 g) in tetrahydrofuran (10 ml), a solution of 2', 5-dichloro-2-methylaminobenzophenone (3.12 g) in tetrahydrofuran (20 ml) is added dropwise. The resultant mixture is mixed with water (5 ml) and stirred at room temperature overnight. The reaction mixture is mixed with a small amount of water and evaporated under reduced pressure to remove the solvent. The residue is made to pH 8-9 with dilute hydrochloric acid and shaken with chloroform. The organic layer is dried and evaporated to give 2',5-dichloro-2-methylaminobenzhydrol (3.05 g). This substance is recrystallized from ether/n-hexane to give crystals melting at 105.5° to 106.5° C. The yield is 97.1 %.
Reaction SMILES: [I-].[CH2:2]([C:4]1[C:9]([CH3:10])=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[C:15]1[O:16]CC(C)(C)[N+]=1C)[CH3:3].C[OH:24]>[OH-].[Na+]>[CH2:2]([C:4]1[C:9]([CH3:10])=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][C:5]=1[C:15]([OH:16])=[O:24])[CH3:3]
Reactant: CCc1c(C2=[N+](C)C(C)(C)CO2)ccc(C(F)(F)F)c1C
Reactant: CO
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Product: CCc1c(C(=O)O)ccc(C(F)(F)F)c1C
Temperature: 25 °C

Procedure:
A solution of 960 mg (2.25 mmol) 2-(2-ethyl-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-ium iodide in 10 ml MeOH and 5 ml 20% NaOH was heated to 70° C. for 17 h The yellow solution was cooled to rt, MeOH distilled off, the residue acidified with conc. HCl to pH 1 and extracted three times with tert-butyl methyl ether. The combined organic phases were washed twice with brine, dried over Na2SO4, filtered and evaporated: 2-Ethyl-3-methyl-4-trifluoromethyl-benzoic acid was obtained as yellow solid: MS (ISN): 231.06 ((M−H)−.).
Reaction SMILES: [CH:1]1([C:4](O)=O)[CH2:3][CH2:2]1.Cl.Cl.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].[OH-].[Na+]>O>[CH:1]1([C:4]2[NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:16]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccccc1N
Reactant: O=C(O)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2[nH]c(C3CC3)nc2c1
Temperature: 160 °C
Yield: 13 %

Procedure:
Cyclopropanecarboxylic acid (4 g, 52 mmol) was treated with phenylenediamine bis-hydrochloride (1 eq) and polyphosphosphoric acid (52 mL) and heated to 160° C. for 6 h. The reaction was cooled to 0° C. and diluted with water, then basified with NaOH (50% aqueous) until pH>10. The solution was extracted with ethyl acetate, dried (MgSO4), filtered and concentrated, purified by flash chromatography (100% ethyl acetate) giving 2-cyclopropylbenzimidazole (1.1 g, 13%). MS found: (M+H)+=159.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N-].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1>CCOCC>[O:14]=[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][O:25][S:22]([C:19]1[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: CCCCCCCCCC(=O)C=[N+]=[N-]
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Solvent: CCOCC
Product: CCCCCCCCCC(=O)COS(=O)(=O)c1ccc(Cl)cc1
Yield: 75.3 %

Procedure:
A 1.2 g quantity of 1-diazo-2-undecanone is dissolved in 50 ml of ether, and 1.6 g of p-chlorobenzenesulfonic acid is slowly added to the solution at room temperature. The mixture is stirred until no nitrogen is evolved. The reaction mixture is washed with water, and the ethereal layer is dried over anhydrous sodium sulfate and distilled in a vacuum to remove the solvent. The residue is recrystallized from ether/petroleum ether to give 1.62 g of 2-oxoundecyl-p-chlorobenzene sulfonate (Compound 68), m.p. 51° to 51.5° C. Yield 75.3%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.C(=O)=O>N1C=CC=CC=1>[N:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: O=Cc1ccncc1
Reactant: O=C(O)CC(=O)O
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccncc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of 4-pyridine carboxaldehyde (36.7 mL, 0.384 mol) and malonic acid (40g, 0.384 mol) in 31 mL of pyridine was added piperdine (0.12 mL) and the mixture was warmed to 100° C. Caution: large volumes of CO2 evolved. After 0.5 h, the reaction was cooled to room temperature (RT) and the solution solidified. This was triturated with 240 mL of water and filtered, and washed with 2×50 mL portions of water. The solid was dried overnight at 42° C. under vacuum (10 mm Hg) to provide 37.1 g of a white solid; mp 295°-297° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[O:16][C@@H:15]([CH3:17])[CH2:14][NH:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:12][C@H:11]([CH3:10])[O:16][C@H:15]([CH3:17])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccc(Br)cc2)C[C@H](C)O1
Temperature: 25 °C
Yield: 112.8 %

Procedure:
To a mixture of 4-bromobenzaldehyde (3.70 g, 20 mmol) and cis-2,6-dimethylmorpholine (2.52 g, 22 mmol) in DCE (100 mL) was added NaBH(OAc)3 (5.30 g, 25 mmol), followed by AcOH (0.5 mL). After addition, the resulting mixture was stirred O/N at rt. The reaction as quenched with sat. NaHCO3 (30 mL) and H2O (30 mL), and was extracted with DCM (30 mL×2). Concentration of the solvents afforded the crude title compound as a pale yellow liquid (6.41 g, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=7.2 Hz, 2H), 7.21 (d, J=7.2 Hz, 2H), 3.64-3.55 (m, 2H), 3.44 (s, 2H), 2.68 (d, J=11.6 Hz, 2H), 1.75 (t, J=11.0 Hz, 2H), 1.54 (d, J=6.0 Hz, 6H); MS ESI 284.0 [M+H]+, calcd for [C13H18BrNO+H]+ 284.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[CH2:13][CH:12]2O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:22])[CH:13]=[CH:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(O)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C1C=CC2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Temperature: 50 °C

Procedure:
To 8-benzyl-4-hydroxy-1-phenyl-1,8-diazaspiro[4.5]decan-2-one (400 mg, 1.19 mmol) in pyridine (10 mL) was added thionyl chloride (0.26 g, 3.57 mmol) at 0° C. under N2. The mixture was heated to 50° C. for 5 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with sat aqueous NaHCO3. The organic layer was separated, dried over Na2SO4 and evaporated to give crude 8-benzyl-1-phenyl-1,8-diaza-spiro[4.5]dec-3-en-2-one, which was purified by column (Petroleum ether/EtOAc 4:1) to give 8-benzyl-1-phenyl-1,8-diaza-spiro[4.5]dec-3-en-2-one. 1H NMR (300 MHz, MeOD) δ 7.89 (d, J=6.0 Hz, 1H), 7.44-7.52 (m, 3H), 7.17-7.27 (m, 5H), 7.14-7.17 (m, 2H), 6.26 (d, J=6.3 Hz, 1H) 3.54 (s, 2H), 2.87-2.91 (m, 2H), 2.35-2.44 (m, 2H), 1.99-2.09 (m, 2H), 1.59-1.64 (m, 2H).
Reaction SMILES: [CH:1]([C@@H:4]1[C:9](=[O:10])[NH:8][CH:7]=[CH:6][N:5]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])([CH3:3])[CH3:2].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>ClCCCl>[CH:1]([C@@H:4]1[C:9](=[O:10])[NH:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1C(=O)NC=CN1C(=O)OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)[C@@H]1C(=O)NCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a stirring solution of (R)-benzyl 2-isopropyl-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate (400 g, 1.46 mol) in DCE (2 L) was added Et3SiH (424 g, 3.65 mol) and TFA (665 g, 5.8 mol) at rt. The reaction was stirred under reflux for 36 h. After cooled to rt, the solution was concentrated to remove the solvent. The residue was diluted with EtOAc (2 L), and it was added slowly into a stirring cooled sat. aq. NaHCO3 (2 L) to make sure that the pH>8. The mixture was extracted with EtOAc (2×2.5 L). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filter and concentrated to give (R)-benzyl 2-isopropyl-3-oxopiperazine-1-carboxylate (402 g, yield 99.75%), which was used for next step without further purification. LC-MS m/z 276.9 [M+H]+. 1H NMR (DMSO-d6 400 MHz): δ 7.93 (s, 1H), 7.39-7.31 (m, 5H), 5.09 (s, 2H), 4.06-4.01 (m, 1H), 3.99-3.92 (m, 1H), 3.23-3.14 (m, 3H), 2.20-2.12 (m, 1H), 0.96-0.94 (m, 3H), 0.85 (d, J=6.0 Hz, 3H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[OH:12][C:6]1[CH:11]=[CH:10][C:9]([CH:2]([OH:3])[C:1]([OH:5])=[O:4])=[CH:8][CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=CC(=O)O
Solvent: O
Product: O=C(O)C(O)c1ccc(O)cc1

Procedure:
The European patent specification EP-0,368,696 describes the condensation of a glyoxylic acid with phenol in the presence of a water-insoluble amine, to form a 12:84 mixture of 2- and 4-hydroxymandelic acid respectively. Then the excess of phenol is extracted with 1,1-dimethyl-1-methoxypropane. Only 70-74% of the paraisomer, 4-hydroxymandelic acid, is isolated leaving a non-separable mixture of approximately 1:1 2- and 4-hydroxymandelic acid.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: Sc1ccccc1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Sc1ccccc1

Procedure:
The title compound was prepared as described in General Method 6 from 0.96 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.0 mmol of benzenethiol, and 1.0 mmol of piperidine in 20 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid (m.p. 78°-80° C.). 1H NMR (DMSO-d6) δ3.37 (bs, 2H), 6.35 (m, 2H), 6.93 (m, 3H), 7.29-7.49 (m, 10H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-])=O.[H][H]>C(OCC)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Product: Nc1ccc2c(c1)C(=O)OC2=O
Temperature: 245 °C
Yield: 52.7 %

Procedure:
In 200 ml of dry ethyl ether, (C2H5)2O, was dissolved 1.93 g of 4-nitrophthalic anhydride (~1% solution) to which was added 0.10 g of 5% palladium-on-charcoal and the mixture hydrogenated in a Paar hydrogenator at 39 psi at room temperature, until no more hydrogen was consumed. The catalyst was removed by filtration and the ether removed from the filtrate, maintained at 0° to -5°C, under vacuo, yielding a yellow crystalline solid mixed with non-crystalline viscous mass. When a small sample of this mixture was placed on a metal plate heated to 245°C, the product melted and polymerized immediately to a tough polymer. Extraction of the crystalline-non-crystalline mixture with ether left 0.46 g of polymer; concentration of the ether followed by cooling, yielded 0.86 g of 4-aminophthalic anhydride.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:5].C(N(CC)C(C)C)(C)C.[Cl:35][C:36]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[CH:17]1[C:8]2[CH2:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH2:12][N:6]([C:4]([C:3]3[CH:21]=[CH:22][C:23]([NH:25][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:43]([Cl:45])=[CH:44][C:36]=4[Cl:35])=[CH:24][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.50 g of 5-(2-chloro-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.28 g of N,N-diisopropylethylamine and 0.45 g of 2,4-dichlorobenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give the desired product as a solid residue, m.p., 150°-165° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7](Cl)=[CH:6][C:5]=1[NH:12]C(=O)C)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[K+].[K+].[Br-]>CS(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][C:5]=1[NH2:12])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Reactant: C1CCNCC1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(N2CCCCC2)c(F)cc1[N+](=O)[O-]
Yield: 52 %

Procedure:
2-Nitro-4-fluoro-5-(piperidin-1-yl)aniline (13.0 g, 52%) was prepared by an analogous procedure as described in preparation 1 (step 3) using N-(2-nitro-4-fluoro-5-chloro phenyl)acetamide (25.0 g, 0.107 mol) (obtained in preparation 1, step 2), piperidine (45.8 a, 0.537 mol), potassium hydroxide (9.0 g, 0.16 mol) and dimethyl sulfoxide (100 mL). mp 112-113° C. IR (KBr) 3472, 1234 cm-1 ; 1H NMR (CDCl3) δ 1.60 (m, 2H, CH2), 1.70 (m, 4H, (CH2)2), 3.22 (m, 4H, N(CH2)2), 5.88 (d, J=7.6 Hz, 1H), 6.08 (brs, 2H, NH2), 7.78 (d, J=14.2 Hz, 1H) ; Mass (m/z) 239 (M+.).
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1.Cl>O>[C:2]1([S:8]([CH:13]2[CH2:14][CH2:15][CH2:16][C:11](=[O:17])[CH2:12]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=C1C=CCCC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1CCCC(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
Benzenesulfinic acid sodium salt (10.25 g) was added to a solution containing 5 ml of cyclohexenone and 30 ml of water, followed by the dropwise addition of 60 ml of 1N hydrochloric acid. The reaction mixture was stirred at room temperature for 24 hours. The crystals so precipitated were filtered and then washed with water, isopropanol and cold ethyl ether. After recrystallization from isopropanol, 5.74 g of 3-(phenylsulfonyl)-cyclohexan-1-one were obtained in the form of white crystals. Yield: 97%
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1.[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:11]([O:10][P:9]([CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1)([O:13][CH2:14][CH3:15])=[O:16])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: Cc1cc(CCl)on1
Product: CCOP(=O)(Cc1cc(C)no1)OCC
Yield: 74 %

Procedure:
5-Chloromethyl-3-methylisoxazole (1.12 g) was dissolved in triethyl phosphite (2.0 ml) and heated at reflux for 1 h. The residue was then distilled under reduced pressure to give 5-diethylphosphonomethyl-3-methylisoxazole (1.47 g, 74%); bp 122°-5° C. at 0.5 mm; νmax (film) 2980, 2930, 2910, 1605, 1440, 1420, 1390, 1255, 1160, 1060-1010, 980, 900 cm-1 ; δH (CDCl3) 1.35(3H, t, J=7 Hz, OCH2CH3), 2.30(3H, s, CH3 -het), 3.30(1H, d, JH-P =24 Hz, CH2 -P), 4.10(2H, m, OCH2CH3), 6.05(1H, d, J=3 Hz, CH-Het); δC (CDCl3) 11.4 (C5), 16.3, 16.4(OCH2CH3), 24.6, 26.8 (C1), 62.7, 62.8(OCH2CH3), 104.1, 104.2 (C3 ), 160.1 (C4), 163.5, 163.6 (C2); m/e (relative intensity) 233(M+, 18%), 192(47), 177(41), 136(50), 109(100), 97(82), 96(35), 81(76), 43(32) (Found: 233.0831. C9H16NO4P requires 233.0816).