Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[NH:10][C:9](=O)[CH:8]=2)[CH:2]=1.P(Cl)(Cl)([Cl:22])=O.P(Cl)(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>>[Cl:22][C:9]1[CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=1
Reactant: O=c1cc(-c2cccnc2)nc(-c2ccccn2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Temperature: 0 °C

Procedure:
To 6-pyridin-3-yl-2-pyridin-2-yl-3H-pyrimidin-4-one (1 eq, 0.26 mmol, 0.035 g) under inert atmosphere, is added dropwise phosphorus oxychloride (15 eq, 3.9 mmol, 0.36 ml) followed by cautious addition of phosphorus pentachloride (1 eq, 0.26 mmol, 0.054 g). After 4 hours at reflux, the reaction mixture is added slowly to ice/water. The pH is adjusted to pH 7 using NaHCO3 and the aqueous portion is extracted with EtOAc. The combined organic extracts are separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography eluting with 0-100% MeOH in DCM to afford 4-chloro-6-pyridin-3-yl-2-pyridin-2-yl-pyrimidine as a white solid; [M+H]+=269/271.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([O-])=[O:15])[S:13][C:6]=12.[Li+]>>[CH2:1]([NH:3][C:14]([C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[Cl:4])[CH:11]=1)=[O:15])[CH3:2]
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CCN
Agent: [Li+]
Product: CCNC(=O)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from ethylamine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: n.d.; HPLC Rf: 4.18 min; HPLC purity: 98%.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].[CH3:15][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[C:3]([Cl:14])=[C:4]([C:5](=[O:6])[CH3:15])[CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1cccc(Br)c1Cl
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(Br)c1Cl
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-2-chloro-N-methoxy-N-methylbenzamide (0.71 mmol) in 7 mL THF was added a solution of MeMgBr (4.31 mmol, 3M solution in Et2O) at 0° C. The cooling bath was removed after 1 h and stirring was continued at RT overnight. The reaction was quenched with water and sat. aq. NH4Cl solution under cooling. The mixture was extracted with EtOAc (3×), the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (85/15) gives the desired compound as colorless oil;
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.CS(Cl)(=O)=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH2:23][O:24][CH3:25])=[C:18](CO)[CH:19]=1.[Cl-].[Na+]>ClCCl>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH2:23][O:24][CH3:25])=[C:18]([CH2:7][C:6]#[N:3])[CH:19]=1
Reactant: COCOc1ccc(F)cc1CO
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccc(F)cc1CC#N

Procedure:
Triethylamine (5.95 ml) and methanesulfonyl chloride (2.42 ml) were added to a dichloromethane (60 ml) solution of the compound 324-2 (5.23 g), while the solution was stirred under cooling on ice. The obtained mixture was stirred at room temperature for 1 hour. A saturated sodium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in dimethyl sulfoxide (30 ml). Sodium cyanide (2.09 g) and sodium iodide (851 mg) were added to the solution, and the obtained mixture was stirred at 90° C. for 3 hours. The temperature of the reaction solution was returned to room temperature. Thereafter, water was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:0 to 4:1), so as to obtain the title compound (4.33 g).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][O:8][C:9]1[C:14]2=[CH:15][CH:16]=[C:17]3[C:26]([N:25]=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[C:23]4[C:27](=[O:34])[NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[N:18]3)=[C:13]2[CH:12]=[CH:11][CH:10]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH3:32][N:31]([CH3:33])[CH2:30][CH2:29][NH:28][C:27]([C:23]1[C:24]2[C:19](=[N:18][C:17]3[C:26]([N:25]=2)=[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH2:7][C:6]([OH:35])=[O:5])[C:14]2=[CH:15][CH:16]=3)[CH:20]=[CH:21][CH:22]=1)=[O:34]
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(OCC(=O)OC(C)(C)C)cccc4c3nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(OCC(=O)O)cccc4c3nc12
Reaction time: 4 h

Procedure:
To a solution of [11-(2-dimethylamino-ethylcarbamoyl)-benzo[a]phenazin-4-yloxy]-acetic acid tert-butyl ester (18 mg) in dry dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). After stirring for 4 hours the solvent was removed in vacuo to yield crude product. This was triturated with ether to yield the title compound as a yellow solid (10 mg).
Reaction SMILES: [N:1]1(CCOC2C=CC(NC(N)=O)=CC=2)CCCC1.[N:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1)=[C:20]=[S:21]>C(Cl)Cl.CO>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C:25]2[CH:24]=[CH:23][C:22]([NH:19][C:20]([NH2:1])=[S:21])=[CH:27][CH:26]=2)[CH2:33][CH2:32]1
Reactant: CN1CCN(c2ccc(N=C=S)cc2)CC1
Reactant: NC(=O)Nc1ccc(OCCN2CCCC2)cc1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(NC(N)=S)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The title compound is prepared as described in Example 1 for [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea but using 1-(4-isothiocyanato-phenyl)-4-methyl-piperazine and stirring the reaction mixture at RT for 17 h. Title compound: ES-MS: 251.0 [M+H]+; major peak at tR=3.56 min (System 1); Rf=0.27 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][C:6]=1Br.O.CC(O)=O>CC(C)=O.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: O=C(O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A 500 mL three-necked round-bottom flask fitted with an overhead mechanical stirrer and reflux condenser was charged with 4,5-dibromo-furan-2-carboxylic acid (57.0 g, 211 mmol), H2O (168 mL), and HOAc (42 mL). The third neck of the flask was stoppered and the suspension was heated to reflux with a temperature controlled heating mantle held at 125-130° C. Zn dust (24.9 g, 381 mmol) (previously ground in a mortar and pestle to break up lumps) was added portionwise over 50 minutes. Subsequent portions are added after most of the previously added portion has disappeared. After the first portions of the Zn were added, all of the 4,5-dibromofuran-2-carboxylic acid dissolves to give a pale brown solution. Twenty-five minutes after the conclusion of the zinc addition a thick grey-white slurry had formed. HPLC analysis of the reaction slurry at this time indicated complete consumption of the starting 4,5-dibromofuran-2-carboxylic acid and conversion to the desired product. After 35 minutes, heating was discontinued, and the slurry was allowed to cool to ambient temperature. After cooling to ambient temperature the reaction slurry was diluted with cold H2O (175 mL), cooled in an ice bath, and then filtered. The white and grey solids were rinsed with cold H2O, and dried on the filter for 3 hours. The product/Zn mixture was then pumped down under high vacuum with gentle heating to afford white-grey flakes. A portion of the resulting solids (37.3 g) was dissolved in warm acetone (1.8 L, solubility about 20 g/L). The resulting solution was filtered to remove residual zinc dust, and then concentrated under reduced pressure to afford 4-bromo-furan-2-carboxylic acid as a white powder. This material was carried on to the acid chloride formation without purification. 1H-NMR (400 MHz, DMSO-d6): δ 7.96 (1H, d, J=0.8 Hz), 7.04 (1H, d, J=0.8 Hz).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:23].N([O-])=O.[Na+].[ClH:28]>O.[Cu]Cl>[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:23].[Cl:28][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:3]=1[CH2:2][CH2:1][CH2:11][C:9]2=[O:10]
Reactant: Cl
Reactant: O=C1CCCc2ccccc21
Agent: Cl[Cu]
Agent: Nc1cccc2c1CCCC2=O
Agent: O=N[O-]
Solvent: O
Product: O=C1CCCc2c(Cl)cccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
5-Amino-1-tetralone was prepared from α-tetralone according to the literature (J. Am. Chem. Soc. 1994, p4852). A mixture of 5-amino-1-tetralone (80 mg) and concentrated hydrochloric acid (1 mL) was cooled to 0° C. A solution of sodium nitrite (35 mg) in water (0.5 mL) was added dropwise to the stirring solution. The cold diazonium solution was then poured rapidly onto a stirring solution of copper (I) chloride (62 mg) in concentrated hydrochloric acid (1 mL). The reaction mixture was allowed to warn to ambient temperature and then stirred for 1.5 hours. The mixture was then extracted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield 5-chloro-1-tetralone as a brown solid (87 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[CH:16]=[CH:17][C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl-].[NH4+].O>C1COCC1.C(OCC)C>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(Oc3ccc(Cl)cc3)nc2OCCN1Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(Oc2ccc3c(n2)OCCN(Cc2ccccc2)C3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
THF-diethyl ether solution (2.5 mL-2.5 mL) was added a solution of the compound obtained in step 1 (0.51 g) in THF-diethyl ether (2.5 mL-2.5 mL), and the resulting mixture was stirred at room temperature for 2 hr under a nitrogen atmosphere. 1N Aqueous sodium hydroxide solution (0.076 mL), saturated aqueous ammonium chloride (0.076 mL) and water (0.076 mL) were added, and the resulting mixture was stirred at room temperature for 3 hr. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(4-chlorophenoxy)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.20 g, 42%) as a white powder.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH3:26])[N:17]=[CH:16][N:15]=2)=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:35])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][S:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH3:26])[N:17]=[CH:16][N:15]=2)=[CH:7][CH:6]=1)=[O:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCSC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCS(C)=O)cc1
Yield: 76.6 %

Procedure:
A solution of ethyl 4-(2-(4-(2-methylthioethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.25 g, 0.67 mmol) in methylene chloride (20 ml) was stirred under ice-cooling. 80% m-Chloroperbenzoic acid (0.16 g, 0.74 mmol) was added to the solution. The mixture was stirred under ice-cooling for 20 minutes, and then a 1N aqueous solution (20 ml) of sodium hydroxide was added. The mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (=8/2) to give the desired ethyl 4-(2-(4-(2-methylsulfinylethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.20 g, 77%).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12]C2CCCCO2)[C:7]=1[S:19](=[O:22])(=[O:21])[NH2:20])=[O:4].CS(O)(=O)=O>CO>[OH:12][C:8]1[C:7]([S:19](=[O:22])(=[O:21])[NH2:20])=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:24])([CH3:23])[CH3:1])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(OC2CCCCO2)c1S(N)(=O)=O
Agent: CS(=O)(=O)O
Solvent: CO
Product: CC(C)(C)C(=O)Nc1cccc(O)c1S(N)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethyl-N-[2-sulfamoyl-3-(tetrahydro-pyran-2-yloxy)-phenyl]-propionamide (21.9 g, 61.5 mmol) in methanol (220 ml) a solution of methanesulfonic acid (11 ml) in methanol (10 ml) is added within 4 min at 25° C. After stirring for 1 h, the solvent is removed. The residue is partitioned between water and EtOAc. After washings with water, 10% NaHCO3, and brine, evaporation of the dried (Na2SO4) organic phase gave N-(3-hydroxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:15].[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>N1C=CC=CC=1>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:15][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 84.1 %

Procedure:
Following the procedure of Example 1, 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (1.0 g, 5.0 mmol) and trimethylacetyl chloride (0.68 mL, 5.5 mmol) in pyridine (10 mL) provided 2,2-dimethyl-N-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-3-yl)-propionamide (1.2 g). Mp 208-209° C.; Anal. Calcd. for C18H23NO2: C, 75.76; H, 8.12; N, 4.91; Found: C, 76.06; H, 8.03; N, 4.94.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1.N>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:15][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccnc1N
Reactant: O=C(O)CCCOCc1ccccc1
Agent: N
Product: c1ccc(COCCCc2nc3cccnc3[nH]2)cc1
Yield: 86 %

Procedure:
4-(Benzyloxy)butanoic acid (5.0 g) and 2,3-diaminopyridine (1.12 g) were stirred at 150° C. for 10 hr. Under ice-cooling, to the reaction mixture was added concentrated aqueous ammonia, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.36 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH3:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(N)CN>CN(C)C=O.COC(C)(C)C.[Na+].[Cl-].C(OC(C)C)(=O)C.[Cu]I>[CH3:15][C:16]1[N:17]=[CH:18][N:19]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=2)[CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: NCCN
Solvent: CC(=O)OC(C)C
Solvent: COC(C)(C)C
Product: Cc1cn(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cn1
Temperature: 110 °C
Yield: 21.1 %

Procedure:
To a stirred suspension of 1-bromo-3-nitro-5-trifluoromethyl-benzene (4.05 g, 15 mmol), 4-methyl-1H-imidazole (2.01 g, 24 mmol, 98%), and potassium carbonate (3.73 g, 27 mmol) in N,N-dimethylformamide (10 mL) are added ethylenediamine (0.141 mL, 2.1 mmol) and copper(I) iodide (0.204 g, 1.05 mmol). The vigorously stirred mixture is heated to 110° C. for 23 hours. After that, most of the 1-bromo-3-nitro-5-trifluoromethyl-benzene is converted, and the suspension is allowed to cool down to room temperature. The mixture is diluted with tert-butyl methyl ether (30 mL) and 5% aqueous NaCl solution (30 mL) and isopropyl acetate (15 mL) are added. The aqueous layer is separated and extracted with a mixture of tert-butyl methyl ether (10 mL) and isopropyl acetate (5 mL). The organic layers are combined and filtered. The filtrate is washed with water (10 mL), treated for 5 minutes with ethylenediamine (0.303 mL), washed with water (10 mL), 5% aqueous sodium metabisulfite solution (10 mL) and water (10 mL) before it is treated with activated carbon (1.2 g) at room temperature for 1 hour. The suspension is filtered using filter aid, and the filtrate is evaporated to dryness under reduced pressure to give a clear, red-brown oil which solidifies upon standing at room temperature. The obtained solid is purified by column chromatography on silica gel eluting with a 4:5 mixture of ethyl acetate and hexane (in the presence of 0.5 volume % of triethylamine) to afford mainly 4-methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1H-imidazole as a pale yellow solid. Yield: 21.1% (HPLC purity: 96.7 area %) Melting point: 118-119° C.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21](O)=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=1)[CH2:15][C:14]2([CH3:37])[CH3:36].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=1)[CH2:15][C:14]2([CH3:37])[CH3:36]
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)NS(=O)(=O)C3CC3)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.8 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (1.1 g, 9.1 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (361 mg, 9 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A63. A solution of 6-chloro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (520 mg, 1.3 mmol) and 1,1′-carbonyldiimidazole (422 mg, 2.6 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B63. Solution B63 was added to Solution A63 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [6-chloro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (25 mg, 4%) as a white solid: MS (ESI) M+1=504.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH:21]2[C:29]3[C:24](=[C:25]([C:30]4[C:35]([CH3:36])=[CH:34][C:33]([OH:37])=[CH:32][C:31]=4[CH3:38])[CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].[CH2:46]([S:48][CH2:49][CH2:50]O)[CH3:47].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OC(C)C)(C)C>[CH2:46]([S:48][CH2:49][CH2:50][O:37][C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:24]=2[CH2:23][CH2:22][CH:21]3[N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:2]([F:1])[CH:7]=2)=[C:31]([CH3:38])[CH:32]=1)[CH3:47]
Reactant: CCSCCO
Reactant: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(O)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(OCCSCC)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.00 g, 1.58 mmol), 2-(ethylthio)ethanol (0.219 mg, 2.06 mmol) and tributylphosphine (0.417 mg, 2.06 mmol) in tetrahydrofuran (25 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.520 g, 2.06 mmol) under stirring at room temperature, and the mixture was stirred for 16 hr. The reaction mixture was diluted with diisopropyl ether, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give the title compound (1.06 g, yield 93%) as a colorless oil.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][C:7]1=[O:21])(=O)[CH2:2][CH2:3][CH3:4].[CH2:22]([O:24][NH2:25])[CH3:23]>C(O)C>[CH2:22]([O:24][NH:25][CH2:4][CH2:3][CH2:2][CH:1]=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][C:7]1=[O:21])[CH3:23]
Reactant: CCCC(=O)C1C(=O)CC(c2ccc(CC)cc2)CC1=O
Reactant: CCON
Solvent: CCO
Product: CCONCCCC=C1C(=O)CC(c2ccc(CC)cc2)CC1=O

Procedure:
28.6 parts by weight of 2-butyryl-5-(4-ethylphenyl)-cyclohexane-1,3-dione and 6.1 parts by weight of ethoxyamine are stirred in 150 parts by volume of ethanol at room temperature for 8 hours. The mixture is concentrated under reduced pressure, the residue is taken up in 200 parts by volume of methylene chloride and the solution is washed with 5% strength aqueous hydrochloric acid and water dried over sodium sulfate and concentrated under reduced pressure. 2-(Ethoxyaminobutylidene)-5-(4-ethylphenyl)-cyclohexane-1,3-dione is obtained as an oil (active ingredient No. 3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cc1C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(C)c1

Procedure:
15.0 g of 3,4-dimethyl benzoic acid, 29.0 ml of thionyl chloride, 100 ml of methanol, and 1 ml of DMF were processed in a similar manner as in Reference Example 14-(1) to give 15.7 g of methyl 3,4-dimethylbenzoate.
Reaction SMILES: NC1C=CC(C[P:7](=O)([O:11]CC)[O:8][CH2:9][CH3:10])=CC=1.ClC(OCC1C=CC=CC=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[CH:40]1[C:45]([N+:46]([O-:48])=[O:47])=[CH:44][CH:43]=[C:42]([OH:49])[CH:41]=1>C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>[PH:7](=[O:11])([O:49][C:42]1[CH:43]=[CH:44][C:45]([N+:46]([O-:48])=[O:47])=[CH:40][CH:41]=1)[O:8][CH2:9][CH3:10]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCO[PH](=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Diethyl p-aminobenzylphosphonate (1) (Aldrich Chemical Co., Milwaukee, WI) was converted to the p-carbobenzyloxy derivative (2) by the addition of 1.2 equivalents benzyl chloroformate in saturated aqueous sodium bicarbonate (NaHCO3) for 20 minutes at 23° C. That derivative was treated with 1.1 equivalents phosphorous pentachloride (PCl5) in chloroform at 50° C. for 2 hours. Pyridine (5 equivalents) and p-nitrophenol (3 equivalents) were added at 23° C. and subsequent workup provided the ethyl p-nitrophenyl phosphonate (3).