Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1O
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-tert-Butoxycarbonylamino-propionic acid (5-1) (1.0 g, 5.3 mmol) and 2-aminophenol (5-2) (578 mg, 5.3 mmol) in dichloromethane (10 mL) was added N,N′-dicyclo hexyl carbodiimide (1.3 g, 6.4 mmol). The resulting mixture was stirred at room temperature overnight. The volatile solvents were removed by rotovap evaporation then the reaction mixture was directly purified by silica gel chromatography (10-100% Hexane/Ethyl Acetate) to recover the desired product (5-3) as white solid: 1H-NMR (500 MHz, d4-CD3OD) δ7.43 (m, 1H), 6.88 (m, 1H), 6.76 (m, 1H), 6.70 (m, 1H), 3.29 (m, 2H), 2.48 (m, 2H), 1.29 (s, 9H).
Reaction SMILES: [Na+:1].C([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O-:16])=[O:15])=[O:9])(=O)C.[OH-].[Na+].Cl>O>[Na+:1].[SH:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O-:16])=[O:15])=[O:9]
Reactant: COc1ccc(CC(CSC(C)=O)C(=O)Nc2cccc(C(=O)[O-])c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CC(CS)C(=O)Nc2cccc(C(=O)[O-])c2)cc1
Reaction time: 1 h
Yield: 39 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4-methoxyphenyl)propionyl]amino]benzoic acid sodium salt (compound of Example 36) (2.0 g) is dissolved in water (20 ml), and the mixture is adjusted to pH 12.0 with 1N aqueous sodium hydroxide solution under nitrogen. After reacting at room temperature for one hour, the reaction mixture is adjusted to pH 8.0 with 10% hydrochloric acid and is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure and then lyophilized to give the title compound (0.7 g).
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.[N-:11]=[N+:12]=[N-:13].[Na+].CCOCC.O>CN(C)C=O>[N:11]([C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1)=[N+:12]=[N-:13]
Reactant: N#Cc1nc(F)cnc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nc(F)cnc1N=[N+]=[N-]
Reaction time: 0.17 h
Yield: 107.5 %

Procedure:
In 2.0 mL of N,N-dimethylformamide was dissolved 0.20 g of 3,6-difluoro-2-pyrazinecarbonitrile. At 5° C., 0.11 g of sodium azide was added and stirred at the same temperature as above for 10 minutes. The reaction mixture was added to a mixture of 20 mL of ether and 20 mL of water, and the organic layer was separated. The organic layer thus obtained was washed successively with 20 mL of water and 20 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.25 g of 3-azido-6-fluoro-2-pyrazinecarbonitrile was obtained as a yellow-colored oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=3)[N:21]=2)[CH2:13][CH2:14]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Cc1cccc(C)c1N1CCNCC1
Product: Cc1cccc(C)c1N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-(2,6-dimethylphenyl)piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2,6-dimethylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:26][C:27]1[N:32]=[C:31](Cl)[C:30]([Cl:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:26][C:27]1[N:32]=[C:31]([NH:1][C:2]2[CH:3]=[C:4]([S:8]([NH:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:15]=[CH:16][CH:17]=3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[C:30]([Cl:34])=[CH:29][N:28]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)c2cccc(N)c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
To a solution of tert-butyl (3-{[(3-aminophenyl)sulfonyl]amino}phenyl)carbamate (0.30 g, 0.82 mmol) and 2,4,5-trichloropyrimidine (0.14 g, 0.75 mmol) in DMF (2 mL) was added potassium carbonate (0.12 g, 0.90 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous phase was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The resulted crude mixture was purified by column chromatography to give the desired product (70 mg, 18%). LCMS for C21H21Cl2N5O4S (M-tBu+H)+: m/z=454.0, 455.9. 1H NMR (500 MHz, DMSO-d6): δ 9.28 (s, 1H), 8.41 (s, 1H), 8.12 (br, 1H), 7.85 (dt, J=7.4, 1.8 Hz, 1H), 7.55 (br, 1H), 7.57 (dt, J=7.9, 1.8 Hz, 1H), 7.39 (s, 1H), 7.04 (m, 1H), 7.02 (dt, J=8.2, 2.0 Hz, 1H), 6.71 (dt, J=7.5, 1.8 Hz, 1H), 1.43 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N+:12]([O-])(O)=O>S(=O)(=O)(O)O.[Fe]>[NH2:12][C:11]1[C:2]([F:1])=[CH:3][C:4]2[S:8][C:7](=[O:9])[NH:6][C:5]=2[CH:10]=1
Reactant: O=c1[nH]c2ccc(F)cc2s1
Reactant: O=[N+]([O-])O
Agent: [Fe]
Agent: O=S(=O)(O)O
Product: Nc1cc2[nH]c(=O)sc2cc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
6-fluoro-2(3H)-benzothiazolone (82.9 g) was nitrated in conc. sulfuric acid (800 g) with a 98% nitric acid (5% excess of the theoretical amount) at a temperature of 0° to 5° C. under stirring for 1.5 hours. The reaction mixture was poured into ice water and filtered. The solid material separated by the filtration was dried, and recrystallized from acetone, so that 6-fluoro-5-nitro-2(3H)-benzothiazolone (67.7 g) was obtained. The purity of this compound was 92% (this purity was determined by HPLC). The whole amount of this compound was reduced with iron powder to obtain 5-amino-6-fluoro-2(3H)-benzothiazolone (52.4 g). 4 g of the amino compound were subjected to an alkylation operation with the aid of 3-chloromethyl-5-methyl-1,2,4-oxadiazole (2.9 g), in acetonitrile (100 ml) in the presence of potassium carbonate (3 g) as the dehydrochlorinating agent. This operation was carried out under reflux for 2 hours, so that the aimed compound, i.e. 5-amino-6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (5.3 g) was obtained. m.p. 156°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH2:18])[NH:16][N:17]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH:19]1([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:39]=[CH:38][C:32]([C:33](OCC)=[O:34])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.C[Al](C)C.CC(C)=O>C1(C)C=CC=CC=1.C(#N)C>[CH:19]1([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:39]=[CH:38][C:32]([C:33]([NH:18][C:15]4[NH:16][N:17]=[C:13]([O:12][CH2:11][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=5)[CH:14]=4)=[O:34])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH2:20][CH2:21][CH2:22]1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCN(C3CCC3)CC2)cc1
Agent: C[Al](C)C
Solvent: CC(C)=O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN(C5CCC5)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 23.3 %

Procedure:
4-(4-Cyclobutylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide was prepared following the procedure as outlined for Example 100, starting from 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.173 g, 0.69 mmol), ethyl 4-(4-cyclobutylpiperazin-1-yl)benzoate (0.2 g, 0.69 mmol) and a 2M solution of trimethylaluminium in toluene (1.387 mL, 2.77 mmol) in toluene (10 ml) at room temperature for 20 h. The reaction mixture was poured into acetone (20 mL), quenched with excess damp sodium sulphite, filtered and evaporated to afford a yellow solid. Acetonitrile (10 ml) was added and this was filtered to afford the title compound (0.079 g, 23.17%) as a white solid.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[CH3:10][O:11][C:12]1([O:21][CH3:22])[CH2:15][CH:14]([C:16](=O)[CH2:17][C:18]#[N:19])[CH2:13]1>CCO>[C:2]([N:6]1[C:18]([NH2:19])=[CH:17][C:16]([CH:14]2[CH2:15][C:12]([O:11][CH3:10])([O:21][CH3:22])[CH2:13]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: COC1(OC)CC(C(=O)CC#N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC1(OC)CC(c2cc(N)n(C(C)(C)C)n2)C1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a slurry of tert-butylhydrazine hydrochloride (45.1 g, 362.0 mmol) in EtOH (1 L) was added NaOH pellets (12.4 g, 310.3 mmol). After 30 min, crude 3-(3,3-dimethoxy-cyclobutyl)-3-oxo-propionitrile in EtOH (300 mL) was added. The resulting slurry was heated to 75° C. (oil bath). After 14 hr, the reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. Isopropyl ether was added to the resulting slurry. The slurry was stirred for 15 min, filtered, and concentrated to yield a viscous oil. Trituration with ether/hexanes (several crops) gave the title compound (56.2 g, 86% yield over two steps) as a colorless solid: mp 80.9° C. 500 MHz 1H NMR (CDCl3) d 5.50 (s, 1H), 3.51 (bs, 2H), 3.18 (s, 3H), 3.16 (s, 3H), 3.19-3.14 (m, 1H), 2.60-2.54 (m, 2H), 2.20-2.14 (m, 2H), 1.59 (s, 9H). LRMS m/z (APCI+) 254 (M+1).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[CH3:11][OH:12].C(Cl)(Cl)Cl>[N+]([O-])([O-])=O.[Ag+].C(Cl)(Cl)Cl>[C:6]([C@H:9]1[C@:6]([CH3:9])([CH:7]=[CH2:8])[CH2:5][CH2:4][C@@H:3]([C:3]([CH3:4])=[CH2:8])[C@@H:11]1[OH:12])([CH3:7])=[CH2:5]
Reactant: CO
Reactant: COc1ccc(C=O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClC(Cl)Cl
Product: C=C[C@]1(C)CC[C@@H](C(=C)C)[C@H](O)[C@H]1C(=C)C

Procedure:
Diethylaluminum chloride (210 ul, 1.8 M in toluene, 0.379 mmol, 1.1 equivalent) was added dropwise to a solution of ##STR4c## (76 mg, 0.344 mmol, 1.0 equivalent) in dry dichloromethane (10 ml) at −78 C. Agter 1.5 h, triethylamine (500 ul) was added, the cooling bath was removed, and the solution was added to a mixture of saturated NaHCO3 (20 ml) and dichloromethane (2×20 ml), and the organic fractions were combined, dried (MgSO4), and concentrated in vacuo. Flash chromatography (15 g of SiO2; eluent, 4% EtOAc-hexanes; product, fractions 11-23; 10 ml/fraction) afforded a 96:4 mixture of ##STR5a## and a minor diastereomer (70.1 mg, 0.318 mmol, 92% yield): Rf starting material, 0.58; product, 0.41 (5:1 hexanes-EtOAc, anisaldehyde). The diastereomeric mixture was separated by AgNO3-impregnated radial chromatography (2 mm plate; eluent, 5:1 EtOAc-hexanes; product, fractions 10-33; 3 ml/fraction) followed by passage through silica gel (10 g; 150 ml of 4% EtOAc-hexanes) to afford pure ##STR5a## (88% yield) as a clear oil: AgNO3-impregnated TLC: Rf ##STR5a##, 0.08; minor, 0.17 (12% MeOH—CHCl3; anisaldehyde); [α]23D+17.8° (c=0.91, CHCl3); FTIR (film) 3566, 3486, 2969, 2931, 1639, 1454, 1375, 1004, 910, 889 cm-1; sup.1 H NMR (500 MHz, CDCl3) δ 5.78 (dd, 1H, J=10.9, 17.4), 5.06 (s, 1H), 4.88-4.92 (m, 4H), 4.76 (s, 1H), 3.77 (t, 1H, J=10.4), 2.08 (dt, 1H, J=4.8, 10.8), 1.98 (d, 1H, J=10.4), 1.90 (bs, 1H), 1.80 (s, 3H), 1.79 (s, 3H), 1.51-1.66 (m, 3H), 1.42 (dt, 1H, J=3.1, 13.0), 1.06 (s, 3H); sup.13 C NMR (101 MHz, CDCl3) d 148.9, 147.1, 144.2, 114.1, 112.2, 110.3, 69.3, 59.7, 53.7, 41.3, 39.0, 26.2, 25.0, 19.5, 18.1; HRMS (EI, Pos) m/z calculated for [C15H24O]+220.1827, found 220.1826.
Reaction SMILES: [CH2:1]([Mg]Cl)C.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:7])[CH3:6].C(OCC)C.[Cl-].[NH4+]>C1COCC1>[OH:7][C:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)([CH3:1])[CH3:6]
Reactant: CC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
Ethyl magnesium chloride (3M) in anhydrous THF (10 ml) was treated at room temperature under argon with a solution of 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine (281 mg) in anhydrous THF (15 ml). The resulting solid suspension was heated at 70° C. under reflux for 3 hours. The mixture was cooled in ice at 0-5° C. and treated with diethyl ether and a saturated solution of aqueous ammonium chloride. The reaction mixture was stirred for 10 minutes with ice cooling and at room temperature for 10 minutes. The aqueous phase was then extracted with dichloromethane and the ether phase was evaporated. The residue was dissolved in dichloromethane and combined with the other organic extracts. The combined extracts were then washed with saturated brine, dried over MgSO4, filtered and evaporated to give an impure orange solid. The solid was purified by chromatography on a prepacked silica column (“Varian bond elut-trademark), eluting with a mixture of methanol (1-2%) and ammonium hydroxide (1%) in dichloromethane to obtain a pale yellow solid which was triturated with diethyl ether to give 1-(4-(1-hydroxy-1-methylethyl)phenyl)4-(4-pyridyl)piperazine (21% yield) as a pale yellow solid, m.p. 234-235° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl[Sn]Cl.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:18]=[CH:19][C:10]=1[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2cnc3ccccc3n2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A solution of 2-(3-nitrophenyl)quinoxaline (9.4 g, 37.4 mmol), SnCl2.H2O (28 g, 13.48 mmol) in CHCl3 (95 mL) was heated to 90° C. for 15 minutes, cooled to room temperature, added to ice water (190 mL), and basified to pH 10 with 50% aqueous NaOH, adding ice as necessary to maintain the temperature below 10° C. The mixture was extracted with ethyl acetate (500 mL), and the organic phase was filtered through a Celite pad, which was washed once with ethyl acetate (150 mL). The combined organics phases were washed with brine and dried, and then solvent was evaporated in vacuo. The resulting solid was recrystallized from toluene to afford (3-quinoxalin-2-ylphenyl)amine (5.6 g, 68% yield). LCMS calculated for C14H11N3 (M+H): 222.26. found 222. 1H-NMR (400 MHz, DMSO-d6) δH: 9.42 (1H, s), 8.11-8.00 (2H, m), 7.94-7.75 (2H, m), 7.55 (1H, s), 7.42 (1H, d, J=7 Hz), 7.22 (1H, m), 6.72 (1H, m), 5.42 (2H, br. s).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19](Cl)[CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][S-:23].[Na+]>CO>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19]([S:23][CH3:22])[CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(Cl)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl
Agent: [Na+]
Solvent: CO
Product: CSC(C)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl

Procedure:
19.8 g (60 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-5-chloro-6-(1-chloroethyl)pyrimidine and 4.2 g (60 mmol) of sodium methanethiolate were heated at reflux in 100 ml of methanol for 6 hours. The mixture was concentrated and the residue was taken up in water/toluene. The organic phase was dried and concentrated, to give 17.7 g (85% of theory) of a colorless resin which was subsequently reacted without further purification.
Reaction SMILES: [H-].[Na+].C([C:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)(CCC(OC)=O)CCC(OC)=O)#N.C[O:34]CCOC>>[CH:30]1([CH2:29][O:28][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=2[O:24][CH:25]([F:27])[F:26])[CH:5]=[O:34])[CH2:32][CH2:31]1
Reactant: COCCOC
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 60 °C

Procedure:
To a suspension of sodium hydride (80% dispersion in mineral oil, 11.6 g, 388 mmol) in dry 1,2-dimethoxyethane (700 mL) under an argon atmosphere was added a solution of crude dimethyl 4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pimelate (41 g) in dry 1,2-dimethoxyethane (700 mL). The resulting mixture was heated at 60° C. for 1 h, cooled to room temperature, quenched with dilute aqueous hydrochloric acid and concentrated the residue was diluted with water, was acidified to pH 3 and was extracted twice with methylene chloride. The organic extract was washed with acidic water, was dried (sodium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with methylene chloride, followed by trituration with cold ether provided a solid (17.7 g, 43% from 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde): m.p. 115°-116° C. Analysis Calc. for C20H21F2NO5 : C 61.06, H 5.38, N 3.56; found: C 61.16, H 5.40, N 3.52.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[O:29][CH2:30][C:31](OC)=[O:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][NH2:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:20])=[O:21])=[CH:15][C:14]=2[O:29][CH2:30][C:31](=[O:32])[NH:36][CH3:35])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)COc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Reactant: CN
Product: CNC(=O)COc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C

Procedure:
A mixture of 3-[4-(3-fluoro-benzenesulfonyl)-2-methoxycarbonylmethoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, prepared as described in Example 13) and methylamine (2M in THF, 1.2 mL) was heated at 90° C. in a sealed tube for 16 hours. The reaction mixture was cooled and concentrated under reduced pressure, and the crude residue was purified via flash chromatography (hexane/EtOAc, 3/7) to give 109 mg of 3-[4-(3-fluoro-benzenesulfonyl)-2-methylcarbamoylmethoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[NH:9][C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4]>CO.[OH-].[Na+]>[CH3:23][O:22][C:16]1[CH:15]=[C:14](/[CH:13]=[CH:12]/[C:10]2[NH:9][C:8]3[CH:24]=[CH:25][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COC(=O)c1ccc2[nH]c(C=Cc3ccc(OC)c(OC)c3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/c2nc3cc(C(=O)O)ccc3[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
A mixture of 2-[2-(3,4-Dimethoxyphenyl)-vinyl]-1H-benzoimidazole-5-carboxylic acid methyl ester (3.5 g; 11 mmol) in MeOH (75 mL) and 2.5N NaOH solution (7.5 mL) was refluxed for 3 hours. The reaction mixture was cooled to ambient temperature and stirred for 18 hours. The reaction mixture was concentrated to dryness. The residue was dissolved in H2O, and acidified with 2N HCl. Precipitate was collected. Recrystallization from MeOH gave 600 mg (15%) of the title compound as creamy solid, mono-hydrochloride, m.p. over 285° C. Anal. Calcd. for C18H16N2O4HCl: C, 59.92, H, 4.75; N, 7.76. Found: C, 59.62; H, 4.80; N, 7.66. Mass spectrum: (EI; M+) m/z 324. 1H-NMR (DMSO-d6; 400 MHz) δ13.5(broad s, 1H), 8.24 (d, 1H), 8.14-8.2 (d, 1H), 8.02-8.06 (dd, 1H), 7.8 (d, 1H), 7.34 (d 1H), 7.26-7.28 (dd, 1H), 7.2-7.24 (d, 1H), 7.1 (d, 1H), 3.87 (s, 3H), 3.83 ppm (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)[N:10]([CH3:24])[C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[NH2:38][C:39]1[CH:40]=[C:41]([C:48](=[O:50])[CH3:49])[CH:42]=[CH:43][C:44]=1[NH:45][CH2:46][CH3:47]>>[C:48]([C:41]1[CH:42]=[CH:43][C:44]([NH:45][CH2:46][CH3:47])=[C:39]([N:38]=[C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12](=[O:13])[C:11](=[C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[S:15]3)[N:10]2[CH3:24])[CH:40]=1)(=[O:50])[CH3:49]
Reactant: CCNc1ccc(C(C)=O)cc1N
Reactant: CN1C(=S)N(Cc2ccccc2)C(=O)C1=C1Sc2ccccc2N1C
Agent: COS(=O)(=O)c1ccc(C)cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1N(C)C(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 1, intermediate 3-benzyl-1-methyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxoimidazolidin-4-one was alkylated with methyl p-toluenesulfonate and condensed with 3′-amino-4′-ethylaminoacetophenone to yield the title compound. 1H-NMR (CDCl3): δ 8.11 (1H, d), 7.84 (1H, dd), 7.51 (1H, dd), 7.31 (1H, m), 7.16 (1H, m), 6.95-7.12 (7H, m), 6.08 (1H, br t), 4.46 (2H, hs m), 3.99 (2H, m), 3.78 (3H, s), 3.50 (3H, s), 2.65 (3H, s), 1.06 (3H, t); MS(ESI): 512 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]1[CH2:17][C:18]([O:20]C)=[O:19].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:13]([F:15])([F:14])[F:16])=[CH:7][CH:8]=2)[N:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cn1c(=O)ccc2ccc(OC(F)(F)F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)ccc2ccc(OC(F)(F)F)cc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetate (0.49 g, 1.62 mmol) was dissolved in THF (4 mL). Sodium hydroxide (1.08 mL of a 3 N aqueous solution, 3.25 mmol) was added and the reaction mixture was stirred 60° C. for 2 h. The resulting solution was diluted with ethyl acetate and washed with water. The aqueous phase was separated, adjusted to pH 2 with aqueous HCl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum to give 2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid. Retention time (min)=1.75, method [1], MS (ESI) 288.1 (M+H).