Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[Cs+].[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[CH:6]=[O:7].C[Si](C)(C)[C:15]([F:18])([F:17])[F:16].Cl>C1COCC1.O>[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[CH:6]([OH:7])[C:15]([F:18])([F:17])[F:16]
Reactant: O=Cc1c(F)cccc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OC(c1c(F)cccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.1 %

Procedure:
Caesium fluoride (32 mg, 2.1 mmol) was added to a mixture of 2,6-difluoro-benzaldehyde (2 ml, 18.2 mmol) and trimethyl(trifluoromethyl)silane (2 ml, 19.6 mmol) in THF (30 ml) at room temperature. The suspension was stirred at room temperature for 6 hours and stored at room temperature 18 hours. A mixture of concentrated hydrochloric acid (3 ml) in water (7 ml) was added and the solution was stirred at room temperature for 4 hours. The mixture was concentrated to give the product (3.4 g, 87% yield) which was used without further purification.
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[OH-].[K+].Cl[CH:21](Cl)[C:22]([OH:24])=[O:23].[OH-].[Na+].[CH:28](O)(C)[CH3:29]>O.CO.O>[CH3:2][C:1]1([CH3:3])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH:21]([C:22]([O:24][CH2:28][CH3:29])=[O:23])[O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]1=2
Reactant: O=C(O)C(Cl)Cl
Reactant: CC(C)O
Reactant: CC(C)(c1ccccc1O)c1ccccc1O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1Oc2ccccc2C(C)(C)c2ccccc2O1

Procedure:
A mixture of 2,2'-isopropylidene bisphenol (3.65 g, 0.01594 mol), potassium hydroxide (2.68 g of 85 percent, 0.0478 mol) and dichloroacetic acid (1.31 ml, 0.01594 mol) in 65 ml cf isopropyl alcohol is heated at reflux. After 20 hours at reflux, an additional 1.79 g of 85 percent KOH and 1.31 ml of dichloroacetic acid are added and the reaction mixture is heated at reflux for 2 days. The reaction mixture is then diluted with 200 ml of H2O, acidified by the addition of concentrated HC1 (10 ml) and extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over MgSO4 and concentrated. The residue is washed with petroleum ether to afford 3.7 g of crude product as a red-brown syrup. This material is then purified by an esterification-saponification-esterification procedure (esterification agent methanol, H2SO4). Dry column chromatography yields 0.97 g of crude product, which is saponified (NaOH, MeOH-H2O ), and purified by dry column chromatography to afford 0.60 g of a white solid. Esterification of this material (EtOH, H2SO4) and purification by preparative thin layer chromatography (elution with 1:4 ethyl acetate-hexanes) yields 0.25 g of product as a clear syrup: IR (neat) 3.34, 5.65, 6.95, 8.2, 13.2 cm-1; 1H NMR (CDCl3) δ1.28 (t, 3, CH2CH3), 1.75 and 1.9 (2s, 6, (CH3)2C), 4.24 (q, 2 CH2CH3), (s, 1, CH), 6.9-7.6 (m, 8, Ar--H); m/e 312.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH:6]([CH2:11][CH3:12])[CH2:7][C:8]([OH:10])=O)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[N:41]=[C:40]([NH:42][NH2:43])[CH2:39][N:38]=[C:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:36]=2[CH:50]=1>O1CCCC1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[N:41]=[C:40]([NH:42][NH:43][C:8](=[O:10])[CH2:7][CH:6]([N:5]3[C:1](=[O:18])[C:2]4=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]4[C:4]3=[O:13])[CH2:11][CH3:12])[CH2:39][N:38]=[C:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:36]=2[CH:50]=1
Reactant: CCC(CC(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCC(CC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)N1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 20, 3-phthalimidovaleric acid and carbonyldiimidazole are allowed to react in tetrahydrofuran. To this mixture is added 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine to give 3-phthalimidovaleric acid, 2-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl)hydrazide which is warmed with acetic acid to give N-[2-(8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)butyl]phthalimide
Reaction SMILES: [CH:1](N1CCCCC1)=[O:2].[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Li])=[C:14]([F:19])[C:13]=1[F:20])[CH3:10]>C1COCC1.C1COCC1.CCCCCC>[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:1]=[O:2])=[C:14]([F:19])[C:13]=1[F:20])[CH3:10]
Reactant: [Li]c1ccc(OCC)c(F)c1F
Reactant: O=CN1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C=O)c(F)c1F
Temperature: -20 °C

Procedure:
A solution of 0.1 mol of N-formylpiperidine in 10 ml of THF is added dropwise at -60° C. to the solution of 4-ethoxy-2,3-difluorophenyllithium in THF/hexane prepared according to 1b). The mixture is then warmed to -20° C. in the course of 1 hour. Customary working up (recrystallization from petroleum ether (boiling range 40°-60° C.) gives colourless crystals, m.p. 70° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:20]([F:23])([F:22])[F:21])=[C:9]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]([OH:26])=O.CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH2:50])=[CH:47][CH:46]=1>O>[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH:50][C:24]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([C:20]([F:21])([F:22])[F:23])[CH:7]=3)=[O:26])=[CH:47][CH:46]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2cc(C(F)(F)F)c(SCc3ccccc3)cc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(C(F)(F)F)c(SCc3ccccc3)cc2c1O
Temperature: 37.5 °C
Reaction time: 20 h

Procedure:
A mixture of 0.15 g of 4-hydroxy-6-[(phenylmethyl)thio]-7-(trifluoromethyl)-3-quinolinecarboxylic acid and 1.2 mL of dimethylformamide is treated with 0.075 g of carbonyldiimidazole. The mixture is stirred 20 h at 35-40° C. The solution is cooled to 25° C. and it is treated with 0.075 mL of distilled water and then it is stirred for 10 min. The solution is treated with 0.053 mL of 4-chlorobenzylamine and it is stirred for 18 h. The mixture is diluted with 1.0 mL of distilled water and then it is decanted from a dark, oily precipitate. This precipitate is treated with 1 mL of glacial acetic acid and the mixture is shaken for 5 min. The solid which formed is collected by filtration and it is washed with a few mL of 50% aqueous acetic acid. The solid is dried in a stream of air to give 48 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]([CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:11]1)[CH2:4]/[C:5](=[N:7]/[OH:8])/[NH2:6].CCN(C(C)C)C(C)C.[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>C(Cl)Cl>[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([NH:6]/[C:5](=[N:7]\[OH:8])/[CH2:4][CH:3]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)[CH2:11]2)[C:2]([F:1])([F:26])[F:27])=[O:43])=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N/C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)=N\O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N/C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)=N\O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
In a 10 mL round-bottomed flask, (Z)-4,4,4-trifluoro-N′-hydroxy-3-((3-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)methyl)butanimidamide (120 mg, 302 μmol) and DIEA (117 mg, 158 μl, 906 μmol) were combined with CH2Cl2 (2.00 ml) to give a colorless solution. 4-Fluorobenzoyl chloride (47.9 mg, 302 μmol) in CH2Cl2 (1 ml) was added drop-wise and the resulting mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo to afford 120 mg (38%) of (Z)-4-fluoro-N-(4,4,4-trifluoro-1-(hydroxyimino)-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butyl)benzamide and used as is. MH+=520.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[CH:3]1[CH2:4][C@H:5]([CH3:23])[C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:22].C1CCN2C(=NCCC2)CC1.[C:35]([N:39]=[C:40]=[O:41])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl.C(OCC)(=O)C>[C:35]([NH:39][C:40]([O:22][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH3:21])[C@H:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)[CH2:4][CH:5]3[CH3:23])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@H]1CC2N(C)C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CC1C[C@H]2N(C)C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](OC(=O)NC(C)(C)C)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 70, 51 mg in 4 ml methylene chloride was added DBU (200 microliters) followed by 63.65 mg. t-butylisocyanate. After stirring the mixture for 48 hours at room temperature, the reaction mixture was diluted with ethyl acetate, the organic layer washed with water, brine, dried and concentrated to a residue which was purified by preparative chromatography over silica gel using 3:1 CHCl3 /acetone to yield pure title compound 72.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[Br:12].[H-].[Na+].Cl[CH2:16][C:17]1[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH:21]=1.O>CN(C)C=O>[Br:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:16][C:17]1[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH:21]=1
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(CCl)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(CNc2ccc(C(F)(F)F)cc2Br)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
4-Amino-3-bromobenzotrifluoride (15.0 g, 62.5 mmol) was dissolved in N,N-dimethylformamide (400 mL). Thereafter, sodium hydride (5.0 g, 126 mmol) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 2 hours. Thereafter, an N,N-dimethylformamide (30 mL) solution of the tert-butyl 3-(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (9.20 g, 42.0 mmol) synthesized by a method described in the known methods (European Journal of Organic Chemistry, 4264-4276; 2008 etc.) or a method similar thereto was further added to the reaction solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 3 hours. Subsequently, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=3:1) to obtain tert-butyl 3-(((2-bromo-4-(trifluoromethyl)phenyl)amino)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (6.46 g, 37%) in the form of a colorless amorphous product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]#[N:11])[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[Br:12][C:13]1[CH:14]=[C:15]([SH:19])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.C1C[O:30]CC1>>[Br:12][C:13]1[CH:14]=[C:15]([S:19]([C:2]2[CH:3]=[C:4]([C:10]#[N:11])[S:5][C:6]=2[N+:7]([O-:9])=[O:8])=[O:30])[CH:16]=[CH:17][CH:18]=1
Reactant: Sc1cccc(Br)c1
Reactant: C1CCOC1
Reactant: N#Cc1cc(Br)c([N+](=O)[O-])s1
Solvent: CCN(CC)CC
Product: N#Cc1cc(S(=O)c2cccc(Br)c2)c([N+](=O)[O-])s1
Reaction time: 1 h
Yield: 60 %

Procedure:
A 12-L, three neck, round bottom flask equipped with a mechanical stirrer and temperature probe was charged with 4-Bromo-5-nitro-thiophene-2-carbonitrile (Example 25: step d; 273 g, 1.174 mol), 3-bromothiophenol (127 mL, 1.232 mol) and THF (4L). A cold water bath was added. Triethylamine (172 mL, 1.232 mol) was charged to a 250 mL addition funnel and added dropwise to the mixture over 45 min, resulting in a temperature increase from 16.9° C. to 22.3° C. After 1 hour, the reaction was complete and transferred in portions to a 5-L rotary evaporator bulb and concentrated to dryness under vacuum. The solids were transferred to a 10-L glass carboy, diluted with EtOAc (2L) and satd. NaHCO3 (2L) and stirred vigorously. The resulting solid precipitate was removed by filtration, washed with H2O (1L) and dried in a vacuum oven resulting in the title compound as a bright yellow powder (241.56 g, 60%). 1H-NMR (DMSO): δ 8.0 (1H, s), 7.8 (1H, d), 7.6 (1H, d), 7.3 (1H, t), 7.1 (1H, s).
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([N:17]1[CH2:18][CH2:19][N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl 2,3-dibromopropionate (142.7 g, 0.549 mol) in dry toluene (2000 mL) was added N,N′-dibenzylethylene diamine (132 g, 0.549 mol), followed by triethylamine (110.8 g, 1.098 mol), under N2 at 40° C. (a dense white precipitate formed immediately, thus good stirring was necessary). The mixture was heated at 80° C. overnight, cooled and filtered. The filtrate was then washed with H2O, dried over MgSO4, and concentrated under reduced pressure. The residue oil was taken on to the next step without further purification (GC-MS shows one peak at 6.79) or purified by column chromatography (EtOAc/hexane 1:4). Weight of crude product: 169.6 g (91%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([Cl:19])[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:8])[CH3:7].C(Cl)Cl>C(Cl)(Cl)Cl>[C:6]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([Cl:19])[CH:13]=[CH:14][C:15]=2[S:2]([Cl:1])(=[O:5])=[O:3])[CH2:10]1)(=[O:8])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CCc2cccc(Cl)c2C1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2c(S(=O)(=O)Cl)ccc(Cl)c2C1
Temperature: 0 °C

Procedure:
51.75 ml. (0.78 mole) of chlorosulfonic acid was added dropwise with stirring to a solution of 20.7 g. (0.099 mole) 2-acetyl-8-chloro-1,2,3,4-tetrahydroisoquinoline in 25 ml. of methylene chloride at -70° C. To effectuate a solution of the reactants 10 ml. of dry chloroform was added and the reaction mixture stirred for one hour at -70° C. The reaction mixture was then refluxed at 40°-45° C. for 2 hours and then stirred at ambient temperature for about 16 hours. The reaction mixture was then cautiously poured onto one liter of ice. The crude reaction product was then extracted into methylene chloride (3×100 ml.), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness at reduced pressure to afford 2-acetyl-8-chloro-5-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline as whitish yellow solid with a melting point of 105°-115° C.
Reaction SMILES: [O:1]1[C:5]([C:6]2[C:7]3[N:8]([C:16]([C:19]([O:21]CC)=[O:20])=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)=[CH:4][N:3]=[CH:2]1.C1COCC1.[OH-].[Na+].Cl>O.CCO>[O:1]1[C:5]([C:6]2[C:7]3[N:8]([C:16]([C:19]([OH:21])=[O:20])=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Temperature: 50 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a mixture of ethyl 8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (2.47 g), THF (75 mL) and EtOH (25 mL) was added 8N aqueous sodium hydroxide solution (1.42 mL), and the mixture was stirred at 50° C. for 4 hr. To the reaction mixture was added 1N hydrochloric acid at 0° C., and the mixture was diluted with water. The insoluble substance was collected by filtration, and washed with cooled IPE to give the title compound (2.21 g).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1.O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[CH:23][N:24]=1
Reactant: COc1ccc(C#N)cn1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (1.8 g, 8.7 mmol) in toluene (50 ml) at 0° C., trimethylaluminum (2M solution in toluene, 5.2 ml, 10.4 mmol) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 6-methoxy-3-cyanopyridine (1.75 g, 13 mmol) in toluene (100 ml) was added over 10 minutes and the mixture was heated to 85-90° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride and methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1000 ml) and filtered. The white solid (2 g, 75%) was used in the next reaction without further purification. Anal. Calc'd. for C14H16N3SClO3.0.5 H2O: C, 47.93, H, 4.88, N, 11.98. Found: C, 48.01, H, 4.82, N, 11.32.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:8]=1)C.[OH-].[Li+].C1COCC1.CO>O>[Cl:19][C:14]1[CH:13]=[C:12]([C:10]2[N:9]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:8]=[C:7]([CH2:6][C:5]([CH3:35])([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:4]([OH:36])=[O:3])[CH:11]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCOC(=O)C(C)(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-n2nc(CC(C)(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Yield: 89.4 %

Procedure:
The title compound was prepared by Method 2 from 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionic acid ethyl ester (0.11 g, 0.21 mmol), lithium hydroxide (88 mg, 2.1 mmol), THF (2.3 mL), MeOH (0.87 mL) and water (0.87 mL) giving 93 mg (90%) of 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionic acid. HPLC: Rt=3.42 (Method B). MS (ES+): mass calculated for C27H24Cl2N2O3, 494.12; m/z found 495.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.50 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.26-7.19 (m, 3H), 7.16 (d, J=9.0 Hz, 2H), 7.08 (d, J=7.1 Hz, 1H), 7.03 (dd, J=2.0 Hz, 8.4 Hz, 1H), 6.97 (d, J=9.0 Hz, 2H), 6.20 (s, 1H), 3.78 (s, 3H), 3.37 (d, J=14.0 Hz, 1H), 3.14 (d, J=14.0 Hz, 1H), 2.31 (s, 3H), 1.46 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:31])[N:20]=[CH:19][N:18]=1>>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[O:23][C:21]1[CH:22]=[CH:17][N:18]=[C:19]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:20]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1cc(Oc2c(Cl)cccc2Cl)ncn1
Product: COc1cc(Nc2nccc(Oc3c(Cl)cccc3Cl)n2)ccc1-n1cnc(C)c1
Yield: 29 %

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 4-chloro-6-(2,6-dichloro-phenoxy)-pyrimidine. It was obtained as a yellow solid in 29% yield.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>O>[NH:13]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: c1ccc(COCCCCNCCCCOCc2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: OCCCCNCCCCO
Reaction time: 18 h

Procedure:
To a solution of bis(4-(benzyloxy)butyl)amine (300 mg, 0.879 mmol) was in a mixed solvent of Dioxane (5 ml)/Water (5 mL), was added PdOH2 (30.8 mg, 0.044 mmol). The reaction was stirred under H2 at 40 PSI for 18 h. LC-MS showed no starting material and formation of desired product. The mixture was filtered through a pad of celite, washed with dioxane/water (10 mL, 1/1). The filtrate was concentrated and dried over high vacuum pump to give the titled compound (130 mg, 0.806 mmol, 92% yield). LC-MS Method A: m/e=162.01 [M+1]; Rt=0.18 min.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([SH:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:21]Cl)[CH:16]=1>O.CO>[F:1][C:2]1[C:10]2[N:9]=[C:8]([S:11][CH2:21][C:17]3[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=[CH:19][N:18]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2[nH]c(S)nc12
Reactant: COc1ccnc(CCl)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccnc(CSc2nc3c(F)cccc3[nH]2)c1

Procedure:
To a solution of 4-fluoro-2-mercapto-1H-benzimidazole (1.15 g, 0.0068 mol) in methanol (60 ml) NaOH (0.54 g, 0.014 mol) dissolved in water (3 ml) and 4-methoxy-2-chloromethylpyridine hydrochloride (1.32 g, 0.0068 mol) dissolved in methanol (20 ml) were added in the given order. The mixture was refluxed for one hour whereupon the solution was evaporated. The residue was partitioned between methylene chloride and water. After separation the organic solution was dried over MgSO4 and evaporated giving an oil which was purified on silica gel (50 g) using 1% methanol in methylene chloride as eluent. In this way the title compound was obtained (1.35 g, 69%). NMR data for the product is given below.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH:26]1([C:29]([N:31]2[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]2)=[O:30])[CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][N:13]([C:37]([CH:34]3[CH2:33][CH2:32][N:31]([C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])[CH2:36][CH2:35]3)=[O:38])[CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH3:9])=[O:7])=[CH:24][CH:25]=1
Reactant: O=C(O)C1CCN(C(=O)C2CC2)CC1
Reactant: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)C3CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 633, step 3 and 1-(cyclopropylcarbonyl)piperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 97, the title compound was obtained.