Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[C:29]=4[F:30])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1cccc(F)c1F
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(F)c4F)c3O2)cc1
Yield: 16.6 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,3-difluorophenyl)boronic acid (0.618 g, 3.91 mmol) generally according to the procedure described for Intermediate 184 provided 0.090 g (77%) of (±)-[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33].C(O)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH:22][C:32]([C:31]([CH3:36])([CH3:35])[CH3:30])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 49.1 %

Procedure:
3.36 g (13.1 mmol) of 1,4-dibenzyl-2-aminomethylpiperazine prepared according to a protocol identical to the one used in steps 6.1 and 6.2 of Example 6 are dissolved in 5.5 ml (3 equivalents; 39.3 mmol) of triethylamine and 100 ml of dichloromethane and are treated by rapid dropwise addition of 2.63 ml (1.5 equivalents; 19.6 mmol) of 2,2-dimethylpropanoyl chloride dissolved in 30 ml of CH2Cl2. The solution is refluxed for 4 hours. A few ml of ethanol are then added, after which the solution is washed twice with water, once with saturated NaHCO3 solution and then with water until a neutral pH is obtained. After drying the organic phase (MgSO4), filtration on paper and evaporation of the solvents, the residue is chromatographed on a column of silica gel, eluting with an MeOH/CH2Cl2 mixture (0.5/99.5 v/v). 2.44 g of 1,4-dibenzyl-2-tert-butylcarbonylaminomethylpiperazine are thus obtained in the form of a viscous product. Yield: 49%. Rf═0.36 (95/5 v/v CH2Cl2/MeOH).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=2[O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=3[F:43])=[O:34])=[C:28]([F:44])[CH:27]=2)[CH:17]=1)=[O:15])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:79]([NH2:81])[CH3:80].Cl>O1CCCC1.O>[CH2:79]([NH:81][C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=2[O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=3[F:43])=[O:34])=[C:28]([F:44])[CH:27]=2)[CH:17]=1)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:45])[CH3:80]
Reactant: CCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O)sc34)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Temperature: 60 °C

Procedure:
To a stirred suspension of (2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid (100 mg, 0.16 mmol) in 10 ml of anhydrous tetrahydrofuran were added HATU (73 mg, 0.19 mmol) and N,N-diisopropylethylamine (62 mg, 0.48 mmol). The mixture was heated at 60° C. for 10 minutes, followed by addition of 2M ethylamine solution in THF (0.25 ml, 0.50 mmol). The mixture was heated at 60° C. for another 5 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give tert-butyl (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate as white solid. Yield: 73 mg, 70%.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:17]C)[CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COc1ccc2sc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1c2cc(O)ccc2sc2c([N+](=O)[O-])ccc(Cl)c12
Reaction time: 48 h

Procedure:
The requisite 1-chloro-7-hydroxy-4-nitrothioxanthone was prepared as follows: To a suspension of 5.0 g of 1-chloro-7-methoxy-4-nitro-thioxanthone in 50 ml of methylene chloride was added 20 ml of boron tribromide in methylene chloride (1M). The mixture was stirred for two days, and an additional 20 ml of boron tribromide was added. The mixture was stirred for three hours at room temperature and heated under reflux for two hours. An additional 20 ml of boron tribromide was added and the mix was heated under reflux for two hours. The mixture was cooled in an ice bath and 50 ml of methanol was added carefully. The solution was heated under reflux for one hour, and the solvent was removed in vacuo. The residue was boiled in about 50 ml of ethanol, collected, and retreated with hot ethanol to provide the product as an orange powder, mp 240°-254° (dec).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH2:27][CH:28]=O)[C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:30][NH2:31]>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH2:27][CH2:28][NH:31][CH3:30])[C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CN
Reactant: N#Cc1cccc(-c2ccc(C(CC=O)C(=O)Nc3cc(Cl)cc(Cl)c3)cc2)c1
Solvent: ClCCCl
Product: CNCCC(C(=O)Nc1cc(Cl)cc(Cl)c1)c1ccc(-c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
A mixture of 2-(3′-cyano-biphenyl-4-yl)-N-(3,5-dichloro-phenyl)-4oxo-butyramide (300 mg, 0.71 mmol) and MeNH2 (2M in THF, 1.77 mL, 3.54 mmol, 5 eq) in 1,2-dichloroethane (3.5 mL) was stirred at r.t. for 1 h and then Na(AcO)3BH (299 mg, 1.4 mmol, 2 eq) was added. The reaction mixture was stirred at r.t. for 16 h. The mixture was then partitioned between EtOAc (20 mL) and 10% NaHCO3 (10 mL) and the organic phase separated. The organic phase was washed with 10% NaHCO3 (10 mL×2), saturated brine (10 mL), dried (Na2SO4), and concentrated. Chromatography on silica gel (Et3N/MeOH/CH2Cl2 1:10:90) gave 56.5 mg (18%) of the title compound as a yellowish gum. 1H NMR (300 MHz, CDCl3): δ 7.89 (m, 2H), 7.72 (m, 1H), 7.61 (m, 7H), 7.14 (t, 1H), 4.04 (dd, 1H), 2.85 (t, 2H), 2.59 (s, 3H), 2.50 (m, 1H), 2.16 (m, 1H). MS(ESI): 438.0 (M+1), 440.0 (M+3).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(O)[CH3:8].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:8]
Reactant: Cc1ncsc1C(C)(O)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=C(c1ccccc1)c1scnc1C

Procedure:
1-(4-Methyl-5-thiazolyl)-1-phenylethanol (2.5g) in chloroform (25ml) was treated with thionyl chloride (4.5ml). The mixture was heated under reflux overnight and then evaporated to dryness. Aqueous sodium hydrogen carbonate was added and the mixture was extracted with dichloromethane. The material thus obtained was purified by flash chromatography to give the title compound as an oil. Treatment with anhydrous hydrogen chloride in diethylether gave 1-(4-methyl-5-thiazolyl) -1-phenylethene hydrochloride, m.p. 131-133.5° C.
Reaction SMILES: [F:1][C:2]([F:18])([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:3]([O:5]CC)=[O:4].CO.[OH-].[Na+:22]>O>[F:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([F:18])[C:3]([O-:5])=[O:4].[Na+:22]
Reactant: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])C(F)(F)c1ccc2ncccc2c1

Procedure:
8.1 g (32.2 mmol) of ethyl difluoro(quinolin-6-yl)acetate was added to a reaction balloon. Methanol (40.5 mL) and water (2.9 mL) were added. To this solution, 1.29 g sodium hydroxide (32.2 mmol) was added at room temperature for 16 h. The resulting solids were filtered off and dried under vacuum. Yield 4.5 g (18.4 mmol; 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].CS(C)=[O:26]>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[OH:26])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C(c2ccncc2)c2ccc(F)c(F)c2)cc1F
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Product: OC(c1ccncc1)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1
Yield: 79.9 %

Procedure:
A solution of 5.66 g (0.0179 mole) of 4-[bis(3,4-difluorophenyl)methyl]pyridine and 12 drops of 50% NaOH in 50 ml of DMSO was stirred at room temperature for 4.5 h with air bubbling through the reaction mixture. Water was added to the solution, and a tan precipitate was collected. This was recrystallized from CH2Cl2 -hexane to give 4.75 g (79.9%) of the title compound as a white, crystalline solid, mp 147°-149° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:37])([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)(=[O:15])=[O:14])([O-])=O.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.O>CCO>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:37])([C:29]([F:32])([F:31])[F:30])[C:33]([F:34])([F:35])[F:36])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c([N+](=O)[O-])c1
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c(N)c1
Reaction time: 18 h
Yield: 87.5 %

Procedure:
To a solution of 2-(4-(4-((2,4-dinitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.13 g, 0.22 mmol) in EtOH (5 mL) was added palladium, 10 wt % (dry basis) on activated carbon, wet, Degussa type E101 NE/W, water about 50% (26 mg, 0.24 mmol, Sigma-Aldrich, St. Louis, Mo.). The reaction vessel was carefully evacuated and backfilled with hydrogen. This was repeated twice and then the solution was left under an atmosphere of hydrogen (1 atm; 101.3 kpascal) for 18 h. The reaction vessel was then carefully evacuated and backfilled with N2. The solution was filtered through a syringe filter and the filtrate was concentrated onto silica. Purification by silica gel chromatography (0 to 6% MeOH/DCM) afforded 2-(4-(4-((2,4-diaminophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (96 mg) as an off-white solid.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CS(O[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[C:31]([CH2:38][CH2:39][NH:40][C:41](=[O:43])[CH3:42])[CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=O)=O.Cl>O.CO>[C:41]([NH:40][CH2:39][CH2:38][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:30]=1[CH:29]=[C:28]([O:27][CH2:26][CH2:25][CH2:24][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=3)=[CH:7][CH:8]=1)[CH:37]=[CH:36]2)(=[O:43])[CH3:42]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(=O)NCCc1cccc2ccc(OCCCOS(C)(=O)=O)cc12
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OCCCOc3ccc4cccc(CCNC(C)=O)c4c3)cc2)cc1
Reaction time: 0.33 h

Procedure:
In a 100 ml round-bottomed flask containing 30 ml of methanol, 0.06 g of sodium is added in small portions. When the sodium has been completely used up, 0.0033 mol of methyl 4′-hydroxy[1,1′-biphenyl]-4-carboxylate is added and the mixture is stirred for 20 minutes. The methanol is removed by evaporation under reduced pressure, the residue is taken up in 15 ml of DMF, and then 0.0027 mol of the compound obtained in Step B is added. The reaction mixture is then heated at reflux for 12 hours and subsequently cooled and poured into 100 ml of water and 10 ml of 3M HCl. After extraction with ethyl acetate, the organic phase is washed with a 10% sodium hydroxide solution and then with water. After drying over MgSO4 and removal of the solvent by evaporation under reduced pressure, the title compound is purified by chromatography on silica gel.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([OH:19])[CH2:11][C@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=[O:14])=[CH:6][C:5]=1[CH3:20].[CH3:21]I>C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([O:19][CH3:21])[CH2:11][C@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=[O:14])=[CH:6][C:5]=1[CH3:20]
Reactant: CI
Reactant: C=CC[C@@H](C[C@@H](O)c1ccc(F)c(C)c1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](C[C@@H](OC)c1ccc(F)c(C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 217 mg NaH in 20 mL THF was added (S)-2-((R)-2-(4-fluoro-3-methylphenyl)-2-hydroxyethyl)pent-4-enoic acid in 5 mL THF slowly at room temperature. To this mixture was added methyl iodide (289 μL) dropwise followed by stirring for 3 h at 25° C. The reaction was quenched by the addition of 10 mL 1M HCl and then extracted with ethylacetate (3×30 mL). The combined organic layers were washed with brine (2×20 mL) and dried over sodium sulfate. Evaporation of solvent afforded an oil which was used without further purification in the next reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:8]([OH:10])=O.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]1>>[C:25]1([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:8](=[O:10])[CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:19]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(O)C(c1ccccn1)c1ccccn1
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C(c1ccccn1)c1ccccn1

Procedure:
Bis(2-pyridyl)acetic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)bis(2-pyridyl)acetamide.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)=[O:4]>CCOC(C)=O.[Pd]>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:4]
Reactant: CNC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(Oc2ccc(N)cc2)c1
Yield: 56.4 %

Procedure:
A slurry of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H2 atm (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95% CH2Cl2). The resulting oil solidified under vacuum overnight to give 4-(3-(N-methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([NH2:33])[CH2:29][CH2:30][O:31][CH3:32]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:33]=[C:28]([CH2:29][CH2:30][O:31][CH3:32])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: COCCC(N)=NO
Product: CCc1ccc(C2CC(c3nc(CCOC)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
60 mg (0.17 mmol) of the compound from Example 38A and 32 mg (0.26 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 31 mg (42% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:10][C:6]=2[CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:10][C:6]=2[CH:5]=1
Reactant: CCOC(=O)Cc1nc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1nc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of ethyl 5-nitrobenzimidazole-2-acetate (206 mg, 0.83 mmol, 1 equiv.), 10% palladium on carbon (88 mg, 0.08 mmol, 0.1 equiv.), and absolute ethanol (8 mL) was stirred at room temperature under hydrogen (balloon). After 45 minutes, the reaction was filtered through Celite®, and the filtrate was concentrated to afford crude ethyl 5-aminobenzimidazole-2-acetate. This was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[S:7][CH:8]=[C:9]([Br:11])[CH:10]=1)[OH:5].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15]>C(Cl)Cl>[Br:11][C:9]1[CH:10]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:14](=[O:15])[C:13]([F:20])([F:19])[F:12])[S:7][CH:8]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCC(O)c1cc(Br)cs1
Solvent: ClCCl
Product: O=C(NCCC(O)c1cc(Br)cs1)C(F)(F)F

Procedure:
3-Amino-1-(4-bromothiophen-2-yl)propan-1-ol and ethyl trifluoroacetate (2.0 mL) were stirred in CH2Cl2 (10 mL) at room temperature overnight. Concentration under reduced pressure gave N-(3-(4-bromothiophen-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide which was used in the next step without additional purification. Yield (0.77 g, 28% in three steps); 1H NMR (400 MHz, DMSO-d6) δ 9.36 (br.s, 1H), 7.51 (d, J=1.5 Hz, 1H), 6.90-7.00 (m, 1H), 5.86 (d, J=5.0 Hz, 1H), 4.75-4.83 (m, 1H), 3.20-3.30 (m, 2H), 1.80-1.94 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14](OC(=O)C)(=O)C>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](=[O:13])[CH3:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 3-nitrophenyl acetic acid (20 g), pyridine (44 g) and acetic anhydride (106 g) was refluxed for four hours. Complete disappearance of starting material was observed by tlc (silica gel eluted with 1:1 parts by volume diethyl ether:hexane), and the brown solution was then evaporated to dryness in vacuo at 40°. The resulting residue was refluxed in the presence of concentrated HCl (7.5 ml) and ethanol (78 ml) for one hour; and to the hydrolysis product was added ice water (400 ml) and the precipitating 3-nitrophenyl acetone was filtered and washed with water. Additional product was obtained by extracting the filtrate with methylene chloride, drying over sodium sulfate, and evaporating the organic solvents. The crude products were combined and dissolved in a minimum amount of methanol:methylene chloride (1:1 parts by volume). Silica gel (30-50 g, flash chromatography, EM 230-400 mesh) was added and the solvent evaporated. The dried silica gel was placed on a column (3 in.×6 in.) containing the same silica gel and eluted with 4:6 parts by volume ethyl acetate:hexane. The solution containing the desired product was evaporated to give the title compound. NMR for this product (in CDCl3) shows a 3 proton singlet at 2.34 ppm; a 2 proton singlet at 3.63 ppm; a 2 proton multiplet at 7.5 ppm; and a 2 proton multiplet at 8.0 ppm.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])=[O:23].[O-]CC.[Na+].[CH:29]([S:31]([CH2:34][CH3:35])(=O)=[O:32])=[CH2:30]>C(O)C>[CH2:29]([S:31]([CH2:34][CH2:35][O:21][N:20]=[CH:19][C:4]1[C:3]([S:22]([CH3:24])=[O:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=1)=[O:32])[CH3:30]
Reactant: C=CS(=O)(=O)CC
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCS(=O)CCON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O

Procedure:
In a manner similar to that employed in Example 12 an ethanol solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime was reacted with sodium ethoxide and ethyl vinyl sulfone to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-[2-(ethylsulfinyl)ethyl]oxime, m.p.144-148° C. Compound 27.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[C:10]=2[CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[CH:35]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH:45]([CH3:48])[CH:46]=O)=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[C:10]=2[CH:15]=[CH:46][CH:45]([CH3:48])[CH2:44][C:41]2[CH:40]=[CH:39][C:38]([CH:35]([CH3:37])[CH3:36])=[CH:43][CH:42]=2)=[CH:7][CH:8]=1
Reactant: CC(C=O)Cc1ccc(C(C)C)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: Cc1noc(-c2ccc(Br)cc2)c1C=CC(C)Cc1ccc(C(C)C)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-triphenyl-phosphonium bromide and 3-(4-isopropyl-phenyl)-2-methyl-propionaldehyde