Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[C:18]([O:20]CC)=[O:19].Cl>[OH-].[Na+].O>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(=O)Nc1cccc(NC(=O)C(=O)OCC)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)Nc1cccc(NC(=O)C(=O)O)c1Cl

Procedure:
Diethyl N,N'-(2-chloro-m-phenylene)dioxamate (0.50 gram) is heated at reflux in 1.0N aqueous sodium hydroxide (10 ml.) for one hour. The reaction mixture is diluted with water (15 ml.). Concentrated hydrochloric acid is added to pH 3 and the solid product collected by filtration (0.27 grams, M.P.> 320°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[NH:12][C:13]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:18]=3[NH:17][C:16]3[N:24]=[CH:25][CH:26]=[CH:27][C:15]=3[C:14]=2[N:28]=1.[C-:29]#[N:30].[Na+]>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:29]#[N:30])[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[NH:12][C:13]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:18]=3[NH:17][C:16]3[N:24]=[CH:25][CH:26]=[CH:27][C:15]=3[C:14]=2[N:28]=1
Reactant: ClCc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: N#CCc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Yield: 45.3 %

Procedure:
A solution of 2-[2,6-dichloro-4-(chloromethyl)phenyl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepine (8.7 mg, 0.02 mmol), sodium cyanide (2.0 mg, 0.04 mmol) in dimethyl sulfoxide (1.0 mL) was stirred at 25° C. for 1 hour. The reaction mixture was diluted with methanol and purified on preparative LCMS at pH 10 to give the desired product (3.8 mg, 45%). LC/MS: 419 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[C:13]2=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:15]([CH2:16][CH3:17])=[C:11]3[N:12]2[C:7](=[CH:8][CH:9]=[CH:10]3)[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]([CH2:3][C:5]1[CH:6]=[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[N:12]2[C:13]=1[C:14]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[C:15]3[CH2:16][CH3:17])[CH3:25]
Reactant: CCc1c(-c2ccc(O)cc2)c2c(C(=O)N(C)C)cc3cccc1n32
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(O)cc2)c2c(CN(C)C)cc3cccc1n32
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
4-Ethyl-3-(4-hydroxyphenyl)pyrrolo[2,1,5-cd]indolizine-2-carboxylic acid dimethylamide (0.14 g, 0.37 mmol) was dissolved in 25 ml of dry tetrahydofurane under a nitrogen atmosphere. Lithium aluminium hydride (20 mg, 0.53 mmol) was added in portions and stirring was continued for 1/2 hours. The reaction mixture was quenched with 0.02 ml of water, 0.04 ml of a 2 M sodium hydroxide solution and then 0.04 ml of water again. The resulting precipitate was filtered off and washed with ethyl acetate. The solvent was removed and the crude product was purified by column chromatography over silica gel 60, using 10% of methanol in dichloromethane as the eluent. Fractions containing the product were collected and the solvent was evaporated to afford 63 mg (53%) of the title compound as a yellow solid. M.p. 176-178° C. MS(SP): m/z 318 (M+). 1H-NMR (DMSO-d6, 300 MHz) δ: 1.35 (t, 3H); 2.27 (s, 6H); 3.10 (q, 2H); 3.94 (s, 2H); 6.98 (d, 2H); 7.25 (s, 1H); 7.57 (d, 2H); 7.72 (dd, 1H); 8.02 (d, 1H); 8.09 (d, 1H); 9.70 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)=[CH:7][CH:6]=[C:5]([O:36][CH3:37])[N:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])=[CH:7][CH:6]=[C:5]([O:36][CH3:37])[N:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)nc3OC)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(OC)nc3OC)c2)=C(C)C1=O
Yield: 86.2 %

Procedure:
N-(2,6-Dimethoxypyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.100 g, 0.196 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.079 g, 0.169 mmol, 87%).
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOCC.O.OO.[Ni]>[C:2]1([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:14]=[N-:15])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Ni]
Agent: OO
Solvent: O
Solvent: CCOCC
Product: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 0.59 g (3 mmol) of benzophenone hydrazone in 12 ml of ether is added dropwise at room temperature to a suspension of 2.95 g of nickel peroxide hydrate in 12 ml of ether, the mixture is stirred for one hour and the violet solution is filtered with suction through Celite and concentrated. The 3 mmol of diphenyldiazomethane obtained in this way are dissolved in 32 ml of absolute acetone and, while cooling in ice, added dropwise to a solution of 1.31 g (2.5 mmol) of 2-[N-(1S -menthyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)2-azabicyclo[3.3.0]octane-3-carboxylic acid (see Example 45) in 32 ml of absolute acetone. The mixture is then stirred at room temperature for 38 hours and concentrated, and the crude product is purified by column chromatography on silica gel (mobile phase toluene/ethanol 99.5:0.5 and cyclohexane/ethyl acetate 8:2).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Cl-].[Cl-].[Al+3].[C:16]1([O:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([C:19]1[CH:20]=[CH:21][C:16]([O:22][CH3:23])=[CH:17][CH:18]=1)=[O:5]
Reactant: O=C(Cl)c1cc(I)ccc1Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(I)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
2-chloro-5-iodobenzoyl chloride (10.7 g, 35.5 mmol) was dissolved in methylene chloride (200 mL). The resulting mixture was cooled in an ice-water bath. To the mixture was added aluminum trichloride (10.4 g, 78.2 mmol), and then added dropwise a solution of anisole (4.2 g, 38.9 mmol) in methylene chloride (50 mL). After the completion of dropwise addition, the resulting mixture was warmed up to room temperature and stirred for 3 hr. The reaction mixture was poured into ice-water and quenched. To the reaction mixture was added 3 mol/L hydrochloric acid. The resulting mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with methylene chloride (150 mL×2). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure. The resulting crude product was purified with a silica-gel column chromatography (ethyl acetate:petroleum ether=0-1:100) to produce 12.0 g of a product in a yield of 91%.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][P:8]([O-:14])[O:9][CH2:10][CH:11]([CH3:13])[CH3:12]>>[CH3:7][P:8]([CH2:1][CH:2]1[O:6][C:4](=[O:5])[CH2:3]1)(=[O:14])[O:9][CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)COP(C)[O-]
Reactant: C=C1CC(=O)O1
Product: CC(C)COP(C)(=O)CC1CC(=O)O1

Procedure:
A mixture of 4.2 parts of diketene and 0.33 parts of bis-(t-butylcyclohexyl)perdicarbonate was added dropwise over 1 hour to 27.2 parts of vigorously stirred isobutyl methylphosphonite which was heated at 85° in a nitrogen atmosphere. After the addition the reaction mixture was passed down a wiped-wall still at a temperature of 50° C. and a pressure of 0.13 mb to remove the excess phosphonite. The residue was distilled on the wiped wall still at a temperature of 75° and a pressure of 0.13 mb. The product isobutyl methyl(2-oxo-4-oxetanylmethyl)phosphinate was obtained as a colourless oil with a characteristic infra-red band at 1820 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])([C:10]#[N:11])[C:12]#[N:13])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc([N+](=O)[O-])cc1
Yield: 10.8 %

Procedure:
Using 5.00 g of (4-nitrobenzyl)malononitrile, 60 ml of N,N-dimethylformamide, 1.10 g of sodium hydride (60% in oil), and 4.85 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.80 g of 2-(4-nitrobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (18)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21](Br)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:33]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CC(NC(=O)c1ccc(Br)s1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)c1cccc(-c2ccc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)s2)c1
Yield: 73.1 %

Procedure:
In a 5 ml glass tube were placed 5-bromo-thiophene-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.12 mmol), 3-isopropyl phenyl boronic acid (37 mg, 0.23 mmol), Cs2CO3 (114 mg, 0.34 mmol), Pd(PPh3)2Cl2 (6.4 mg, 0.009 mmol), DME (0.8 mL), ethanol (0.2 mL), and a magnetic stir bar. The vial was sealed with septum and placed into the Microwave cavity. The vial was irradiated in a Microwave synthesizer at 140° C. for 20 min. The mixture was diluted with EtOAc and washed with 1N HCl and water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (42 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N+:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])#[C-:15]>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]1[O:6][CH:15]=[N:14][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Product: COC(=O)c1ncoc1-c1ccc([N+](=O)[O-])cc1Cl

Procedure:
The procedures of Example 1-(l) were followed, except for replacing the 2-methoxy-4-nitrobenzoic acid with 18.1 g (0.09 g) of 2-chloro-4-nitrobenzoic acid and replacing the ethyl isocyanoacetate with 9.9 g (0.1 mol) of methyl isocyanoacetate, to give 16.2 g (0.057 mol, 63.7% based on the 2-chloro-4-nitrobenzoic acid) of the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:14][C:15]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=1[CH:17]=O>>[OH:14][C:15]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: Cc1ccc(O)c(C=O)c1
Product: Cc1ccc(O)c(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1

Procedure:
6-[4-(2-Hydroxy-5-methyl-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-hydroxy-5-methylbenzaldehyde (available from Aldrich) (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.23 (s, 3H), 2.58-2.63 (m, 4H), 3.48-3.63 (m, 4H), 3.69 (s, 2H), 5.39 (s, 1H), 6.73-6.78 (m, 2H), 6.98-7.00 (m, 1H), 7.85 (s, 1H), 10.10 (br s, 1H), 12.75 (br s, 1H). Mass spectrum (ES) MH+=301.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1C(O)=O.[OH:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][C:13]=1[C:21]([NH2:23])=[O:22]>>[NH:3]1[CH2:2][CH2:7][CH:6]([O:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:13]=2[C:21]([NH2:23])=[O:22])[CH2:5][CH2:4]1
Reactant: NC(=O)c1sc2ccccc2c1O
Reactant: O=C(O)N1CCCCC1Cl
Product: NC(=O)c1sc2ccccc2c1OC1CCNCC1

Procedure:
Referring to Scheme 4, methoxybenzothiophene ester 1, for example, is converted to the corresponding hydroxybenzothiophene carboxylic acid 2 with boron tribromide. Carboxylic acid 2 is coupled with Hca amine to yield hydroxybenzothiophene amide 3. 1-Substituted 4-hydroxypiperidine 4 is coupled with amide 3 to yield (piperidin-4-yloxy)benzothiopheneamide 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[S:15](=[O:19])(=[O:18])[NH:16][CH3:17].[C:20](Cl)(=O)C.C(O)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH3:20])=[O:12])=[CH:4][C:3]=1[S:15](=[O:19])(=[O:18])[NH:16][CH3:17]
Reactant: CNS(=O)(=O)c1cc(C(=O)CCC(=O)O)ccc1Cl
Reactant: CC(=O)Cl
Solvent: CO
Solvent: CCO
Product: CNS(=O)(=O)c1cc(C(=O)CCC(=O)OC)ccc1Cl

Procedure:
A mixture of 12 g of 4-(4-chloro-3-methylsulfamoylphenyl)-4-oxobutanoic acid and 1.2 g of acetyl chloride in 120 ml of methanol is reacted for 48 hours and worked up, analogously to the instructions indicated in Example 2(a). Methyl 4-(4-chloro-3-methylsulfamoylphenyl)-4-oxobutanoate of melting point 112°-114° C. (from ethanol) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:18])([F:17])[CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])[NH2:5].[F:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>ClCCCl.ClC(Cl)C>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([NH:5][C:27]([NH:26][C:24](=[O:25])[C:23]2[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:22]=2[F:21])=[O:28])[CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:17])([F:18])[CH:11]([F:16])[C:12]([F:14])([F:15])[F:13]
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Temperature: 40 °C
Yield: 83.4 %

Procedure:
To a solution of 1.31 g 3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy) aniline in 5 mL 1,2-dichloroethane under an atmosphere of nitrogen at room temperature was added 0.87 g 2,6-difluorobenzoyl isocyanate dissolved in 10 mL dichloroethane dropwise over a 10 minute period. The mixture was stirred, warmed to 40° C. for a one hour period, then concentrated under vacuum to a brown solid 2.0 g. The mixture was chromatographed using a Michel-Miller low pressure silica gel column eluted with 4:1 dichloromethane/heptane. Like fractions were pooled and concentrated under vacuum to give 1.67 g of a light tan solid, mp 156-7° C. Proton and 19F nmr spectra were consistent with the proposed structure. Anal. calcd C17H7Cl2F9N2O3: C, 38.58; H, 1.33; N, 5.29. Found: C, 38.64; H, 1.40; N, 5.44.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)=[CH:5][C:4]=1[C:32]([F:35])([F:34])[F:33])#[N:2].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][N:9]([CH2:27][C:28]([F:29])([F:30])[F:31])[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:32]([F:33])([F:34])[F:35])[CH:5]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N(CCOc2ccc(N)cc2)CC(F)(F)F)cc1C(F)(F)F
Reaction time: 0.67 h
Yield: 92.7 %

Procedure:
To a solution of 1,1-dimethylethyl [4-({2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]ethyl}oxy)phenyl]carbamate (0.132 g, 0.262 mmol; Example 27B) in CH2Cl2 (5 mL) at rt was added Et3SiH (0.10 mL, 0.66 mmol), followed by TFA (2 mL). The mixture was stirred 40 min and slowly poured into satd NaHCO3. The whole was extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo, yielding 0.098 g of the title compound as a colorless gum which was used without further purification: MS (APCI) m/z 404 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH2:21][CH:22]=O>>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[C:5]2[N:6]([CH:21]=[CH:22][N:8]=2)[CH:7]=1
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Reactant: O=CCCl
Product: Cc1c(Br)cn2ccnc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 237 mg, 0.716 mmol), using a similar method to that used in Example 5 (Step 1) and replacing 1-chloropropan-2-one with 2-chloroacetaldehyde (185 μL, 1.43 mmol) (233 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-pyridylethylmercaptan and DBU in DME. ES-MS m/e (%): 324 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>COCCOC>[F:26][C:21]1[C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][C:34]([F:33])([F:46])[F:45])[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1c(F)cc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1c(F)cc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 58.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4,6-difluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.234 mmol) in DME (3 ml)/2M Na2CO3 (0.410 ml, 0.819 mmol) was treated with 2-trifluoromethoxybenzeneboronic acid (72 mg, 0.351 mmol) and Pd[PPh3]4 (54 mg, 0.046 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a white crystalline solid (70 mg, 59%). MS m/e 509.24 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:14][C:15]([O:17]CC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][CH2:39][CH2:40][O:41][C:42]([NH:44][CH2:45]C(O)=O)=[O:43]>>[Cl:8][C:6]1[CH:5]=[C:4]([CH:9]([NH:14][C:15](=[O:17])[CH2:45][NH:44][C:42]([O:41][CH2:40][CH2:39][NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)=[O:43])[CH2:10][C:11]([OH:13])=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)CC(NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)CNC(=O)OCCNc1ccccn1
Product: O=C(O)CC(NC(=O)CNC(=O)OCCNc1ccccn1)c1cc(Cl)cc(Cl)c1

Procedure:
prepared by reaction of 3-(3,5-dichlorophenyl)-3-(9H-fluoren-9-ylmethoxycarbonylamino)propionic acid with the solid phase polystyrene A OH (Rapp, Art. No. HA 1 400 00), is reacted with [2-(pyridin-2-ylamino)ethoxycarbonylamino]acetic acid and cleaved off from the support, giving 3-(3,5-dichlorophenyl)-3-{2-[2-(pyridin-2-ylamino)ethoxycarbonylamino]ethanoylamino}propionic acid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])=[N:5][NH:6]2.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])=[N:5][N:6]2[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cccc(I)c12
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1nn(CCN2CCOCC2)c2cccc(I)c12
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A mixture of Example 162A (100 mg), 4-(2-chloroethyl)morpholine (48 mg), and Na2CO3 (82 mg) in DMF (5 mL) was heated overnight at 80° C., cooled to room temperature, and partitioned between 1N HCl and ethyl acetate. The aqueous layer was basified with 1N KOH and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated to provide 45 mg of the desired product. MS (ESI(+)) m/e 503 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1>OS(O)(=O)=O>[CH3:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: COC(=O)c1ccc(C)s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of concentrated HNO3 (7.2 mL, 111.5 mmol) in concentrated H2SO4 (20 mL) was added dropwise to the solution of methyl 5-methylthiophene-2-carboxylate (F-2) (13.4 g, 86.0 mmol) in concentrated H2SO4 (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 mins and poured into ice-water. The precipitate was filtered and washed with water. A solid was collected as the product (14.8 g).