Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:17][N:18]([CH3:34])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24]>>[CH3:34][N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN(C)C
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c(C)c1C(=O)NCCCN(C)C
Yield: 75.9 %

Procedure:
6-Pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol) was condensed with 5-formyl-2,4-dimethyl-1H- pyrrole-3-carboxylic acid (3-dimethylaminoproyl)amide (50 mg) to give 67 mg (75%) of the title compound as yellow-brown solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH:32]4[CH2:35][NH:34][CH2:33]4)=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH:32]4[CH2:33][N:34]([C:1](=[O:3])[CH3:2])[CH2:35]4)=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OC4CNC4)ccc23)CC1
Solvent: ClCCl
Product: CC(=O)N1CC(Oc2ccc3c(C4CCN(C(=O)OC(C)(C)C)CC4)ncnc3c2)C1
Reaction time: 8 h

Procedure:
Acetic anhydride (66 μL, 703 μmol) was added dropwise with stirring at rt to a mixture of 4-[7-(Azetidin-3-yloxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (180 mg, 469 μmol), as prepared in the previous step, in DCM (1.0 mL). The resulting homogeneous yellow solution was stirred overnight, and was then partitioned with DCM (3 mL) and IM NaHCO3 (1×4 mL). The organic layer was dried (Na2SO4), concentrated, and purified by silica flash chromatography (8:2 DCM/acetone/3% DMEA eluent) to afford the title compound as a white crystalline film (88.3 mg, 44% over two steps). LC/MS (ESI): calcd mass 426.2, found 426.9 (MH)+.
Reaction SMILES: [Na].C(O[C:5](=[O:11])[C:6]([O:8][CH2:9]C)=[O:7])C.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>CO.CC(OC)(C)C>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH2:20][C:5](=[O:11])[C:6]([O:8][CH3:9])=[O:7])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: COC(C)(C)C
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 48.5 %

Procedure:
Sodium (1.0 g, 43 mmol) was dissolved in MeOH (50 mL) and then evaporated to a dry white powder. To the powder was added MTBE (100 mL) and diethyloxalate (5.14 g, 35.2 mmol). To the resulting solution was added a solution of 1-(4-methylphenyl)ethanone (5.0 g, 37.3 mmol) in MTBE (50 mL) dropwise over 45 min. The resulting suspension was allowed to stir for 1 h, and the precipitate was filtered and washed with MTBE/hexanes (1:1, 50 mL). The solid was suspended in 1 N HCl (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were dried (MgSO4), filtered, and concentrated to an oily residue which crystallized on standing at rt. The yellow solid was triturated with MTBE/hexanes (1:1) and filtered to give the title compound (3.76 g, 46%) as a white solid.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=[O:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[BH4-].[Na+].Cl>CCO.O1CCOCC1>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CO)cnc32)cc1
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (37.6 g, 125 mmol) in EtOH (500 mL) and 1,4-dioxane (500 mL) was added NaBH4 (4.72 g, 125 mmol) in one portion. After about 3 h, aqueous HCl (1N, 400 mL) was slowly added to the reaction mixture. The mixture was concentrated to one-half the original volume under reduced pressure and EtOAc (1000 mL) and water (500 mL) were added to the mixture. The layers were separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (35.9 g, 95% yield) as a tan solid: LC/MS (Table 2, Method a) Rt=1.97 min; MS m/z: 304 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:12][NH:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[O:4]=[C:3]([N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:2][N:13]([CH3:12])[CH2:14][CH2:15][OH:16]
Reactant: CNCCO
Reactant: O=C(CCl)N1CCCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(CCO)CC(=O)N1CCCCCC1

Procedure:
A mixture of 4.8 g (27 mmol) of 1-(2-chloroacetyl)perhydroazepine, dissolved in 40 ml of 2-butanone, 3.6 g (48 mmol) of 2-(methylamino)ethanol and 6.6 g (48 mmol) of potassium carbonate is heated to 70° C. for 5 h.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[N:24]1([C:30]2[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:27]3[CH2:26][CH2:25][N:24]([C:30]4[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:39][CH:40]=4)[CH2:29][CH2:28]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
DIPEA (2.348 mL, 13.48 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2 g, 8.99 mmol) and ethyl 4-(piperazin-1-yl)benzoate (2.316 g, 9.89 mmol, CAS 80518-57-6) in DMF (20 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, then evaporated to dryness and redissolved in DCM (150 mL) and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product which was triturated with ether. The solid was collected by filtration and dried under vacuum to give ethyl 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]benzoate (3.40 g, 90%) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=O)(=[O:12])=[O:11])([O-])=O.B>O1CCCC1>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:31][CH2:32][CH:23]1[CH2:21][NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1])(=[O:12])=[O:11]
Reactant: O=C(NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C1CCc2ccccc2C1
Agent: B
Solvent: C1CCOC1
Product: Nc1ccccc1S(=O)(=O)NCCCCCCNCC1CCc2ccccc2C1
Yield: 76 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-2-naphthalencarboxylic acid[6-(2-nitrobenzenesulfonylamino)-hexyl]-amide (0.090 g, 0.19 mmol) in tetrahydrofuran (5 mL) cooled to 0° C. was added 2 mL 1M solution of borane:THF complex and the reaction mixture was refluxed for 12 h. The reaction mixture was cooled in an ice bath and quenched with 2 mL of 1N HCl. The reaction mixture was neutralized with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (3×25 mL). The organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford an oil which was purified by preparative TLC to afford the titled compound (0.06 g, 70%); hydrochloride salt mp (162-163° C.).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[C:20]1([C:14]2([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CN2CCN(C3(c4ccccc4)CCCCC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ccc(C2(N3CCNCC3)CCCCC2)cc1

Procedure:
1-benzyl-4-(1-phenylcyclohexyl)piperazine (0.47 g) was dissolved in 86 mL methanol and 14 mL 0.2N HCl in methanol. The mixture was hydrogenated over palladium black (0.1175 g) and 3 atm. of hydrogen at room temperature for 1 hour. The reaction was filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluted with the appropriate mixture of methanol and chloroform to yield pure 1-(1-phenylcyclohexyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[CH:20]=[C:19]([CH3:21])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[CH:20]=[C:19]([CH3:21])[S:18][C:16]=2[N:17]=1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[N:4]([NH2:15])[CH:3]=1.[CH3:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=2)[N:4]([NH:15][C:23]([C:22]2[C:17]([CH3:16])=[N:18][C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:20][CH:21]=2)=[O:24])[CH:3]=1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccc(C(F)(F)F)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2cc(C(F)(F)F)ccc21
Yield: 28.5 %

Procedure:
A mixture of 3-methyl-5-trifluoromethyl-indol-1-ylamine (223 mg, 1.04 mmol), 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (224 g, 1.04 mmol), HATU (475 mg, 1.25 mmol), DIPEA (404 mg 3.13 mmol) is stirred in DMF at 150° C. for 1 h. The reaction is quenched with water, extracted with extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 10% MeOH in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-methyl-5-trifluoromethyl-indol-1-yl)-amide (122 mg, 28%). MS: 412 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.22 (s, 1H), 8.79 (d, 1H), 8.66 (d, 1H), 8.06 (t, 1H), 7.91 (s, 1H), 7.60 (dd, 1H), 7.51 (s, 2H), 7.29 (s, 3H), 2.88 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.O([C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1)S(C(F)(F)F)(=O)=O>CCOCC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)=[CH:2]1
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: C1=C(c2ccsc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
3-Thiophene boronic acid (128 mg, 1.00 mmol), cyclohexenyl triflate (230.2 mg, 1.00 mmol) was dissolved in Et2O (4 mL) and 2M Na2CO3 (1 mL). The mixture was degassed and Pd(PPh3)4 (0.05 mmol) added. After stirring at room temperature for 4 h the mixture was filtered through celite, rinsed with Et2O, dried (Na2SO4) and subjected to column chromatography (silica, pentane) to yield 150 mg of a volatile liquid. GC-MS: M+=164.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Br:18])[C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1cccc2oc(-c3ccc(Cl)cc3)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2nc3c(CBr)cccc3o2)cc1
Yield: 87.6 %

Procedure:
A mixture of 2-(4-chlorophenyl)-4-methylbenzoxazole (P0001; 5.44 g), N-bromosuccinimide (4.77 g) and 2,2′-azobisisobutyronitrile (92 mg) in CCl4 (54 ml) was refluxed overnight. The insoluble was removed by filtration, and the filtrate was concentrated and cooled. The precipitates were collected and washed with CCl4 to give pale brown crystals of 2-(4-chlorophenyl)-4-(bromomethyl)benzoxazole (P0002; 6.31 g).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][CH2:21][O:22][CH:23]([F:25])[F:24])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[NH2:8][C@@H:9]([CH2:20][CH2:21][O:22][CH:23]([F:24])[F:25])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOC(F)F)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCOC(F)F)C(=O)OCc1ccccc1

Procedure:
(S)-benzyl 2-(tert-butoxycarbonylamino)-4-(difluoromethoxy)butanoate (161 mg, 0.448 mmol) was stirred in 30% TFA in dichloromethane (5 mL) for 1 h. The resulting mixture was concentrated down on rotovap and redissolved and concentrated down with toluene three times, and finally the residue was dried on high vacuum pump. The desired product was used as-is in the next step.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[F:8][C:9]1[C:10]([O:22]C)=[N:11][CH:12]=[C:13]([O:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])[CH:14]=1>C(#N)C.C(Cl)Cl>[F:8][C:9]1[C:10]([OH:22])=[N:11][CH:12]=[C:13]([O:15][C:16]([F:20])([F:21])[CH:17]([F:18])[F:19])[CH:14]=1
Reactant: COc1ncc(OC(F)(F)C(F)F)cc1F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Oc1ncc(OC(F)(F)C(F)F)cc1F

Procedure:
Sodium iodide (1.80 g, 12.0 mmol) and then chlorotrimethylsilane (1.5 ml, 11.8 mmol) were added to a solution of 3-fluoro-2-methoxy-5-(1,1,2,2-tetrafluoroethoxy)pyridine (1.65 g, 6.79 mmol) in 8 ml of acetonitrile with stirring and under nitrogen and the mixture was heated at reflux for 2 5 hours. It was then allowed to cool and was diluted with 20 ml of methylene chloride. The resulting solution was extracted with water and with saturated aqueous sodium hydroxide, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain the title compound as a solid. This was recrystallized from toluene to obtain 0.95 g of the product as a white solid. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].N1C=CC=CC=1.[CH2:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)[CH3:16]>C1C=CC=CC=1>[CH2:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[O:22])=[CH:19][CH:18]=1)[CH3:16]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCc1ccc(C(=O)Nc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8.2 gm. of o-aminophenol in 70 cc. of dry pyridine is added a solution of p-ethylbenzoyl chloride (prepared from 10 gm. of p-ethylbenzoic acid and thionyl chloride) in 20 cc. of benzene. An exothermic reaction occurs and the reaction mixture is stirred overnight at ambient temperature. The mixture is concentrated in vacuo and taken up between a 1:1 mixture of benzene and ether and 2.5 N hydrochloric acid. The organic layer is washed with saturated sodium bicarboxate, water, then dried and concentrated. Recrystallization from benzene-hexane gives 4- ethyl-2'-hydroxybenzanilide, m.p. 103°-105°C.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])N=N2)=[CH:6][C:5]=1[CH3:27].[OH-].[K+]>CO.O>[Cl:25][C:23]1[CH:24]=[C:19]([C:13]2([C:15]([F:18])([F:17])[F:16])[CH2:14][N:10]2[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:28])=[C:5]([CH3:27])[CH:6]=2)[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: COC(=O)c1ccc(N2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)N=N2)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(N2CC2(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Temperature: 80 °C
Yield: 36.9 %

Procedure:
To a solution of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-[1,2,3]triazol-1-yl]-2-methyl-benzoic acid methyl ester (Example 2.1) (3.6 g, 8.33 mmol) in methanol (10 ml) was added aqueous potassium hydroxide (40% w/v) (35 ml) and the reaction mixture heated at 80° C. for 15 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The aqueous phase was acidified by addition of aqueous hydrochloric acid (1M) and extracted again with ethyl acetate (3×200 ml). The combined organic extracts were washed with brine and concentrated. The residue was purified by column chromatography on silica gel (eluent: 15% v/v ethyl acetate in hexane) to give 4-[2-(3,5-dichloro-phenyl)-2-trifluoromethyl-aziridin-1-yl]-2-methyl-benzoic acid as a white solid (1.2 g). 1H-NMR (DMSO-d6, 400 MHz): 12.57 (s, 1H), 7.70 (d, 1H), 7.65 (s, 3H), 6.99 (s, 1H), 6.97 (d, 1H), 3.27 (s, 1H), 3.05 (s, 1H), 2.45 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:13][CH:14]([O:24]C1CCCCO1)[CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC)[O:7]C(OCC)=O)=[O:5])[CH3:2].C[Si](C)(C)Br.C>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]([CH2:13][CH:14]([OH:24])[CH2:15][P:16](=[O:17])([OH:23])[OH:20])[OH:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)ON(CC(CP(=O)(OCC)OCC)OC1CCCCO1)C(=O)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N(O)CC(O)CP(=O)(O)O
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a solution of diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (5.01 g.) in methylene chloride (10 ml.), was added dropwise trimethylbromosilane (6.73 g.) with stirring under ice-cooling. The mixture was stirred for an hour under ice-cooling and for additional 2 hours at ambient temperature and evaporated under reduced pressure to remove off the solvent and unreacted excess trimethylbromosilane. The residue was dissolved in water (50 ml.), stirred for an hour at ambient temperature and washed twice with chloroform (20 ml. and 10 ml. portions). The combined chloroform washings were extracted with water (30 ml.). The aqueous extract was washed once again with chloroform (5 ml.) and combined with the above-remained aqueous solution and then evaporated to dryness under reduced pressure to give a tarry residue. This residue was dissolved in water (40 ml.) treated with an activated charcoal (300 mg.) and evaporated to dryness under reduced pressure to give oily 3-(N-ethoxycarbonyl-N-hydroxyamino)-2-hydroxypropylphosphonic acid (2.6 g.).
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=[O:8])C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:18]#[N:19])=[CH:13][CH:12]=1.[OH-].[NH4+]>CCCCCC>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:18]([NH2:19])=[O:8])=[CH:15][CH:16]=1
Reactant: N#CC(c1ccc(F)cc1)(c1ccc(F)cc1)c1cccc(F)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCC
Product: NC(=O)C(c1ccc(F)cc1)(c1ccc(F)cc1)c1cccc(F)c1
Temperature: 130 °C

Procedure:
A solution of concentrated sulfuric acid (10 mL) and glacial acetic acid (10 mL) was added to bis(4-fluorophenyl)-3-fluorophenylacetonitrile (3.18 mmol) at rt. The resulting orange solution was stirred and heated at 130° C. for 3 h. The reaction was cooled to 0° C., poured into ice water (50 mL) and neutralized with ammonium hydroxide. The organics were extracted with chloroform (3×50 mL). The organics fractions were combined washed with brine (2×20 mL), dried (Na2SO4) and concentrated under reduced pressure to afford a yellow-orange solid. The solid was stirred with hot hexane (50 ml) for 30 mins and filtered. Crystallization from dichloromethane/hexane gave the desired product bis(4-fluorophenyl)-3-fluorophenylacetamide 16 as a white crystalline solid (147 mg, 0.43 mmol, 11%, 4 steps).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](Br)[CH:11]([CH3:13])[CH3:12].[I-].[Na+]>>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)CBr
Agent: [I-]
Agent: [Na+]
Product: CC(C)COc1ccc(C=O)cc1
Yield: 100.6 %

Procedure:
The compound was synthesized as in Example 24.1, using 4-hydroxybenzaldehyde (200 mg, 1.64 mmol) and isobutyl bromide (449 mg, 1.97 mmol) in place of 1-chloro-3,3-dimethylbutane (no sodium iodide was used) to give 4-isobutoxybenzaldehyde (294 mg, quant. crude) as a yellow oil that was used without further purification or characterization.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[S:12]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:13]=[C:11]([C:10]2[CH:9]=[C:8]([OH:7])[CH:16]=[CH:15][CH:14]=2)[S:12][CH:5]=1
Reactant: NC(=S)c1cccc(O)c1
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Product: Oc1cccc(-c2nc(CCl)cs2)c1
Temperature: 120 °C
Yield: 38.1 %

Procedure:
To a solution of 1,3 dichloroacetone (0.42 g, 3.26 mmol) in toluene (5 mL) was added 3-hydroxythiobenzamide (0.25 g, 1.63 mmol) and the reaction mixture was heated at 120° C. for 1 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness, added water and extracted with EtOAc (×3). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 10% EtOAc-Hexane) to get the desired product (0.14 g, 38%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.[NH:26]1[CH:30]=[CH:29][CH:28]=[N:27]1>O1CCOCC1>[N:26]1([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=3[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=2)[CH:30]=[CH:29][CH:28]=[N:27]1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: c1cn[nH]c1
Solvent: C1COCCO1
Product: CC(C)Cc1cc(-c2cccc(Cn3cccn3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 80 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (90.4 mg, 0.203 mmol; see Example 1(e)) in dioxane (2.0 mL) was added pyrazole (41.5 mg, 0.609 mmol) and the reaction mixture was stirred for 18 h at 80° C., after which another portion of pyrazole (60.4 mg, 0.887 mmol) was added and the reaction mixture stirred for a further 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using EtOAc:petroleum ether (2:8) as eluent to give the sub-title compound in 98% yield as a colourless syrup (86 mg, 0.199 mmol).