Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[C:18]([CH3:26])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.CO.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[C:18]([CH3:26])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)ccc1C(=O)O
Temperature: 50 °C

Procedure:
As shown in Reaction Scheme 7, methyl 4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-carboxylate (0.25 g, 0.65 mmol) was suspended in THF (5 mL), MeOH (5 mL) and water (2.5 mL), and NaOH (0.26 g, 6.5 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated in vacuo, acidified with 2N HCl, and the resulting solid was collected by filtration. This yielded 0.25 g (quantitative) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.62 (s, 3H), 7.05 (t, 1H), 7.57-7.90 (m, 9H), 10.62 (br, 1H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and pyridine-3-sulfonyl hydrochloride, of Preparation 2, following the method described in Example 3, Step B 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.97 (m, 1H), 8.78 (m, 1H), 8.60 (m, 1H), 8.50 (d, 1H), 8.03 (m, 1H), 7.88 (m, 2H), 7.42 (m, 1H), 7.23 (m, 2H), 7.13 (m, 1H), 6.66 (m, 1H), 6.65 (m, 2H), 4.43 (s, 2H), 4.39 (s, 2H), 4.35 (s, 2H), 1.47 (s, 9H); MS 547 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][CH2:13][CH:14]1[O:16][CH2:15]1.O.[OH-].[Li+]>C(OCC)(=O)C>[F:11][C:8]([F:9])([F:10])[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:15][CH:14]([OH:16])[CH2:13][CH3:12]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCC1CO1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(O)COc1cccc(C(F)(F)F)c1

Procedure:
40.5 g of 3-hydroxybenzotrifluoride, 18.0 g of α-butylene oxide and 1.0 g of lithium hydroxide monohydrate are heated in a bomb tube (pressure reactor) for 16 hours to 140° C. After cooling the reactor, the reaction mixture is dissolved in 200 ml of ethyl acetate and the organic phase is washed with water and then dried over sodium sulfate and concentrated. The desired product, 1-(3-trifluoromethylphenoxy)-2-butanol, is obtained in a yield of 54.0 g and in high purity. The product can be used in the subsequent reaction without further purification.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([C:30]#[N:31])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[C:13](=[O:29])[NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1.[OH-].[Na+].Cl>C(O)C>[F:22][C:21]([F:23])([F:24])[C:19]1[CH:20]=[C:15]([NH:14][C:13]([C:7]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:30]#[N:31])[C:3]([OH:32])=[O:2])=[O:29])[CH:16]=[C:17]([C:25]([F:27])([F:28])[F:26])[CH:18]=1
Reactant: COC(=O)C(C#N)=Cc1ccc(O)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CC(=Cc1ccc(O)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
3-({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)-2-cyanoacrylic acid methyl ester (50 mg, 0.11 mmol) was dissolved in ethanol (5 mL). 2 N sodium hydroxide (0.11 ml, 0.22 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was recrystallized (ethyl acetate) to give the title compound (13.5 mg, 30.4%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: CC(C)(N)CO
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC(C)(C)CO)cn2)cn1
Yield: 79 %

Procedure:
As described for example 36b, 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (65 mg, 0.178 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (61 mg, 79%) which was obtained as a white solid. MS: m/e=436.2 [M+H]+.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:30]=[C:29]([CH3:31])[C:27]([NH2:28])=[C:26]([CH3:32])[CH:25]=1.[C:33](OC)(=[O:36])[CH:34]=[CH2:35].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(N(CC)CC)C>[NH2:28][C:27]1[C:29]([CH3:31])=[CH:30][C:24]([CH2:35][CH2:34][CH2:33][OH:36])=[CH:25][C:26]=1[CH3:32]
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(CCCO)cc(C)c1N
Temperature: 100 °C
Reaction time: 6 h
Yield: 65.1 %

Procedure:
Palladium acetate (68 mg) and 720 mg of tris-o-tolylphosphine were mixed in a Schlenk tube under a nitrogen atmosphere. After 15 ml of triethylamine, 6 g of 4-bromo-2,6-dimethylaniline and 3.2 g of methyl acrylate had been added, the tube was heated to 100° C. in an oil bath and kept there for 6 h. The mixture was added to water and extracted 3 times with ethyl ether. After drying in vacuum 6.2 g of a yellow solid was obtained. The solid was dissolved in THF and 3.5 g of lithium aluminum hydride was added. After 6 h the reaction was poured into water and purified by column chromatography (silica, hexane:ethyl acetate 2:1). A mixture of 3-(4-amino-3,5-dimethyl-phenyl-propan-1-ol and 3-(4-amino-3,5-dimethylphenyl)propan-1-ol (3.5 g) was obtained. The mixture was dissolved in ethyl acetate and 50 mg of palladium (10 wt %) on carbon was added. Hydrogen was bubbled through the solution for one h. After removing the palladium catalyst and the solvent, 3.1 g of 3-(4-amino-3,5-dimethyl-phenyl)-prop-2-en-1-ol was obtained. 1H-NMR (200 MHz, CDCl3): 6.77 (s, 2H), 3.64 (t, 2H), 3.47 (b s, 2H) 2.54 (t, 2H), 2.15 (s, 6H), 1.82 ppm (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[O:4][C:3]=1[C:17](OC)=[O:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.O>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)[O:4][C:3]=1[CH2:17][OH:18]
Reactant: COC(=O)c1oc(-c2ccc(C(F)(F)F)cc2)cc1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)oc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A solution of methyl 3-methyl-5-[4-(trifluoromethyl)phenyl]furan-2-carboxylate (3.8 g) in tetrahydrofuran (30 mL) was added dropwise to a suspension of lithium aluminum hydride (0.5 g) in tetrahydrofuran (30 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (3.4 g, 97%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]([F:17])([F:16])[F:15])[C:8]([C:18]([O:20]CC)=[O:19])=[CH:7]2.[OH-].[Na+]>CO.O>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]([F:15])([F:16])[F:17])[C:8]([C:18]([OH:20])=[O:19])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)ccc2NC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=Cc2cc(OC(F)(F)F)ccc2NC1C(F)(F)F
Temperature: 25 °C

Procedure:
The ethyl 1,2-dihydro-6-(trifluoromethoxy)-2(trifluoromethyl)-3-quinolinecarboxylate from Step 4 (880 mg, 2.5 mmol) and 2.5 N aqueous sodium hydroxide (2 mL) were mixed in methanol (15 mL) and water (15 mL). The solution was heated on a steam bath for 2 hours. The reaction was allowed to cool to room temperature and was extracted with diethyl ether (50 mL). The aqueous layer was acidified (pH=1) with 3 N HCl and extracted with ethyl acetate (2×50 mL).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=3[C:16]=1[C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=[CH:5]2.[Br:28]Br.C([O-])(=O)C.[K+]>C(O)(=O)C>[Br:28][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:12]1[O:13][C:14]3[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=3[C:16]=1[C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8]2
Reactant: BrBr
Reactant: CC(C)(C)CC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)CC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Yield: 44.2 %

Procedure:
Following the procedure described in Step 4 of Example 1, 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-3,3-dimethyl-1-butanone (0.378 g, 1.05 mmol) was brominated using, bromine (0.08 mL, 1.6 mmol), and potassium acetate (1.02 g, 10.4 mmol), in glacial acetic acid (17 mL). Purification by flash chromatography (Biotage apparatus) using 15-20% chloroform in hexane as an eluant furnished the title compound as a dark brown gum (0.203 g). 1HNMR (300 MHz, DMSO-d6): δ10.95 (s, 1H), 8.35 (s, 1H), 8.2 (d, 1H, J=8.3 Hz), 8.0 (d, 1H, J=8.3 Hz), 7.95 (t, 2H, J=8.3 Hz), 7.85 (d, 1H, J=8.3 Hz), 7.35-7.55 (m, 3H), 2.65 (s, 2H), and 0.85 ppm (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4].FC1C([O:21][C:22](=O)[CH2:23][S:24][C:25](=[O:27])[CH3:26])=C(F)C(F)=C(F)C=1F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:25]([S:24][CH2:23][C:22]([NH:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4])=[O:21])(=[O:27])[CH3:26]
Reactant: NCC(=O)NCC(=O)NCC(=O)O
Reactant: CC(=O)SCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)SCC(=O)NCC(=O)NCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of H-Gly-Gly-Gly-OH (1.28 g, 6.76 mmol), S-acetyl-thioglycolic acid pentafluorophenyl ester (Novabiochem, 2 g, 6.76 mmol) and DIPEA (1.14 ml, 6.76 mmol) in a mixture of DMF (25 ml) and water (12 ml), was stirred overnight at room temperature. The reaction mixture was filtered to remove some remaining H-Gly-Gly-Gly-OH, brought to pH2 with 1M aqueous HCl and evaporated to dryness. The residue was triturated with acetone to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1.[C:11]1(O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: CC(O)c1ccc(Br)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccccc1)c1ccc(Br)cn1
Yield: 94.4 %

Procedure:
A solution of 1-(5-bromopyridin-2-yl)ethanol (1.0 g, 4.95 mmol), phenol (835 mg, 8.87 mmol), and triphenylphosphine (1.8 g, 6.86 mmol) was stirred in dry tetrahydrofuran (70 mL) at 0° C. under nitrogen atmosphere. To this mixture was added dropwise diisopropyl diazene-1,2-dicarboxylate (1.4 g, 6.92 mmol) over 5 minutes, and the reaction was monitored by thin layer chromatography. After complete disappearance of starting material, the solvent was removed under reduced pressure and the resultant oil was purified by flash column chromatography (hexane/ethyl acetate, 1/1) to give 5-bromo-2-(1-phenoxyethyl)pyridine (1.3 g, 94.4%) as a white solid. LRMS (M+H+) m/z: calcd 278.01. found 278 1H NMR (300 MHz, DMSO) δ 8.60 (d, J=2.1 Hz, 1H), 7.93 (dd, J1=8.4 Hz, J2=2.1 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.18 (m, 2H), 6.86 (m, 3H), 5.39 (m, 1H), 1.63 (d, J=6.3 Hz, 3H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[N:2]1.[Cl:11][C:12]1[C:17]([C:18](O)=[O:19])=[C:16]([F:21])[C:15]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:11][C:12]1[C:17]([C:18]([NH:10][C:8]2[CH:9]=[C:4]3[CH:3]=[N:2][NH:1][C:5]3=[N:6][CH:7]=2)=[O:19])=[C:16]([F:21])[C:15]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:14][CH:13]=1
Reactant: Nc1cnc2[nH]ncc2c1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]ncc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
1H-Pyrazolo[3,4-b]pyridin-5-amine (1.55 g, 11.6 mmol), 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (3.59 g, 12.1 mmol), EDCI (2.44 g, 12.7 mmol), and HOBt (0.25 g, 0.16 mmol) were dissolved in DMF (30 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated. The residue was diluted with ethyl acetate (500 mL), and the organic layers were washed with water (3×50 mL). The organic layers were dried, filtered and concentrated. The crude solids were washed with DCM (3×50 mL) to give 6-chloro-2-fluoro-3-(propylsulfonamido)-N-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (2.7 g, 58%) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.7 (s, 1H), 8.6 (s, 1H), 8.1 (s, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 3.1 (m, 2H), 1.9 (m, 2H), 1.1 (t, J=7.6 Hz, 3H); m/z (APCI-neg) M−1=410.2, 412.2.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](N(C)C)=[O:7])=[CH:4][CH:3]=1.O(Cl)Cl.[NH:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.O.O.O.C([O-])(=O)C.[Na+]>ClCCCl.ClC(Cl)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:17]2[NH:16][CH:20]=[CH:19][CH:18]=2)=[O:7])=[CH:11][CH:12]=1
Reactant: CN(C)C(=O)c1ccc(Cl)cc1
Reactant: c1cc[nH]c1
Agent: CC(=O)[O-]
Agent: ClOCl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc[nH]1

Procedure:
A mixture of 183 g (1 mole) of p-chloro-N,N-dimethylbenzamide and 153g (1 mole) of phophorous oxychloride in 300 ml of 1,2-dichloroethane is heated under reflux for 30 minutes, after which a solution of 67g (1 mole) of pyrrole in 300 ml of dichloroethane is added drop-wise. It is cooled and a solution of 408g (3 moles) of sodium acetate trihydrate in 1600 ml of water is added dropwise for 45 minutes, after which the mixture is again heated under reflux for 30 minutes. The resulting mixture is poured onto ice, the organic layer is separated, and the aqueous layer is washed with chloroform. The combined organic solutions are washed with sodium bicarbonate and brine and dried over magnesium sulfate. Evaporation of the solvent in vacuo gives a dark oil, which is distilled in vacuo through a heated Vigreaux column to give a white solid; mp 106°-9° C. It is recrystallized from cyclohexane to give 2-p-chlorobenzoylpyrrole as white needles; m.p. 110°-113° C.
Reaction SMILES: F[C:2]1[N:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:8]=1)=[O:5].Cl.Cl.[NH:29]1[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38][NH2:39])=[C:32]2[CH:31]=[CH:30]1>>[NH:29]1[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38][NH:39][C:2]3[N:26]=[CH:25][CH:24]=[CH:23][C:3]=3[C:4]([NH:6][C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:22])([C:14]([F:16])([F:15])[F:17])[C:18]([F:21])([F:20])[F:19])[CH:8]=3)=[O:5])=[C:32]2[CH:31]=[CH:30]1
Reactant: NCc1ccnc2[nH]ccc12
Reactant: O=C(Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1)c1cccnc1F
Agent: Cl
Product: O=C(Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1)c1cccnc1NCc1ccnc2[nH]ccc12

Procedure:
The titled compound was prepared from 2-fluoro-N-[3-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 510 (M+H). Calc'd. for C23H17F6N5O2—509.41.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C[Si](C)(C)[C:16]([F:19])([F:18])[F:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Cl-].[NH4+].Cl.C(OCC)(=O)C>CO.O1CCCC1>[F:17][C:16]([F:19])([F:18])[C:2]1([OH:1])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(C(F)(F)F)CCNC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (600 mg), trimethyl(trifluoromethyl)silane (0.57 mL), 1M N,N,N-tributylbutane-1-aminium fluoride/tetrahydrofuran solution (0.50 ml) and tetrahydrofuran (6 mL) was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution (2 mL) and 1M N,N,N-tributylbutane-1-aminium fluoride/tetrahydrofuran solution (1 mL) were added, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate, washed successively with water and brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a pale-brown solid. The obtained solid was dissolved in methanol (1 mL), and 4M hydrochloric acid/ethyl acetate solution (2 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 4 hr, and the reaction system was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (1 mL) was added to the residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (260 mg) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[C:14]#[CH:15])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.O1CCCC1>O>[NH2:13][C:9]1[C:8]([C:14]#[CH:15])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)=[O:27])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: C#Cc1c(Oc2ccc(N)cc2)ccnc1N
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1c(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccnc1N

Procedure:
4-(4-Aminophenoxy)-3-(1-ethynyl)-2-pyridinamine (260 mg), para-fluorophenyl isocyanate (0.13 ml) and tetrahydrofuran (5 ml) were stirred at room temperature for 20 hours. Water was added to the reaction solution, the tetrahydrofuran was distilled off, and then a small amount of ethyl acetate was added and the precipitated solid was filtered off to obtain 20 mg of a light brown solid.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(CCO)cc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc(CCBr)cc1
Temperature: 25 °C

Procedure:
Phosphorus tribromide (1.42 g) was added, dropwise, to a solution of methyl 4-(2-hydroxyethyl)phenylacetate (2.7 g--see Preparation 21) in carbon tetrachloride (20 ml) at 0°. When the addition was complete, the mixture was allowed to warm to room temperature and then heated under reflux for 2 hours. Ice (100 g) was added and the mixture was partitioned between dichloromethane (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing hexane (40%) then with dichloromethane. The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 1.02 g.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([NH2:9])=[N:7][CH:8]=1.[F:15][C:16]([F:27])([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:17](Cl)=[O:18]>>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([NH:9][C:17](=[O:18])[C:16]([F:15])([F:27])[C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])=[N:7][CH:8]=1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Product: O=C(Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-])C(F)(F)C(F)(F)C(F)(F)F

Procedure:
5-(Trifluoromethyl)-3-nitro-2-aminopyridine is reacted with perfluorobutyryl chloride to yield 5-(trifluoromethyl)-3-nitro-2-(2,2,3,3,4,4,4-heptafluorobutyramido)pyridine, which when hydrogenated yields 6-(trifluoromethyl)-1-hydroxy-2-(perfluoro-n-propyl)-1H-imidazo(4,5-b)pyridine.