Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:13])([F:12])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]([F:3])([F:12])[F:13])[CH2:11][CH2:10]1)=[O:24]
Reactant: FC(F)(F)CN1CCNCC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCN(CC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
To as stirred solution of 1-(2,2,2-trifluoroethyl)piperazine dihydrochloride (181.6 mg, 753 μmol) and triethylamine (182 mg, 250 μL, 1.79 mmol) in dichloromethane (5 mL) cooled to 0° C., 2-chloroacetyl chloride (85.1 mg, 60.0 μL, 753 μmol) was added drop-wise over 2 min then stirred for 10 min. The reaction mixture was warmed to 25° C. over 3 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution (25 mL) and dichloromethane (25 mL). The organic layer was separated, washed with water (25 mL) and brine (50 mL), dried over sodium sulfate, and concentrated to give 2-chloro-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethanone (123.3 mg, 504 μmol, 67%) as an orange oil. 1H NMR (DMSO-d6) δ: 4.73 (br. s, 2H), 3.45 (br. s, 4H), 3.23 (q, J=10.3 Hz, 2H), 2.61 (d, J=20.8 Hz, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[N+:20]([O-])=O)=[C:6]([CH3:23])[CH:5]=1.C(O)(=O)C>[Fe].O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[NH2:20])=[C:6]([CH3:23])[CH:5]=1
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2[N+](=O)[O-])c(C)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2N)c(C)c1
Temperature: 50 °C

Procedure:
A mixture of 4-(2-nitro-4,5-dimethylphenoxymethyl)-3-methylbenzoic acid methyl ester prepared in Reference Example 1 (7.21 g), acetic acid (88 ml) and water (8.8 ml) was stirred at 50° C. To the reaction solution, iron powder (6.11 g) was gradually added, and the mixture was stirred for 1 hour at 50° C. After cooling, the mixture was filtered and the filtrate was concentrated and azeotroped with toluene. To the residue, ethyl acetate-water (100 ml-100 ml) was added and the mixture was filtrated over Celite (registered trademark). The organic layer was washed, dried, concentrated under reduced pressure to give the title compound (4.66 g) having the following physical data.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[NH:13])=[CH:10][CH:9]=1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=O>C(Cl)(Cl)Cl>[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[NH:14][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:13]=2)=[CH:10][CH:9]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc(-c3ccc(Cl)cc3)c[nH]2)cc1
Reaction time: 1 h

Procedure:
To a two-phase mixture of 30% K2CO3 solution (5 ml) and chloroform (5 mL) containing 276 mg of 4-fluorobenzamidine was added a solution of 468 mg of 2-bromo-4′-chloroacetophenone in chloroform (3 mL). After stirring for 1 hr, the reaction mixture was filtered. The white crystallinesolid was washed with distilled water and dried in a vacuum oven overnight to afford 2-(4-fluorophenyl)4-(4-chlorophenyl)imidazole (Compound 1).
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])=[C:22]([CH3:32])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:33])[Si](C(C)(C)C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOC(C)=O>[CH2:16]([C:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:1])=[C:10]([CH3:33])[CH:11]=1)([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])([CH3:29])[CH3:31])=[C:22]([CH3:32])[CH:21]=1)[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)(c1ccc(CCC(C)(C)O)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(CCC(C)(C)O)c(C)c1
Yield: 79 %

Procedure:
To a solution of 4-(4-{1-[4-(tert-butyl-dimethylsiloxy)-3-methylphenyl]-1-ethylpropyl}-2-methylphenyl)-2-methylbutan-2-ol (0.25 g, 0.50 mmol) in anhyd THF (1.5 mL) was added a 1.0M solution of TBAF in THF (0.70 mL, 0.70 mmol). After 1.5 h the reaction mixture was diluted with EtOAc (30 mL), washed with satd NH4Cl (20 mL) and brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/Hex, 0:100 to 40:60) to yield the title compound (0.14 g, 74%) as a white tacky solid: 1H-NMR (C6D6) δ 7.23-7.28 (2H, m), 7.16-7.22 (2H, m), 7.11 (1H, dd, J=2.3, 8.3), 6.64 (1H, d, J=8.3), 5.39 (1H, br s), 2.66 (2H, m), 2.25 (6H, s), 2.21 (4H, q, J=7.3), 1.62 (2H, m), 1.14 (6H, t, J=7.3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([OH:13])=O)[CH:6]=1)=[O:4].C(Cl)(=O)C([Cl:17])=O>ClCCl>[Cl:17][C:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][N:8]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccnc(C(=O)O)c1
Solvent: ClCCl
Product: COC(=O)c1ccnc(C(=O)Cl)c1

Procedure:
To 4-(methoxycarbonyl)picolinic acid (150 g, 1.62 mol) in dichloromethane (500 mL) was added oxalyl chloride (400 mL) keeping the temperature at 25-30° C. for 3 days. The reaction was evaporated in vacuo to afford methyl 2-(chlorocarbonyl)isonicotinate as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:13][N:12]2[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:28]=2)=O)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[N:11]3[CH2:15][CH:14]([O:16][C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH2:13][N:12]3[C:25]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)c2ccnc(Oc3ccccc3)n2)C1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(OC1Cn2c(-c3ccnc(Oc4ccccc4)n3)c(-c3ccc(F)cc3)c(=O)n2C1)N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A solution of morpholine-4-carboxylic acid 1-[2-(4-fluorophenyl)acetyl]-2-(2-phenoxypyrimidine-4-carbonyl)-pyrazolidin-4-yl ester, 42, (154 mg, 0.287 mmol) in dimethylformamide (3 mL) is added dropwise to a −10° C. suspension of sodium hydride (16.4 mg of a 60% dispersion in mineral oil, 0.410 mmol) in tetrahydrofuran (3 mL). After 1 hour at −10° C., the reaction was warmed to 0° C. for 2 hours. The orange-colored solution is then quenched by slowly adding saturated NH4Cl (400 μL). The cooling bath is removed, and the solution allowed to warm to room temperature. The reaction mixture is concentrated in vacuo and the resulting residue is dissolved in THF (25 mL) and filtered through a pad of Celite. The filtrate is concentrated in vacuo and the residue purified by Prep HPLC to afford 47 mg (32% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.46 (d, J=4.9 Hz, 1H), 7.47-7.18 (m, 9H), 7.08 (t, J=8.7 Hz, 2H), 6.89 (d, J=4.9 Hz, 1H), 5.66 (m, 1H), 4.16 (m, 2H), 4.02 (d, J=12.9 Hz, 1H), 3.87 (dd, J=12.9, 5.1 Hz, 1H), 3.79-3.30 (m, 8H1); HRMS m/z calcd for C27H25FN5O5 (MH+) 518.1840, found 518.1815.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:14][CH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][C:10]=1[Cl:13])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(Cl)c(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(CBr)c1Cl
Yield: 95.4 %

Procedure:
1.0 g of azobisisobutyronitrile was added to a solution of 84.0 g (0.38 mol) of methyl 2,4-dichloro-3-methylbenzoate and 67.6 g (0.38 mol) of N-bromosuccinimide in 380 ml of carbon tetrachloride. The reaction mixture was refluxed for 3.5 hours and then cooled, and the precipitate which had formed was filtered off with suction. The filtrate was concentrated under reduced pressure and the resulting residue was triturated with methyl t-butyl ether. 108.0 g of methyl 3-bromomethyl-2,4-dichlorobenzoate were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](=O)[CH3:7].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14].C(O)(C)C>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:4]([C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[CH3:1])[CH:5]=[C:6]([CH3:7])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=N)N
Reactant: CC(=O)C=Cc1ccccc1C
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=CC1c1ccccc1C
Yield: 61 %

Procedure:
Upon heating a solution of 16.0 g of 2-methylbenzylideneacetone and 13.0 of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2-amino-6-methyl-4-(2-methylphenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 159°C (isopropanol) is obtained. Yield: 61 percent of theory.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)CC(=O)C>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: NCCC(O)c1ccccc1
Solvent: CC(=O)CC(C)C
Solvent: Cc1ccccc1C
Product: OC(CCNC1=NCCN1)c1ccccc1

Procedure:
A mixture of 8 parts of α-(2-aminoethyl)benzylalcohol, 6.5 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred and refluxed for 3 hours with waterseparator. The reaction mixture is cooled and the separated oily product is dissolved in 4-methyl-2-pentanone. The solvent is evaporated in vacuo, yielding α-{2-[N-(2-imidazolin-2-yl)amino]ethyl} benzylalcohol as a residue.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.C(OCC)(=O)C>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH2:20][C:21]3[N:22]=[C:23]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=4)[O:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Nc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(C=Cc2nc(CNc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
4-(4-[1,2,3]Triazol-1-yl-butyl)-phenylamine (0.304 g, 1 mmol) is dissolved in anhydrous N,N-dimethylformamide (5 ml) followed by the addition of sodium hydride (0.024 g, 1 mmol). After stirring for 15 min at room temperature 4-chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole (0.324 g, 1.5 mmol) is added and the mixture stirred for 16 h at 80° C. Ethyl acetate (25 ml) is added, the mixture is washed with brine, dried over sodium sulfate and concentrated in vacuo. After flash column chromatography (ethyl acetate/hexanes 1:1->2:1) [4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethyl}-amine 1 can be isolated as a yellow solid. Yield 0.14 g (29%); m.p. 103–105° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:15]([O-])=O)=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.[H][H]>CO.[Pd]>[NH2:12][C:5]1[CH:4]=[C:3]([NH2:15])[C:2]([F:1])=[CH:7][C:6]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(N)c(CC(=O)O)cc1F
Temperature: 25 °C
Yield: 99.9 %

Procedure:
(5-Fluoro-2,4-dinitro-phenyl)-acetic acid 9b (10 g, 38.7 mmol) was dissolved in 150 mL of methanol under stirring at room temperature, and palladium on activated carbon (5%, 1.5 g) was then added to the solution. The reaction mixture was hydrogenated under 0.3 Mpa of hydrogen. The reaction was completed until TLC showed the disappearance of starting materials. The above mixture was filtered twice and the filtrate was concentrated under reduced pressure to give the title compound (2,4-diamino-5-fluoro-phenyl)-acetic acid 9c (7.12 g) as a brown solid which was directly used in the further reaction.
Reaction SMILES: [CH:1](Cl)([O:6][CH:7]([F:9])[F:8])[C:2]([F:5])([F:4])[F:3].[F-:11].[K+]>>[CH:7]([O:6][CH:1]([C:2]([F:5])([F:4])[F:3])[F:11])([F:9])[F:8]
Reactant: FC(F)OC(Cl)C(F)(F)F
Reactant: [F-]
Agent: [K+]
Product: FC(F)OC(F)C(F)(F)F
Temperature: 278 °C
Reaction time: 18 h
Yield: 13.3 %

Procedure:
A 1 liter autoclave (316SS, Parr) was charged with 171 g (0.93 moles) isoflurane and 116 g (2.0 moles) potassium fluoride. The reaction mass was heated with stirring to 278° C. After 18 hours at 278° C., the pressure was 500 psi. The autoclave was then cooled to room temperature for transfer to the laboratory. Products were then distilled into a dry ice cooled trap by heating the autoclave on a hot plate. The trap contents (134 g) were distilled through a four foot vacuum jacketed column packed with glass beads to give 20.8 g CHF2OCHFCF3 (bp 23.5° C.). The material remaining in the distillation flask (104.0 g) was 98% isoflurane. Based on the materials isolated, the percent conversion was 13% (33% yield). Details of the distillation are given below.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[CH2:9][C@H:10]([OH:38])[C@@H:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C@H:10]([OH:38])[C@@H:11]([NH:25][C:26]([C@@H:27]([NH:32][C:33](=[O:34])[O:35][CH3:36])[C:28]([CH3:30])([CH3:31])[CH3:29])=[O:37])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 23R (0.34 g, 0.54 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL), stirred at 25° C. for 1 hour, and concentrated. The residue was partitioned between dichloromethane and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The crude product (0.251 g) was used without further purification.
Reaction SMILES: ClC1C=C(Cl)C=CC=1[NH2:4].[H-].[Na+].[N+:12]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])([O-])=O>CN(C=O)C>[NH2:12][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:4])=[O:18]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-dichloro-aniline (322 mg, 2.0 mmol) in DMF was treated with 95% NaH (53 mg, 2.1 mmol) at 0° C., and then 2-nitro-benzoyl chloride was added (390 mg, 2.1 mmol). After stirring for 2 h at rt, the mixture was concentrated and co-evaporated with water, diluted with CH2Cl2, washed with aq. NaHCO3, dried and concentrated. The crude residue was dissolved in EtOH, and subjected to hydrogenation at 1 atm overnight, filtered through Celite and concentrated to give the crude product 2-amino-benzamide.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:12]1(C)[CH:17]=CC(S([O-])(=O)=O)=C[CH:13]=1.[NH+]1C=CC=CC=1>CC(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][O:10][C:12]([CH3:17])([CH3:13])[O:11]2)=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: OCC(O)c1ccc(Br)nc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)OCC(c2ccc(Br)nc2)O1
Yield: 267.4 %

Procedure:
To a solution of 1-(6-bromopyridin-3-yl)ethane-1,2-diol (4.20 g) in acetone (80 mL) was added pyridinium p-toluenesulfonate (1.50 g), and the mixture was stirred with heating under reflux for 3 hr. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (4.12 g, yield 72%) as a pale-yellow solid. MS: 260 (MH+).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH3:22])=[C:6]([CH:23]([CH3:25])[CH3:24])[N:5]=1)([CH3:3])[CH3:2].[CH2:26](Cl)Cl.CCCCCC>>[CH:1]([C:4]1[C:9]([CH:10]([OH:11])[CH3:26])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH3:22])=[C:6]([CH:23]([CH3:24])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCCCCC
Product: CCCCc1c(C(C)C)nc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5butylpyridine (Example 24) according to the procedures described in Example 101. 1H NMR (300 MHz, CDCl3): δ 7.1 (m, 4 H), 4.7 (dq, J=3 Hz, 1 H), 3.7 (septet, J=7 Hz, 1 H), 3.2 (septet, J=7 Hz, 1 H), 2.2 (t, J=1.5 Hz, 2 H), 1.6 (d, J=5 Hz, 1 H), 1.4 (d, J=7 Hz, 3 H), 1.3 (m, 16 H), 0.8 (t, J=7Hz, 3H). FAB-MS: calcd for (C23H32FNO) 357, found 358 (M+H). mp 103-104° C. Rf=0.2 (60% CH2Cl2/hexane).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[N:17]=[C:16]([C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][CH2:24][N:25]3C(OC(C)(C)C)=O)=[CH:20][CH:19]=2)[CH:15]=[CH:14][C:13]=1[O:35][S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])=[O:11]>C(Cl)Cl>[NH:25]1[C:26]2[C:21](=[CH:20][CH:19]=[C:18]([C:16]3[N:17]=[C:12]([C:10]([O:9][CH3:8])=[O:11])[C:13]([O:35][S:36]([C:39]([F:41])([F:42])[F:40])(=[O:38])=[O:37])=[CH:14][CH:15]=3)[CH:27]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)ccc1OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (18 mL) was added to tert-butyl 7-(6-(methoxycarbonyl)-5-(trifluoromethylsulfonyloxy)pyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29E) (2.00 g, 3.9 mmol) in anhydrous DCM (25 mL). The reaction mixture was stirred at rt for 1.5 hours, concentrated under reduced pressure, diluted with DCM, and washed with saturated NaHCO3. The aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure to provide the desired product methyl 6-(1,2,3,4-tetrahydroquinolin-7-yl)-3-(trifluoromethylsulfonyloxy)picolinate (29F) in sufficient purity for subsequent use. 1H NMR (300 MHz, CDCl3) δ 7.88 (1H d), 7.66 (1H, d), 7.39 (1H, d), 7.29 (1H, dd), 7.08 (1H, d), 4.03 (3H, s), 3.39 (2H, m), 2.83 (2H, t), 2.02 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[N:12]=[CH:13][NH:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH:9]=[CH:10][C:5]=2[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]1=[O:29].[H-].[Na+].Cl[C:33]1[CH:38]=[N:37][CH:36]=[CH:35][N:34]=1>CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[N:12]([C:33]4[CH:38]=[N:37][CH:36]=[CH:35][N:34]=4)[CH2:13][NH:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH:9]=[CH:10][C:5]=2[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]1=[O:29]
Reactant: Clc1cnccn1
Reactant: Cc1cccc(-c2[nH]cnc2-c2ccc3c(c2)n(C)c(=O)n3-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C2=C(c3ccc4c(c3)n(C)c(=O)n4-c3ccccc3)N(c3cnccn3)CN2)c1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-Methyl-1-phenyl-5-(5-m-tolyl-1H-imidazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (prepared as described previously in Example 200, 33 mg, 0.087 mmol) in DMF (0.1 mL) was added NaH (4 mg, 0.095 mmol). After stirring for 20 min, 2-chloropyrazine (9.3 mL, 0.10 μmol) was added and the reaction mixture was heated to 120° C. for 14 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by LC (Waters Symmetry C8, formic acid/acetonitrile/water) to afford 2 mg of the title compound.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].FC(S(O)(=O)=O)(F)F.ClC(Cl)(Cl)C(=N)O[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:19]([CH:2]([OH:3])[C:1]([O:5][CH3:6])=[O:4])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: COC(=O)CO
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(O)Cc1ccccc1

Procedure:
To a solution containing methyl glycolate (2.5 mL, 32 mmol) and trifluoromethyl-sulfonic acid (150 mL) in CH2Cl2 (10 mL) was added benzyl 2,2,2-trichloro-acetimidate (7.0 mL, 37 mmol). After stirring for several min, the mixture was poured into aqueous NaHCO3 and extracted with Et2O. The organic extract was washed with saturated aqueous NaCl, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 9-17% EtOAC/Hex to afford the title compound: 1H NMR (CDCl3): d 7.34 (m, 5H); 4.62 (s, 2H); 4.11 (s, 2H); 3.78 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].CC(O)=O>CCOC(C)=O.[Pd]>[NH2:8][C:6]1[C:5]([F:11])=[CH:4][C:3]([CH2:12][C:13]([OH:15])=[O:14])=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)c([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(F)c(CC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2,5-difluoro-4-nitrophenyl)acetic acid (440 mg, 2.03 mmol) in 20 ml of EtOAc was added HOAc (121 mg, 2.03 mmol) and 200 mg of Pd/C was stirred at room temperature under H2 atmosphere for 3 hours. The reaction mixture was filtrated and concentrated to give (4-amino-2,5-difluorophenyl)acetic acid.
Reaction SMILES: [CH2:1](/[C:3](=[CH:7]\[C:8](=[O:10])[CH3:9])/[C:4]([NH2:6])=[O:5])[CH3:2].O.[BH4-].[Na+].Cl>CO>[CH2:1](/[C:3](=[CH:7]\[CH:8]([OH:10])[CH3:9])/[C:4]([NH2:6])=[O:5])[CH3:2]
Reactant: CC/C(=C\C(C)=O)C(N)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC/C(=C\C(C)O)C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
24 (ethyl (2E)-4-oxopent-2-enamide) (5.18 g, 36.7 mmol) is dissolved in MeOH (6 ml) and H2O (54 ml) and cooled to 0° C. NaBH4 is added to the resulting solution (426 mg, 11.3 mmol) in portions over 15 min. After 30 min of additional stirring at 0° C., the reaction mixture is acidified with 2 M HCl (1.15 ml) and extracted with AcOiPr (2×1 l). The organic phases are washed with brine (2×25 ml). The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. The residue is purified by flash chromatography (MeOH:CH2Cl2 5:95 to 7.5:92.5) and yields 25 (rac-Ethyl (2E)-4-hydroxypent-2-enamide) (4.60 g, 88%) as a viscous brown oil.