Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=1.[OH-].[Na+].O1CCCC1.Cl>O>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[N:21][C:12]=1[CH2:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cccc(OCc2ncc3ccccc3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(OCc2ncc3ccccc3n2)c1

Procedure:
A mixture of 5.50 g (0.01869 moles) of 3-(2-quinazolinylmethoxy)benzoic acid methyl ester, 30.1 ml (0.0301 moles) of 1N sodium hydroxide and 22 ml of tetrahydrofuran is heated at reflux for 50 minutes. The mixture is allowed to come to room temperature and evaporated in vacuo giving a solid residue. After the addition of water and filtration through Celite the filtrate is acidified with 2.4M hydrochloric acid. The resulting precipitate is filtered, washed with water until the washings are pH 6. The precipitate is dried overnight in a vacuum desiccator and azeotroped with toluene on a rotoevaporator. Drying in vacuo gives the title compound, 4.75 g colorless solid, m.p. 221°-224° C.; IR (KBr) 1695, 1576, 1285, 1220 cm-1 ; NMR (DMOS-d6) 9.73 (s, 1H), 7.34-8.22 (8H, aromatic) 5.56 (2H, s), 3.43 (1H, broad).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>C1COCC1>[F:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([NH:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:24]=1
Reactant: Nc1cccnc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cccnc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
LiHMDS (1.0M in THF, 50 mL, 50 mmol) was added dropwise to a stirred solution of pyridin-3-ylamine (2.5 g, 26.4 mmol) in anhydrous THF (20 mL) under a nitrogen atmosphere at −70° C. After 10 min stirring at −78° C., a solution of 2,4-difluoro-1-nitrobenzene (4.0 g, 25.1 mmol) in THF (40 mL) was added dropwise at −78° C. The reaction mixture was slowly warmed to RT. After 4 h stirring at RT, the crude mixture was quenched by addition of an aqueous solution of NH4Cl and the aqueous fraction extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound as a red solid (quantitative). 1H NMR (CDCl3, 300 MHz): δ 9.58 (1H, br s), 8.61 (1H, d, J=2.64 Hz), 8.55 (1H, d, J=4.76 Hz), 8.29 (1H, dd, J=9.47, 5.92 Hz), 7.66-7.61 (1H, m), 7.40 (1H, dd, J=8.19, 4.75 Hz), 6.74 (1H, dd, J=10.95, 2.62 Hz), 6.60-6.51 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH3:15])=[O:5].[F:23][CH2:24][C:25](Cl)=[O:26]>N1C=CC=CC=1>[F:23][CH2:24][C:25]([NH:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH3:15])=[O:5])=[O:26]
Reactant: COc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2N)c(C)c1
Reactant: O=C(Cl)CF
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)CF)c(C)c1
Yield: 86.9 %

Procedure:
4.8 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-4-methoxyaniline, 1.9 g of pyridine and 2.32 g of fluoroacetyl chloride are treated in the same manner as described in Example 1-(1), whereby 5.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-methoxyaniline are obtained as colorless needles.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]3)=[O:16])[NH:12][C:9]2=[N:10][CH:11]=1.[CH3:25][C@H:26]1[NH:30][C@H:29]([CH3:31])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:23][C:20]1([F:24])[CH2:21][CH2:22][N:17]([C:15]([C:13]2[NH:12][C:9]3=[N:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:30]4[C@H:26]([CH3:25])[CH2:27][CH2:28][C@H:29]4[CH3:31])[CH:7]=[C:8]3[CH:14]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: C[C@@H]1CC[C@@H](C)N1
Reactant: O=C(c1cc2cc(OCCCCl)cnc2[nH]1)N1CCC(F)(F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CC[C@@H](C)N1CCCOc1cnc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Yield: 6 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from [5-(3-chloro-propoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, (2R,5R)-(−)-trans-2,5-dimethylpyrrolidine (commercially available) and potassium carbonate in acetonitrile to give 23 mg (6%) of the desired product as a light yellow solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[NH:16][C:15](=[O:23])[CH:14]([C@H:24]3[CH2:29][CH2:28][C@H:27]([N:30]4[C:38](=[O:39])[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:31]4=[O:40])[CH2:26][CH2:25]3)[O:13][C:12]2=1.IC.ClCCl>CN(C)C=O.CO>[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[N:16]([CH3:1])[C:15](=[O:23])[CH:14]([C@H:24]3[CH2:29][CH2:28][C@H:27]([N:30]4[C:38](=[O:39])[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:31]4=[O:40])[CH2:26][CH2:25]3)[O:13][C:12]2=1
Reactant: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)C(=O)N3
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: ClCCl
Product: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)C(=O)N3C
Temperature: -5 °C
Reaction time: 14 h

Procedure:
Sodium carbonate (405 mg, 3.82 mmol, 3.5 eq) is added at −5° C. to a stirred solution of 2-[trans-4-(6-methoxy-2-oxo-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione (500 mg, 1.09 mmol, 1.0 eq) in N,N-dimethylformamide (30 mL), followed by iodomethane (408 μL, 6.55 mmol, 6.0 eq). After 14 hours stirring at −5° C., solvent is removed and the residue is extracted with ethyl acetate (3×100 mL) and water (100 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 50:1, v/v) to afford 2-[trans-4-(6-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione as a light red semisolid (420 mg, 81% yield).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]([C:9]1[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:12]=[C:11]([C:20](=[O:24])[CH:21](Br)[CH3:22])[N:10]=1)([CH3:8])[CH3:7]>O.CC(C)=O>[N:1]([CH:21]([CH3:22])[C:20]([C:11]1[N:10]=[C:9]([C:6]([CH3:5])([CH3:8])[CH3:7])[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:12]=1)=[O:24])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(Br)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(N=[N+]=[N-])C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A solution of 1.2 g (18 mmol) of sodium azide in 9.0 mL of water was added dropwise to a solution of 5.5 g (16 mmol) of 1[4,6 bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]-2-bromo-1-propanone in 35 mL of acetone. The mixture was stirred for 2 hours then added to 100 mL of water and extracted with ethyl acetate. The organic layers were washed with brine, dried (anhydrous sodium sulfate), and evaporated to yield 4.7 g (96%) of the azide product, mp 91° C.-92° C., suitable for further synthesis.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[O:15]>>[C:1]1([CH2:7][C:8]([OH:12])([C:9]([OH:11])=[O:10])[CH2:16][C:14](=[O:15])[C:13]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C(=O)O
Reactant: O=C(O)C(=O)Cc1ccccc1
Product: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O

Procedure:
According to the study by the present inventors, it has been found that PtALD can catalyze the aldol condensation reaction of indolepyruvic acid with pyruvic acid (or oxalacetic acid) to yield 4-(indol-3-ylmethyl)-4-hydroxy-2-oxoglutaric acid (IHOG), and the reaction of phenylpyruvic acid with pyruvic acid to yield 4-phenylmethyl-4-hydroxy-2-oxoglutaric acid (PHOG).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[F:11].[CH2:12]([CH2:14][NH2:15])[OH:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:9])[CH2:10][NH:15][CH2:14][CH2:12][OH:13])=[CH:4][C:3]=1[F:11]
Reactant: Fc1cc([C@@H]2CO2)ccc1Cl
Reactant: NCCO
Product: OCCNC[C@H](O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.6 %

Procedure:
(R)-2-(4-chloro-3-fluorophenyl)oxirane (1.66 g, 9.62 mmol) was added dropwise to ethanolamine (3.5 mL, 53.9 mmol). The (R)-2-(4-chloro-3-fluorophenyl)oxirane residue was rinsed with 4 mL of THF and this was added to the reaction mixture. The clear solution was stirred at room temperature for 48 h. TLC indicated complete consumption of the starting material. The mixture was treated with water (30 mL) under ice bath and then extracted with ethyl acetate (40 mL). The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic phase was washed with water and brine, dried and concentrated in vacuo to afford (R)-1-(4-chloro-3-fluorophenyl)-2-(2-hydroxyethylamino)ethanol (2.06 g) as a colorless oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.54 (br. s., 3H) 2.64-2.77 (m, 1H) 2.84 (td, J=5.00, 3.59 Hz, 2H) 2.93 (dd, J=12.27, 3.59 Hz, 1H) 3.72 (t, J=5.10 Hz, 2H) 4.72 (dd, J=8.88, 3.59 Hz, 1H) 7.08 (dd, J=8.31, 1.89 Hz, 1H) 7.20 (dd, J=9.82, 1.89 Hz, 1H) 7.31-7.43 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)(=[O:23])=[O:22])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1

Procedure:
(compound D1) (0.531 g), 4-biphenylsulphonylchloride (0.834 g). Reaction conditions: −30° C., 10 min; −30° C., 30 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(Cl)cc4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(Cl)cc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-(4-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (146.2 mg, 0.32 mmol, 1.00 equiv) in MeOH/THF (1:1)(16 mL), a solution of sodium hydroxide (64 mg, 1.60 mmol, 5.00 equiv) in water (1.5 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. The solid was dissolved in DMF and sent for prep-HPLC to purification. This resulted in 49 mg (35%) of 3-(4-(4-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=2[CH2:11][N:12]2[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[C:13]2=[O:31])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(#N)C>[F:36][C:34]1[CH:33]=[CH:32][C:10]([CH2:11][N:12]2[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:29])([F:30])[F:28])[CH:21]=3)[C:13]2=[O:31])=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:7][CH:6]=2)[CH:35]=1
Reactant: CC1(C)C(=O)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)N1Cc1ccc(F)cc1Nc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)C(=O)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)N1Cc1ccc(F)cc1Nc1ccc(NS(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
150 mg of compound 240.1 were dissolved in 5 ml of acetonitrile and admixed with 145 mg of cesium carbonate and 41 mg of methanesulfonyl chloride. Subsequently, the mixture was stirred at 60° C. for 6 h; the next day, a further 1.2 equivalents of methanesulfonyl chloride were added and the mixture was stirred at 60° C. for a further 8 h. For workup, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography (method [RP1]). N-(4-{5-Fluoro-2-[3-(4-fluoro-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]phenylamino}phenyl)methanesulfonamide was obtained. Molecular weight 582.13 (C26H23F5N4O4S); retention time Rt=3.88 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[C:5]2[C:10](=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:28]>NN.C(O)C.[OH-].[K+]>[CH3:1][O:2][C:3]1[C:4]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:39])[F:38])[CH:31]=2)=[C:5]2[C:10](=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:28]
Reactant: COc1cc(NCCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(NCCCN)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of the above phthalimide 10 in 100 mL of 65% hydrazine and 100 mL of ethanol was refluxed under argon for 3 hours. After cooling to room temperature, the solution was diluted with 10% aqueous KOH solution and extracted with dichloromethane three times. The combined extract was washed with brine, dried (K2CO3), concentrated, and column chromatographed on silica gel using dichloromethane and methanol as eluants to give 1.86 g (80% yield) of 6-methoxy-8-[(3-aminopropyl)amino]-4-methyl-5-(3-trifluoromethylphenyloxy)quinoline. 1H NMR (CDCl3) δ 8.40 (d, J=4 Hz, 1 H), 7.34 (t, J=8 Hz, 1 H), 7.21 (d, J=8 Hz, 1 H), 7.06 (m, 2 H), 6.93 (d, J=8 Hz, 1 H), 6.48 (s, 1 H), 6.4 (bs, 1 H, NH), 3.83 (s, 3 H, OMe), 3.42 (t, J=8 Hz, 2 H), 2.99 (t, J=8 Hz, 2 H), 2.62 (s, 3 H, Me), 1.98 (pentet, J=8 Hz, 2 H), 1.80 (bs, 2 H, NH2). 13C NMR (CDCl3) δ 160.0, 151.1, 145.0, 143.5, 142.7, 130.2, 125.2, 118.4, 118.2, 112.2, 107.5, 92.9, 56.8, 41.6, 40.4, 33.1, 23.4. The succinic acid salt was prepared by treating 0.457 g (1.12 mmol) of the quinoline with 0.134 g (1.13 mmol) of succinic acid in 10 mL of methanol. The resulting solution was concentrated to dryness, crystallized from diethyl ether to give a quantitative yield of the succinic acid salt PQ1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:19][C:20](=O)[C:21]([F:24])([F:23])[F:22]>C(O)C>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]2[N:3]([CH:19]=[C:20]([C:21]([F:24])([F:23])[F:22])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(Cl)cccc1Cl
Reactant: O=C(CBr)C(F)(F)F
Solvent: CCO
Product: FC(F)(F)c1cn2cccc(OCc3c(Cl)cccc3Cl)c2n1
Yield: 44.5 %

Procedure:
A mixture of 2-amino-3-(2,6-dichlorobenzyloxy)-pyridine (1.345 g) and 3-bromo-1,1,1-trifluoroacetone (1.147 g) in ethanol (26 ml) was refluxed for 5 hours, cooled, and concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed with water, dried, and concentrated under reduced pressure to give a solid, which was purified by flash chromatography on silica gel to give 8-(2,6-dichlorobenzyloxy)-2-trifluoromethylimidazo[1,2-a]pyridine as a white solid (803 mg).
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].C([O:9]CC)C.O1CCOCC1.CN1C=CC=C1>[Cl-].[Zn+2].[Cl-].CCCCCC.C1(C)C=CC=CC=1.C1C=CC=CC=1.C1COCC1>[Cl:4][C:3]([Cl:6])([Cl:5])[C:2]([OH:9])=[O:1].[O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: CCOCC
Agent: Cn1cccc1
Agent: O=CC(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=C(O)C(Cl)(Cl)Cl

Procedure:
As a result of their studies on the process, Kondo, Suda and Tunemoto found that it was possible to obtain the 2,2,2-trichloro-1-(N-hydrocarbylpyrryl-2)-ethanol adduct in almost quantitative yield by reacting chloral with N-hydrocarbylpyrrole at from -10° C. to about 36° C. without using a Lewis acid catalyst such as zinc chloride. As reported in their above referred to co-pending application, it was discovered that the rate of this reaction--which is preferably conducted in the presence of solvents which do not directly affect on the reaction, for example, ethereal solvents such as diethyl ether, dioxane, THF, and the like, and hydrocarbons such as benzene, toluene, hexane, and the like--is dependent on the origin (or the purity) of chloral used. Chloral from a freshly opened bottle did not react with N-methylpyrrole at room temperature and only after prolonged reflux (sometimes several days) was the adduct formed. In contrast, chloral from an old bottle reacted instantly at room temperature. Acting on the hypothesis that trichloroacetic acid, which is formed easily by the oxidation of chloral, does catalyze this reaction, they found that the addition of organic acid such as trichloroacetic acid, acetic acid or p-toluenesulfonic acid to the reaction mixture accelerates this reaction. They further report that among these three acids p-toluenesulfonic acid appears more effective than the others and that in carrying out the process in the presence of a protonic acid added preferably in the form of an organic acid or a cation exchange resin, the adduct (i.e., the 2,2,2-trichloro-(N-hydrocarbylpyrryl-2)-ethanol) has been readily formed in almost quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1.Br[C:29]1[C:38]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2.C([O-])([O-])=O.[Cs+].[Cs+]>ICCC.COCCOC.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16]([C:29]3[C:38]([O:39][C:40]([F:41])([F:42])[F:43])=[CH:37][CH:36]=[C:35]4[C:30]=3[CH:31]=[CH:32][CH:33]=[N:34]4)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1)[nH]c(=O)n2C
Reactant: FC(F)(F)Oc1ccc2ncccc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCCI
Solvent: O
Product: Cc1noc(C)c1-c1cc(-c2c(OC(F)(F)F)ccc3ncccc23)c2c(c1)[nH]c(=O)n2C
Temperature: 120 °C

Procedure:
To a microwave vial containing 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (52 mg, 0.14 mmol, 1 equiv.) was added 5-bromo-6-(trifluoromethoxy)quinoline (124 mg, 0.42 mmol, 3 equiv.), Cs2CO3 (230 mg, 0.70 mmol, 5 equiv.) and PEPPSI™-IPr catalyst (9.5 mg, 0.014 mmol, 0.1 equiv.) and dissolved in DME-H2O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 120° C. for 30 min in microwave. The reaction was concentrated in vacuo and purification was then carried out by reverse phase HPLC.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2([CH:36]=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH2:31]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([C:30]5([CH:36]=[O:37])[CH:31]=[CH:32][CH:33]=[CH:34][CH2:35]5)[CH:25]=[CH:26][C:27]=4[O:28][CH3:29])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCCl
Solvent: CC#N
Product: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole (2.01 g; 9.13 mmol), K2CO2 (2.0 g), and 1-[3-(3-chloropropoxy)-4-methoxy-phenyl]phenyl -methanone (3.93 g; 11.3 mmol) and acetonitrile (50 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was evaporated and the residue was partitioned between water (150 ml) and dichloromethane (400 ml). The dichloromethane solution was washed with water and brine (100 ml), dried over MgSO4, then concentrated to an oil. The purification was done by flash chromatography over a silica gel column (SiO2, 40 g; eluted with dichloromethane, 300 ml; 1% methanol in dichloromethane, 850 ml). The material thus obtained as a colorless oil solidified on standing. Recrystallization from ethanol (150 ml) gave 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]-phenylmethanone as white crystals, 3.07 g (63%), m.p.=140°-141° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:37])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[CH:21]=3)[CH:15]=2)[N:10]([C:33](=[O:35])[CH3:34])[C@@H:9]([CH3:36])[CH2:8]1)[CH3:3].[ClH:38]>O1CCOCC1>[ClH:38].[C:33]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:37])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:36])(=[O:35])[CH3:34]
Reactant: CC(=O)N1c2ccc(-c3cn(CCCNC(=O)OC(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cn(CCCN)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of 1-methylethyl((2S,4R)-1-acetyl-6-{1-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]-1H-1,2,3-triazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation, see Intermediate 73) (543 mg, 1.055 mmol) in 1,4-dioxane (1 mL) was treated with HCl (4N in 1,4-dioxane, 4.00 mL, 16 mmol) and the resulting mixture was stirred for 2 h at room temperature then concentrated in vacuo. The residue was co-evaporated twice with toluene then triturated with Et2O and filtered off to give 1-methylethyl {(2S,4R)-1-acetyl-6-[1-(3-aminopropyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride (370 mg, 0.771 mmol, 73% yield) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:17][C:18]1([CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][O:20][CH2:19]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][C:18]2([CH3:22])[CH2:21][O:20][CH2:19]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(COc2ccc(Br)cc2C=O)COC1
Temperature: 140 °C
Yield: 50.1 %

Procedure:
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (14 g, 70 mmol), KI (5 g) and K2CO3 (19 g, 140 mmol) in DMF (100 mL) was added toluene-4-sulfonic acid 3-methyl-oxetan-3-ylmethyl ester (18 g, 70 mmol). The mixture was heated at 140° C. for 2 h, and then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water for 3 times, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (10 g).