Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][NH2:16].N1C=CN=C1>ClC(Cl)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][CH2:15][CH2:14][CH:13]([CH3:17])[CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC(C)CCN
Agent: c1c[nH]cn1
Solvent: CC(Cl)Cl
Product: CC(C)CCNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To a stirred solution of 2,4-dichloro-5-nitropyrimidine (13.8 g, 99.28 mmol) and 3-methylbutan-1-amine (7.0 g, 80.45 mmol) in dichloroethane (150 mL) was added imidazole (3.78 g, 55.58 mmol) at 0° C., the resulting mixture was stirred at 0° C. for 30 minutes then stirred at rt for 16 h. The solvent was removed under reduced pressure to give a crude residue was purified by silica gel column chromatography (eluent: 2% ethyl acetate in hexane) to yield 5.5 g of the desired compound. 1H NMR (CDCl3, 300 MHz) δ 0.98 (d, J=6.8 Hz, 6H), 1.56-1.81 (m, 3H), 3.60-3.75 (m, 2H), 8.40 (br s, 1H), 9.01 (s, 1H); MS m/z 245[M+H+].
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>[OH-].[K+].O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:26][C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccncc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1C(=Cc2ccncc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 21.7 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.50 g, 1.95 mmol) was reacted with 4-pyridinecarboxaldehyde (0.248 g, 2.3 mmol) in 2.5 mL of 4% KOH for 8 hours at room temperature. The reaction was diluted with water, the resulting mixture was filtered, and the filtrate was extracted into EtOAc. The combined extracts were evaporated to dryness, and the resulting yellow solid was purified twice by flash chromatography (silica gel, 120 g, 9% MeOH in DCM) to afford 0.146 g of a yellow oil which crystallized on standing. Recrystallization from minimal iPrOH afforded the title compound as a light yellow powder (0.041 g, 6%), mp 128.5-129° C., CI-MS m/e 345 (M+), 346 M++1);
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:31][CH3:32])=[C:24]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)[CH:23]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Product: COc1ccc(Cl)cc1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (65 mg, 0.199 mmol) and 5-chloro-2-methoxyphenylboronic acid (42 mg, 0.22 mmol) as a colourless gum. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.91 (dd, 1H), 8.18 (d, 1H), 8.13 (m, 3H), 7.98, (d, 2H), 7.86 (d, 1H), 7.66 (d, 2H), 7.36 (dd, 2H), 7.32 (m, 2H), 6.94 (d, 1H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH3:14][S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25]Cl)=[CH:21][CH:20]=1)(=[O:17])=[O:16].C(=O)(O)[O-].[Na+].[I-].[Na+]>C(#N)C>[CH3:14][S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[CH:21][CH:20]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Nc1ccc(OCCCl)cc1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc1ccc([N+](=O)[O-])cc1
Yield: 38.1 %

Procedure:
A suspension of N-methyl-4-nitrophenethylamine (1.1 g), 2-(4-methanesulphonamidophenoxy)ethyl chloride (1.5 g), sodium bicarbonate (0.5 g) and sodium iodide (0.9 g) in acetonitrile (100 ml) was stirred at reflux for 4 days. On evaporation to dryness the resultant oil was partitioned between 2N aqueous sodium bicarbonate solution and methylene chloride. After two further extractions with methylene chloride, the organic portions were combined, washed with saturated brine solution, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The resultant brown oil was chromatographed on silica ("Kieselgel 60"--Trade Mark) eluting with ethyl acetate followed by collection and evaporation of suitable fractions to give the title compound as a yellow solid, (0.9 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:19](Cl)(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[C:19]([NH:9][CH:10]([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CCOC(=O)C(N)C(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)C=Cc1ccccc1)C(C)=O
Reaction time: 0.33 h

Procedure:
Triethylamine (8.3 ml) was added dropwise to a solution of ethyl 2-aminoacetoacetate hydrochloride (5.43 g) and cinnamoyl chloride (5.0 g) in chloroform (90 ml) with ice-cooling and stirring. After 20 minutes, the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was treated with isopropyl ether to give ethyl 2-cinnamoylaminoacetoacetate as crystals; yield 6.1 g (73.9%). Recrystallization from ethanol gave colorless needles melting at 113°-114° C.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:29]12([C:39](=[O:42])[CH2:40]Br)[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[C:29]12([C:39](=[O:42])[CH2:40][N:9]3[C:10](=[O:11])[C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=4[N:7]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([C:20]5[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=5)=[CH:16][CH:15]=4)[C:8]3=[O:12])[CH2:36][CH:35]3[CH2:34][CH:33]([CH2:32][CH:31]([CH2:37]3)[CH2:30]1)[CH2:38]2
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)C34CC5CC(CC(C5)C3)C4)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 1-(1-adamantyl)-2-bromoethanone (1.0 g) and N,N-dimethylformamide (8 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with ethyl acetate, successively washed with water and saturated brine and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.68 g, 47%).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([O:27]C)=[O:26])[C:19]2=[O:35])=[O:13])=[CH:6][CH:5]=1.[OH-:36].[Na+].O>CO>[C:25]([OH:27])(=[O:26])[CH3:24].[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:22][C:21]([OH:36])=[O:23])[C:19]([NH:20][CH:24]([C:25]([OH:27])=[O:26])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:35])=[O:13])=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: COC(=O)C(c1ccccc1)N1C(=O)CN(CCCNC(=O)C=Cc2ccc(C=NN)cc2)C1=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)O
Product: NN=Cc1ccc(C=CC(=O)NCCCN(CC(=O)O)C(=O)NC(C(=O)O)c2ccccc2)cc1

Procedure:
78 mg (0.165 mmol) of methyl (3-(3-(3-(4-(aminoiminomethyl)phenyl)acryloylamino)propyl)-2,5-dioxoimidazolidin-1-yl)phenylacetate are stirred at room temperature for 20 h together with 2 ml of 1N sodium hydroxide solution, 5 ml of water and 5 ml of methanol. Following concentration, the residue is, for purification, chromatographed on Sephadex LH20 using an homogeneous mixture of butanol/glacial acetic acid/water.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:31]([NH:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:32])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C=Nc1ccccc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)Nc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), phenyl isocyanate (8.0 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5 M HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/00/1 (v/v) as eluent.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>C(#N)C>[BrH:1].[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ccc(Br)cn1
Solvent: CC#N
Product: Br
Product: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1

Procedure:
First, 2-bromo-4′-hydroxyacetophenone and 2-amino-5-bromopyridine are dissolved in an inactive solvent such as acetonitrile, and are allowed to react with each other at a reflux temperature for 2 to 6 hours to produce 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine hydrobromide salt as white precipitates. The solvent used in this instance may be acetonitrile or another solvent that is usually employed in a similar reaction, for example, methanol and acetone. The reaction temperature may be a temperature allowing refluxing, for example, 90° C. when the solvent is acetonitrile. The amount of the solvent to be used may be an amount sufficient to effect the reaction, however, it should be noted that if the solvent is too much, it will become difficult to obtain precipitates of reaction products. For example, when 2-bromo-4′-hydroxyacetophenone in an amount corresponding to 10 mmol is used for the reaction, the amount of a solvent to be used can be about 40 to 50 mL.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C(O[C:18](=[O:28])[CH2:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])(C)(C)C.[CH:29]([C:31]1[C:32]([NH:38]C(=O)C(C)(C)C)=[N:33][CH:34]=[CH:35][C:36]=1[CH3:37])=O.[NH4+].[Cl-]>C(OCC)C.C1COCC1>[CH3:37][C:36]1[CH:35]=[CH:34][N:33]=[C:32]2[C:31]=1[CH:29]=[C:19]([CH2:20][C:21]([OH:23])=[O:22])[C:18](=[O:28])[NH:38]2
Reactant: CC(C)(C)OC(=O)CCC(=O)OC(C)(C)C
Reactant: Cc1ccnc(NC(=O)C(C)(C)C)c1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccnc2[nH]c(=O)c(CC(=O)O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a precooled solution of N,N-diisopropylamine (6.2 mL, 0.044 mol) in diethyl ether (125 mL, dried over molecular seives) was added BuLi (2.5 M in hexanes) (17.8 mL, 0,044 mol) and the resulting solution was stirred at rt. for 15 minutes whereafter di-tert-butylsuccinate (5.35 g, 23 mmol) dissolved in diethyl ether (10 mL, dried over molecular seives) was slowly added. After 30 min at −78° C., 3-formyl-4-methyl-2-(pivaloylamino)-pyridine (4.65 g, 21.0 mmol) dissolved in THF (10 mL, LAB-SCAN C2520, dried over molecular seives) was slowly added, and stirring at this temperature was continued for 30 min. The solution was allowed to warm to rt. and poored into a solution of NH4Cl (sat., aqueous, 100 mL). The aqueous phase was extracted three times with diethylether (3×50 mL) and the organic extracts washed with water (50 mL) and brine (50 mL), dried over MgSO4 and evaporated in vacuo. The crude product was recrystallized from ethyl acetate/hexane to yield the diastereomeric mixture which was used as such after drying in vacuo. The diastereomeric mixture was dissolved in HCl (3M, aqueous, 50 mL) the solution was stirred under reflux for 3.5 h, cooled to rt. and washed with diethyl ether (2×50 mL), neutralised with K2CO3 and again washed with chloroform (3×50 mL). After precipitation upon cooling 1.39 g (37%) of the title compound was obtained (mp >250° C.). 1H NMR (D2O/NaOD): δ 8.25 (d, 4.9 Hz, 1H), 7.71 (s, 1H), 6.84 (d, 4.9 Hz, 1H), 2.36 (s, 2H), 1.05 (s, 3H). 13C NMR (D2O/NaOD): δ 180.30, 171.68, 155.44, 148.84, 146.04, 132.61, 127.08, 117.60, 116.21, 27.22, 16.98. FAB+ MS (m/z): 219.10 (M+H+, calc. for C11H10N2O3+H+ 219.0770).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].ClC(Cl)(O[C:26](=[O:32])OC(Cl)(Cl)Cl)Cl.C(Cl)(Cl)=O.FC(F)(F)C=O.[F:44][C:45]([F:49])([F:48])[CH2:46][NH2:47]>C(OCC)C>[Cl:15][C:12]1[CH:11]=[C:10]2[C:9](=[CH:14][CH:13]=1)[NH:8][C:26](=[O:32])[N:47]([CH2:46][C:45]([F:49])([F:48])[F:44])[C:16]2([OH:21])[C:17]([F:20])([F:18])[F:19]
Reactant: NCC(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Agent: O=C(Cl)Cl
Agent: O=CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1Nc2ccc(Cl)cc2C(O)(C(F)(F)F)N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of triethylamine (1.3 ml, 9.4 mmol) and 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2.1 g, 9.4 mmol) in diethyl ether (18 ml) was cooled to 0° C. under nitrogen atmosphere. In a separate round bottom, triphosgene (929 mg, 3.1 mmol) in diethyl ether (11 ml) was cooled to 0° C. To the phosgene mixture at 0° C. was added dropwise the trifluoroethanone mixture. After stirring for 15 minutes, to this reaction was added a mixture of triethylamine (1.3 ml, 9.4 mmol) and trifluoroethylamine in diethyl ether (18 ml). The reaction stirred for two hours at room temperature and then quenched with water (50 ml) and washed with saturated aqueous sodium bicarbonate solution (2×30 ml). The aqueous layer was extracted with ethyl acetate (3×100 ml) and the combined organic extracts were dried over Na2SO4, filtered and concentrated to give crude material which was purified by flash chromatography on silica gel (0-30% ethyl acetate/hexanes). This afforded 6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 9.22 (s, 1H), 7.58 (s, 1H), 7.39 (dd, J=2.0 and 8.6 Hz, 1H), 6.84 (d, J=8.4 Hz), 4.71 (m, 1H), 4.38 (s, 1H), 4.18 (m, 1H). Exact Mass (Electrospray, M+H): Calc'd, 349.0173; Found, 349.0166.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=1[NH2:17])([O-:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:15]=1[N+:12]([O-:14])=[O:13])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Product: O=C(Nc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1cc(Cl)ccc1O
Yield: 8.1 %

Procedure:
Using 5-chlorosalicylic acid and 2-nitro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2c(F)cccc2c1Cl
Reactant: OB(O)c1cccnc1
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: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccnc2)nc2c(F)cccc2c1Cl

Procedure:
Prepared according to general Procedure F using 2,4-dichloro-8-fluoro-3-methylquinoline (250 mg, 1.1 mmol), 3-pyridylboronic acid (134 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium(0) (126 mg, 0.11 mmol), sodium carbonate (202 mg, 1.90 mmol) in toluene:water (5 mL:2 mL) and heating at 130° C. overnight. After purification 4-chloro-8-fluoro-3-methyl-2-(pyridin-3-yl)quinoline was obtained as a white solid. Mass Spectrum (ESI) m/e=273.0 (M+1).
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>O1CCCC1>[C:1]([NH:10][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)(N)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(NCCCS(=O)(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of cumylamine (10.5 g, 78 mmol) in tetrahydrofuran (75 mL) was slowly added a solution of 1,3-propane sultone (9.2 g, 74 mmol) in THF (20 mL). The mixture was stirred at reflux for 4 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration, and washed with THF (2×35 mL). The solid was suspended in EtOH (80 mL). The suspension was stirred at reflux for 15 minutes. The solid product was collected by filtration, washed with EtOH (35 mL) and acetone (35 mL). The resulting solid was dried in vacuo, affording compound DM (5.6 g, 30%). 1H NMR (D2O, 500 MHz) δ ppm 7.41 (m, 5H), 2.74 (m, 4H), 1.88 (m, 2H), 1.66 (s, 6H). 13C NMR (D2O, 125 MHz) δ ppm 138.36, 129.44, 129.41, 126.52, 61.56, 48.04, 41.21, 24.80, 21.81. ES-MS 256 (M−1).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH2:30][NH:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:39](=O)[CH3:40].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[CH2:30][N:31]([CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH2:39][CH3:40])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC=O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1CNC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCN(Cc1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)C1CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[(cyclobutylamino)methyl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (3.6 mg, 6.50×10−3 mmol) in dichloroethane (300 μL) was added acetaldehyde (40 μL, 0.709 mmol) and NaBH(OAc)3 (excess). The reaction was stirred at room temperature for 2 hours and then diluted with EtOAc (10 mL) and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-{[cyclobutyl(ethyl)amino]methyl}-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.69 (25% EtOAc/hexanes). LCMS=583.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.90 (s, 1H), 7.80 (s, 2H), 7.54-7.52 (m, 3H), 5.74 (d, J=8.0 Hz, 1H), 4.99 (d, J=16.1 Hz, 1H), 4.65 (d, J=16.2 Hz, 1H), 4.04-3.98 (m, 1H), 3.64 (d, J=13.9 Hz, 1H), 3.47 (d, J=13.9 Hz, 1H), 3.18-3.12 (m, 1H), 2.48-2.39 (m, 2H), 1.98-1.92 (m, 2H), 1.87-1.74 (m, 2H), 1.67-1.58 (m, 2H), 0.90 (t, J=7.2 Hz, 3H), 0.80 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1/[N:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:17]([Mg]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[C:7]1([CH:6]([NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[O:2][CH3:1])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1ccccc1/N=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1NC(Cc1ccccc1)c1ccccc1
Temperature: -80 °C
Yield: 96.1 %

Procedure:
To a solution of 4.22 g (20.0 mmol) of 9 in 50 mL of THF, 48.0 mL (26.0 mmol) of 0.55 M BnMgCl in THF was added with vigorous stirring at −80° C. This mixture was slowly warmed to room temperature, and then 2 mL of water was added. The resulting mixture was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether=40:1, vol.) to give 5.83 g (96%) of B3.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.N1C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].C(=O)([O-])O.[Na+]>ClCCl>[CH2:11]([C:4]1[CH:3]=[C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:24]=[C:23]([O:22][CH3:21])[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=2)[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CCCCc1cc(N)n2nccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n2nccc2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.5 %

Procedure:
7-Amino-5-n-butylpyrazolo[1,5-a]pyrimidine (1.90 g) and pyridine (20 ml) were dissolved in 20 ml of dry dichloromethane. A dry dichloromethane solution (10 ml) containing 2.6 g of 3,4,5-trimethoxybenzoyl chloride was slowly added dropwise thereto and stirred at room temperature for 10 hours. After addition of 50 ml of a 10% aqueous sodium hydrogen carbonate solution, the reaction mixture was extracted with chloroform. The organic layer was collected, washed with 10% aqueous hydrochloric acid and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane=1:2) and recrystallized from diethyl ether-n-hexane to provide 2.4 g of the object compound as colorless crystals. Table 1 shows the structure and melting point of the compound obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]([NH:13][C:14](=[O:17])[CH2:15]Cl)([CH2:11][OH:12])[CH2:9][OH:10])[CH:7]=1.CC(C)([O-])C.[K+].Cl.O>CC(O)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH2:11][OH:12])[NH:13][C:14](=[O:17])[CH2:15][O:10][CH2:9]2)[CH:7]=1
Reactant: O=C(CCl)NC(CO)(CO)c1cc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1COCC(CO)(c2cc(Br)ccc2F)N1

Procedure:
A mixture of N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide (6.34 g, 18.62 mmol) and potassium tert.-butoxide (2.09 g, 18.62 mmol) in 62 ml tBuOH was refluxed for 30 min. 19 ml 1 N HCl and water were added and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4 and evaporated. The crude product was recrystallized in Hex/EtOAc to provide the title compound as an off-white solid.