Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH3:4][O:5][C:6]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH:11]([C:15](N(OC)C)=[O:16])[CH2:10]1>C1COCC1.O>[C:15]([CH:11]1[CH2:10][N:9]([CH2:8][C:7]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:6]=2[O:5][CH3:4])[C:13](=[O:14])[CH2:12]1)(=[O:16])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1ccc(CN2CC(C(=O)N(C)OC)CC2=O)c(OC)c1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(C(C)=O)CC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
MeMgBr (2.3 mL, 6.8 mmol) was added to a mixture of 1-(2,4-dimethoxybenzyl)-N-methoxy-N-methyl-5-oxopyrrolidine-3-carboxamide (2.0 g, 6.2 mmol) in THF (40 mL) at −10° C. The mixture was stirred at 0° C. for 1 hour then diluted with water and the mixture was extracted with EtOAc. The EtOAc layer was dried over sodium sulfate and concentrated under reduced pressure to afford 4-acetyl-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one. 1H NMR (400 MHz, CDCl3) δ 7.10-7.13 (m, 1H), 6.43-6.45 (m, 2H), 4.41-4.42 (m, 2H), 3.79-3.82 (m, 6H), 3.46-3.20 (m, 3H), 2.61-2.64 (m, 2H), 2.04-2.15 (d, J=7.2 Hz, 3H). MS ESI calc'd. for C15H20NO4 [M+H]+ 278. found 278.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:10]=[C:11]([NH2:27])[S:12][C:13]=1[C:14]1[N:15]=[C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[S:17][CH:18]=1.[CH:28]1[N:32]=[CH:31][N:30]([C:33](N2C=NC=C2)=[O:34])[CH:29]=1.CN(C=O)C>C(Cl)Cl>[CH3:8][C:9]1[N:10]=[C:11]([NH:27][C:33]([N:30]2[CH:29]=[CH:28][N:32]=[CH:31]2)=[O:34])[S:12][C:13]=1[C:14]1[N:15]=[C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[S:17][CH:18]=1
Reactant: Cc1nc(N)sc1-c1csc(C(=O)N2CCOCC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(C(=O)N2CCOCC2)n1
Temperature: 45 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
In a 20 ml vial under Ar, triethylamine (51 μl; 0.37 mmol; 1.10 eq.) is added to a stirred suspension of 4′-methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-amine, obtained in step II as describe above (142.4 mg; 0.34 mmol; 1 eq.), and CDI (54.4 mg; 0.34 mmol; 1 eq.) in dry DCM (5 ml). DMF (0.30 ml) is added to help the solubility. The mixture is stirred at 45° C. overnight. No starting material can be detected by HPLC. The reaction mixture is cooled down to RT. The resulting precipitate is isolated by filtration, washed with diethyl ether and dried under vacuum, affording Intermediate 7 (107.1 mg; 79%). It is used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](C(O)=O)=[CH:5][N:6]=1.[C:10](Cl)(=[O:14])C(Cl)=O.Cl.[NH:17]1[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[N:17]1([C:10]([C:5]2[N:6]=[C:2]([Br:1])[S:3][CH:4]=2)=[O:14])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1CNC1
Reactant: O=C(O)c1cnc(Br)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1csc(Br)n1)N1CCC1
Reaction time: 4 h
Yield: 55.9 %

Procedure:
To a solution of 2-bromothiazole-5-carboxylic acid (752 mg, 3.62 mmol) in DCM (10 mL) was slowly added oxalyl chloride (0.38 mL, 4.34 mmol) and then DMF (1 drop). The mixture was stirred for 4 hours, following which the organics were removed in vacuo, and the residues azeotroped with toluene (10 mL). The crude material was dissolved in DCM (10 mL) and slowly added to a stirred suspension of azetidine hydrochloride (404 mg, 4.34 mmol) and triethylamine (1.8 mL, 13 mmol) in DCM (25 mL). The mixture was stirred at RT for 2 hours before the organics were removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (25 mL), the organic layer washed with brine (25 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in iso-hexane, to give the desired compound (500 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2=[C:17]3[C:4]=1[CH2:5][CH:6](O)[N:7]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)[C:8]3=[N:9][CH:10]=[N:11]2.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Br:24][C:20]1[CH:19]=[C:18]([N:7]2[CH:6]=[CH:5][C:4]3[C:17]4[C:8]2=[N:9][CH:10]=[N:11][C:12]=4[CH:13]=[C:14]([O:15][CH3:16])[C:3]=3[O:2][CH3:1])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2ncnc3c2c(c1OC)CC(O)N3c1cccc(Br)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc3c2c(c1OC)C=CN3c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7,8-dimethoxy-4-(3-bromo-phenyl)-5,6-dihydro-4H-1,3,4-triaza-phenalen-5-ol (0.17 g, 0.42 mmol) (from Example 22, Step A, supra) and triethylamine (0.35 mL, 2.53 mmol) in dichloromethane (30 mL) at 0° C. was added methanesulfonyl chloride (0.13 mL, 1.68 mmol) (Aldrich). The reaction solution was stirred at room temperature for 2 hours. The solution was then concentrated, the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:1:0.01) as eluent to give the desired 4-(3-bromo-phenyl)-7,8-dimethoxy-4H-1,3,4-triaza-phenalene as an off white solid. (Yield 81 mg, 50%).
Reaction SMILES: [CH:1]([C:3]([CH2:5][CH3:6])=[O:4])=[CH2:2].[CH3:7][C:8](/[CH:10]=[CH:11]/C)=[CH2:9].Cl(O)(=O)(=O)=O.[CH2:18]([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>C(O)C>[CH3:18][C@H:2]1[CH:7]=[C:8]([CH3:9])[CH2:10][CH2:11][C@H:1]1[C:3](=[O:4])[CH2:5][CH3:6]
Reactant: C=CC(=O)CC
Reactant: C=C(C)/C=C/C
Reactant: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Product: CCC(=O)[C@@H]1CCC(C)=C[C@@H]1C
Yield: 90 %

Procedure:
Prepared according to general procedure B from ethyl vinyl ketone (59 μL, 0.59 mmol), trans-2-methyl-1,3-pentadiene (94 μL, 0.89 mmol), 70% aqueous perchloric acid (10.2 μL, 0.12 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (32 mg, 0.12 mmol) in ethanol (590 μL) for 4.5 days at −30° C. Purification by silica gel chromatography (9:1 pentane:ether) provided the title compound as a single diastereomer (as judged by GLC analysis) in 90% yield (90 mg, 0.54 mmol) and 90% ee. IR (film) 2964, 2937, 2874, 2833, 1711, 1452, 1377, 1343, 1227, 1195, 1123, 1038, 984.2, 886.0, 841.6 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.37 (m, 1H, CH═CCH3), 2.60 (m, 2H, CHCO and CHCH3), 2.50 (dq, J=17.4, 7.5 Hz, 1H, C(H)HCO), 2.37 (dq, J=17.4, 7.5 Hz, 1H, C(H)HCO), 1.94 (m, 2H, ═CCH2), 1.68 (m, 2H, CH2CH), 1.64 (s, 3H, CH3C═CH), 1.05 (dd, J=7.5, 7.5 Hz, 3H, CH2CH3), 0.76 (dd, J=6.9, 6.9 Hz, 3H, CH3CH); 13C NMR (75 MHz, CDCl3) δ 214.0, 133.7, 126.3, 50.5, 34.6, 31.7, 30.2, 23.8, 19.0, 16.8, 8.1. [α]D=+16.7 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (100° C., 23 psi); (1R, 2S) endo isomer tr=21.3 min, and (1S, 2R) endo isomer tr=20.4 min, exo isomers tr=15.4, 16.6 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(O)(=O)C.[CH2:22]([SH:25])[CH2:23][SH:24].B(F)(F)F>C(Cl)Cl>[C:12]1([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH:2]=[CH:3][C:4]=4[CH:9]=3)[S:25][CH2:22][CH2:23][S:24]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccc2occc2c1
Reactant: SCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(C2(c3ccc4occc4c3)SCCS2)cc1
Reaction time: 8 h

Procedure:
To a solution of benzofuran-5-yl(phenyl)methanone (2.45 g, 11.0 mmol), glacial acetic acid (1.27 mL, 22.0 mmol) and 1,2-ethanedithiol (1.39 mL, 16.5 mmol) in 30 mL DCM at ambient temperature was added boron trifluoride diethyletherate (1.38 mL, 11.0 mmol). The reaction was allowed to stir overnight, and was quenched by the addition of 1N NaOH. The aq. layer was extracted 1×DCM, and the combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography, ISCO, 0-20% EtOAc/hexanes provided 5-(2-phenyl-1,3-dithiolan-2-yl)benzofuran as a clear/colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.48-7.57 (m, 3H), 7.38-7.45 (m, 1H), 7.29-7.36 (m, 2H), 7.24 (t, J=7.3 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H) 3.43 (s, 4H).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([O:11][C:12](=[O:26])[CH2:13][C:14]1[C:15]([NH2:25])=[N:16][NH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:8]CC.[CH3:27][C:28](=O)[CH2:29][C:30](=O)[CH3:31].Cl>C(O)C>[CH2:7]([O:11][C:12](=[O:26])[CH2:13][C:14]1[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:17][N:16]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:27])=[N:25][C:15]=12)[CH3:8]
Reactant: CC(=O)CC(C)=O
Reactant: CCCCOC(=O)Cc1c(N)n[nH]c1-c1ccccc1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1c(-c2ccccc2)nn2c(C)cc(C)nc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 20.0 g (0.055 mole) of 3-amino-5-phenyl-1H-pyrazole-4-acetic acid butyl ester ethanedioate and 5.51 g (0.055 mole) of pentane-2,4-dione in 150 ml of 200 ethanol was treated with 10 ml of concentrated hydrochloric acid and stirred at room temperature for 17 hours.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[C:33]1([C:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:40]2[CH:44]=[CH:43][CH:42]=[CH:41]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.O>[CH:40]1([C:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)[CH:41]=[CH:42][CH:43]=[CH:44]1
Reactant: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(c3ccccc3)(c3ccccc3)C3C=CC=C3)c1C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2.5 g (9.0 mmol) of 3,6-di-tert-butylfluorene in 40 ml of THF, 6.1 ml (9.8 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 4 hours. The resulting solution was ice cooled again, and thereto was dropwise added a solution of 2.5 g (10.8 mmol) of 6,6-diphenylfulvene in 30 ml of THF in a nitrogen atmosphere, followed by stirring at room temperature for 5 hours. Then, 50 ml of water was added. The organic phase extracted with diethyl ether and separated was dried over magnesium sulfate and then filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a solid. The solid was recrystallized from methanol to obtain 3.4 g of a slightly yellow solid. The analyzed values are given below.
Reaction SMILES: [OH-].[Na+].[C:3]1([CH3:15])[CH:8]=[CH:7][C:6]([N:9]2[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18]>O.CCOC(C)=O>[Cl:22][C:21]([Cl:24])([Cl:23])[CH2:20][O:19][C:17](=[O:18])[NH:14][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH3:15])=[CH:8][CH:7]=2)[N:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nccc2N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nccc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaOH (107 mg, 2.67 mmol) was added to a stirred solution of 2-p-tolyl-2H-pyrazol-3-ylamine (for reference procedure see WO 2009/150614, which is incorporated herein by reference in its entirety, 346 mg, 2.00 mmol) in water (1 mL) and EtOAc (4 mL). The mixture was cooled to 0° C., and 2,2,2-trichloroethyl chloroformate (385 L, 2.80 mmol) added. Stirring was continued for 30 min at 0° C. and then for 2 h at RT. The mixture was partitioned between water and EtOAc. The organic phase was washed with brine and concentrated to dryness in vacuo to give the title compound as an orange residue. LCMS (Method 3): Rt 3.90 min, m/z 348, 350 [MH+].
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][C:22]=2[N:23]=1.[C:34](Cl)(=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:12]=[CH:11][C:10]=1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:43])[CH2:30][CH2:29]3)=[CH:24][C:22]=2[N:23]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc3cc(C4CCNCC4)ccc3o2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2nc3cc(C4CCN(C(=O)OCc5ccccc5)CC4)ccc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (Example 61) (70 mg, 0.14 mmol) dissolved in DCM (10 ml) and added TEA (0.1 ml, 0.72 mmol). This mixture stirred at rt for 30 mins and added benzyl carbonochloridate in toluene (48 mg, 0.28 mmol). After 30 mins reaction mixture quenched with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether (1:2) as eluent to afford the titled compound (30 mg) as an off-white solid. M.P.: 172-175° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.49-8.43 (m, 1H), 7.90-7.84 (m, 2H), 7.68 (d, J 1.4, 1H), 7.57 (d, J 8.5, 1H), 7.42-7.22 (m, 6H), 5.17 (s, 2H), 4.42-4.25 (bs, 2H), 3.13 (s, 3H), 3.00-2.78 (m, 3H), 2.00-1.88 (m, 2H), 1.80-1.65 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:24])[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[CH:10]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:26][C:27](OCC)=[O:28]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:24])[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[CH:10]([C:18]3[CH2:23][CH2:22][N:21]([CH:27]([OH:28])[CH3:26])[CH2:20][CH:19]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2c(c1)C(c1ccncc1)CC2(O)c1ccc(F)cc1
Solvent: CC(C)=O
Product: Cc1ccc2c(c1)C(C1=CCN(C(C)O)CC1)CC2(O)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
3-(4'-Fluorophenyl)-3-hydroxy-6-methyl-1-(4-pyridyl)indane (Example 8) (9.0 g) was refluxed with ethyl bromoacetate (5.0 g) in acetone (50 ml) for 3 hrs. The reaction mixture was cooled in a refrigerator overnight and the precipitated pyridinium bromide filtered off. Yield: 7.8 g (56.9%). MP: 177°-78° C. This bromide (7.0 g) was dissolved in methanol (50 ml), cooled to 0° C., and NaBH4 (3.0 g) was added during 1 hour under stirring. The reaction mixture was poured into NH4Cl (10 g) in 1 liter of H2O and finally extracted with ethyl acetate (2×150 ml). The combined organic phases were dried (MgSO4) and the ethyl acetate evaporated. The remaining oil (1-(1-ethylcarboxymethyl-1,2,3,6-tetrahydropyrid-4-yl)-3-(4'-fluorophenyl)-3-hydroxy-6-methylindane) was dissolved in dry tetrahydrofuran (25 ml) and added dropwise to a suspension of LiAlH4 (1.8 g) in dry tetrahydrofuran under ice cooling. The mixture was refluxed for two hours, hydrolysed by careful addition of H2O (5 ml) in tetrahydrofuran (100 ml). The precipitate was filtered off, and the solvent evaporated leaving the title compound as an oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:7]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[N:6]=[CH:5][C:4]=1[C:20]#[N:21].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br-:1].[C:20]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[C:3]=1[CH2:2][N+:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1CBr
Reactant: c1ccncc1
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C[n+]1ccccc1
Product: [Br-]

Procedure:
By the method of Example 5, Step E, 133 g (0.339 mole) of 5-bromomethyl-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole and 666 mL of pyridine were reacted, yielding 98 g of 1-[[4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazol-5-yl]methyl]pyridinium bromide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:18][C:19]1[CH:24]=[C:23]([CH:25]=O)[CH:22]=[C:21]([CH3:27])[N:20]=1.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:18][C:19]1[CH:24]=[C:23]([C:25]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[CH:7]=3)[N:1]=2)[CH:22]=[C:21]([CH3:27])[N:20]=1
Reactant: Cc1cc(C=O)cc(C)n1
Reactant: NC(=O)c1cc(CCN2CCCC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccc(CCN4CCCC4)cc3c(=O)[nH]2)cc(C)n1
Temperature: 120 °C

Procedure:
To a solution of 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzamide (0.16 g, 0.69 mmol) in N,N-dimethyl acetamide (7 mL) under a nitrogen atmosphere was added 2,6-dimethyl-pyridine-4-carbaldehyde (0.09 g, 0.68 mmol), followed by sodium hydrogensulfite (0.14 g, 1.36 mmol) and p-toluenesulfonic acid (0.32 g, 1.7 mmol). The resulting mixture was heated at 120° C. overnight. Then, the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, and was extracted with water. The pH of the water layer was made basic by adding sodium bicarbonate, then the layer was extracted with methylene chloride, dried over anhydrous sodium sulfate, and was evaporated under high vacuum. The crude yellow solid (0.09 g) was purified by column chromatography (silica gel 230-400 mesh; 95/5 methylene chloride/MeOH as eluent) to afford the title compound as a yellow solid. Yield: 54 mg (23%). MP 212.3-213.2° C. 1H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 8.19 (br s, 1H), 7.83-7.77 (m, 1H), 7.76-7.70 (m, 3H), 3.0-3.15 (m, 2H), 2.78-2.88 (m, 2H), 2.7 (s, 6H), 2.58-2.68 (m, 4H), 1.8-1.95 (m, 4H). MS (ES+) m/z: 347.11 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:8].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH3:5][CH:4]([CH3:19])[CH2:3][CH2:2][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:8]
Reactant: O=C(NCc1cccc(O)c1)c1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCOc1cccc(CNC(=O)c2ccc3ncccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a mixture solution of quinoline-6-carboxylic acid 3-hydroxybenzylamide described in Preparation Example E+-4 (13 mg, 0.048 mmol) and N,N-dimethylformamide (0.5 mL) were added potassium carbonate (13 mg, 0.096 mmol) and 1-iodine-3-methylbutane (0.013 mL, 0.096 mmol), and the solution was stirred overnight at room temperature. Water and dichloromethane was added to the reaction solution for extraction, which was then washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate), and the title compound (12 mg, 0.033 mmol, 69%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[C:14]3[CH:39]=[CH:38][N:37](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]=3[N:16]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]4)=[CH:22][C:21]=3[O:35][CH3:36])[N:18]=2)[C:3]=1[C:4]([NH2:6])=[O:5].[OH-].[K+]>O1CCCC1.O1CCOCC1.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]4)=[CH:22][C:21]=3[O:35][CH3:36])[NH:16][C:15]3=[N:37][CH:38]=[CH:39][C:14]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CCCN1CCC(c2ccc(Nc3nc(Nc4cc(F)cc(F)c4C(N)=O)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)c(OC)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCCN1CCC(c2ccc(Nc3nc(Nc4cc(F)cc(F)c4C(N)=O)c4ccnc-4[nH]3)c(OC)c2)CC1

Procedure:
2,4-difluoro-6-({2-{[2-(methyloxy)-4-(1-propyl-4-piperidinyl)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (9.5 g, 13.7 mmol) was dissolved in tetrahydrofuran (100 mL) and dioxane (400 mL). A solution of KOH (35 g) in water (100 mL) was added to the reaction mixture. The mixture was heated to reflux overnight, and cooled. The organic layer was separated, dried over sodium sulfate, filtered, and adsorbed over silica. Purification by flash silica gel chromatography with a gradient from 10 to 100% of a 20:20:2:58 mixture of THF/MeOH/NH4OH/DCM in DCM provided the required product which was contaminated with ˜15% p-toluene sulfonic acid. The residue was dissolved in THF (˜400 mL) and refluxed to dissolve most of the solid. The mixture was cooled and then washed with 2 N aqueous NaOH. The separated clear organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was recrystallized with 20% MeOH in DCM to obtain 2,4-difluoro-6-[(2-{[2-(methyloxy)-4-(1-propyl-4-piperidinyl)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (5.8 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.4 Hz, 3H), 1.40-1.50 (m, 2H), 1.60-1.78 (m, 4H), 1.89-1.98 (m, 2H), 2.20-2.27 (m, 2H), 2.37-2.46 (m, 1H), 2.91-2.98 (m, 2H), 3.83 (s, 3H), 6.22 (dd, J=3.4, 1.9 Hz, 1H), 6.77 (dd, J=8.3, 1.6 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.93 (ddd, J=11.4, 9.0, 2.6 Hz, 1H), 7.00 (dd, J=3.5, 2.2 Hz, 1H), 7.65 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 8.03 (br. s., 1H), 8.17 (s, 1H), 8.53 (d, J=11.4 Hz, 1H), 11.08 (s, 1H), 11.42 (s, 1H); ESIMS (M+H)+=536.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:11]=[C:12]([C:21]([O:23]CC)=[O:22])[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:15]=1)([O:6]CC)=[O:5])C>Cl>[P:4]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[C:12]([C:21]([OH:23])=[O:22])[CH:11]=1)([OH:6])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(CP(=O)(OCC)OCC)cc(C(=O)OCC)c1
Agent: Cl
Product: O=C(O)c1cc(CP(=O)(O)O)cc(C(=O)O)c1
Yield: 43.8 %

Procedure:
A solution of diethyl 5-[(diethoxyphosphinyl)methyl]-1,3-benzenedicarboxylate (0.186 g, 0.5 mmol) in 12 N HCl (2.5 mL) was heated at 100° C. for 24 hours. The resulting precipitate was washed with water and dried under vacuum to give 0.057 g of white powder (41% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:27]([CH3:28])=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[O:29][CH3:30])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:4][CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C>O>[CH3:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[C:27]([CH3:28])=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[O:29][CH3:30])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCC(c1ccc(O)cc1)c1c(C)cc2ccccc2c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc(C(CCCCC(=O)O)c2c(C)cc3ccccc3c2OC)cc1
Yield: 86.3 %

Procedure:
Ethyl 6-(4-hydroxyphenyl)-6-(l-methoxy-3-methylnaphth-2-yl)hexanoate (30 g) was stirred with potassium carbonate (90 g), iodomethane (45 ml), and DMF (150 ml) overnight at ambient temperature. The reaction mixture was poured into cooled water and extracted with IPE. The organic layer was washed with water, dried, and evaporated. The residue was dissolved in ethanol (250 ml) and refluxed with 2.5N sodium hydroxide (250 ml) for 5 hours. Ethanol was removed and the residue was acidified with conc.HCl and extracted with ethyl acetate. The organic layer was washed with water, dried, and evaporated to give the titled compound (25 g) as crude oil.