Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:9]=1)=O)(C)(C)C.Cl.C(O)(=O)C.C(OCC)C>C(O)(=O)C>[CH3:26][O:25][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[O:23][CH3:24])[C:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7])=[O:27]
Reactant: COc1cc(C(=O)c2cccc(NC(=O)C(C)(C)C)c2)cc(OC)c1OC
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc(C(=O)c2cccc(N)c2)cc(OC)c1OC
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
N-tert-butylcarbonyl-3-(3,4,5-trimethoxybenzoyl)aniline (7.10 g, 18.92 mmol), prepared as described above, was dissolved in acetic acid (125 mL, 1.4N) at room temperature. A solution of hydrochloric acid/acetic acid (20 mL) was added and the mixture allowed to stand for 45 minutes. Diethylether (800 mL) was added and the resulting precipitate filtered and dried to yield 3-(3,4,5-trimethoxybenzoyl)aniline (5.24 g, 85.7%) as a tan solid.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25]C)=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:16]=2[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:10][CH:9]=1)(C)(C)C.[ClH:38].[N:39](=[CH:47]CCl)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][Cl:46]>>[ClH:46].[ClH:38].[N:39]1([CH2:47][CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[C:16]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=4)=[CH:17][CH:18]=[C:19]4[C:24]=3[CH:23]=[CH:22][C:21]([OH:25])=[CH:20]4)=[CH:12][CH:13]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=[CH:45]1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)OC(C)(C)C)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reactant: ClCC=NCCCCCCCl
Agent: Cl
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(NCCN3C=CC=CC=C3)cc2)cc1
Yield: 33 %

Procedure:
Using procedures similar to Preparation 18 and Example 58, convert {4-[2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenyl}-carbamic acid tert-butyl ester (200 mg, 0.39 mmol) and 2-(hexamethyleneimino)-ethyl chloride hydrochloride (140 mg, 0.70 mmol) to 77 mg of the title compound (37%). Mass spectrum (ion spray): m/z=531 (M+H).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:23][CH3:24])[C:13]1[N:18]=[C:17]([C:19](=[O:21])[CH3:20])[CH:16]=[C:15]([CH3:22])[N:14]=1>CO>[Br:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:23][CH3:24])[C:13]1[N:18]=[C:17]([C:19](=[O:21])[CH:20]=[CH:4][N:12]([CH3:23])[CH3:13])[CH:16]=[C:15]([CH3:22])[N:14]=1
Reactant: CCN(c1nc(C)cc(C(C)=O)n1)c1ccc(C(C)C)cc1Br
Agent: [Na]
Solvent: CO
Product: CCN(c1nc(C)cc(C(=O)C=CN(C)C)n1)c1ccc(C(C)C)cc1Br
Reaction time: 19 h
Yield: 121.6 %

Procedure:
Sodium (0.08 g, 3.5 mmol) was added to methanol (20 mL) with stirring. After the sodium reacted, a solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methyl-pyrimidinamine (1.0 g, 2.67 mmol) in methanol (5 mL) was added and the reaction mixture was stirred for 5 min. Gold's reagent ((dimethylaminomethyleneaminomethylene))dimethyl-ammonium chloride (0.66 g, 4 mmol) was added and stirring was continued for 19 h. The reaction mixture was concentrated in vacuo; the residue was dissolved in chloroform and the solution was washed with a saturated NaHCO3 solution, dried over MgSO4 and filtered solvent removal in vacuo gave a brown solid, which upon trituration with hexanes afforded N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-dimethylaminopropenoyl)-6-methylpyrimidinamine as a yellow solid (700 mg): NMR (CDCl3, 300 MHz): 7.9-7.65 (br s, 1H), 7.5 (s, 1H), 7.25-7.2 (m, 2H), 7.15 (s, 1H), 6.1-5.8 (br s, 1H), 4.3-4.15 (m, 1H), 3.9-3.75 (m, 1H), 3.2-3.0 (br s, 3H), 3.0-2.85 (m, 1H), 2.8-2.6 (br s, 3H), 2.5-2.3 (br s, 3H), 1.35-1.2 (m, 9H): CI-MS, 431, 433 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:5].N1C=CC=CC=1.[F:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[F:27][CH2:28][C:29]([NH:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:5])=[O:30]
Reactant: Cc1ccccc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)CF
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
14.4 g(0.053 mol) of N-(2-amino-5-nitrobenzoyl)-o-toluidine and 6.3 g(0.08 mol) of pyridine are dissolved in 300 ml of tetrahydrofuran. 12.2 g(0.126 mol) of fluoroacetyl chloride are added to the solution for 10 minutes under ice-cooling. The solution is stirred at the same temperature for 30 minutes and then at room temperature for 2.5 hours. The reaction solution is allowed to stand at room temperature overnight. The crystalline precipitate is collected by filtration, washed with water and then dried. 16.4 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-o-toluidine are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:18]=[C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:11]([C:12](OCC)=[O:13])=[CH:10][N:9]=2)[S:5][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]([CH2:12][OH:13])=[C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH:18]=2)[S:5][CH:6]=1
Reactant: CCOC(=O)c1cnc(Nc2nc(C)cs2)cc1Oc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(CO)cn2)n1
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A solution of ethyl 6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)nicotinate (1.50 g, 3.70 mmol) in THF (15 mL) was added to a 1.0 M solution of lithium aluminum hydride (18.5 mL, 18.5 mmol) in ether at 0° C. and stirred for 30 minutes. The reaction was quenched with sodium sulfate decahydrate, stirred 30 minutes, and filtered. The solids were washed with THF, filtered, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, and concentrated. The residue was triturated with hexanes and filtered to afford (6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)pyridin-3-yl)methanol (1.10 g, 81.8% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.68 (bs, 1H), 8.25 (s, 1H), 8.05 (d, 1H), 7.92 (d, 2H), 7.53-7.64 (m, 3H), 7.36 (d, 1H), 6.47 (s, 1H), 6.19 (s, 1H), 5.20 (t, 1H), 4.71 (d, 2H), 2.13 (s, 3H); Mass spectrum (esi) m/z=364 (100) (M+H).
Reaction SMILES: [CH2:1]([NH2:16])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C.Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35]>CCO>[N+:31]([C:28]1[CH:27]=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=[CH:30][C:29]=1[NH:16][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]#[CH:15])([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C#CCOCCOCCOCCOCCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: C#CCOCCOCCOCCOCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 99.5 %

Procedure:
3,6,9,12-tetraoxapentadec-14-yn-1-amine 7 (1.0 g, 4.3 mmol, 1 equiv.) was dissolved in EtOH (18 mL), and triethylamine (1.68 mL, 8.6 mmol, 2 equiv.) and 1-chloro-2,4-dinitrobenzene (876 mg, 4.3 mmol, 1 equiv.) were added. The reaction flask was fitted with a reflux condenser and the reaction was heated to reflux for 2 h, cooled, and concentrated to a crude yellow oil. The crude mixture was re-dissolved in H2O (25 mL) and extracted with CH2Cl2 (5×10 mL). Organic layers were dried over Na2SO4 and concentrated to a yellow oil that was purified by flash chromatography (CombiFlash Automated Chromatographer, 25 g column, dryloaded with 25 g pre-packed dry loading column. Run using 10% EtOAc:Hexanes to 50% EtOAc:Hexanes gradient over 30 column volumes, followed by EtOAc flush) to yield 2 as a yellow solid (1.70 g, >98% yield). IR (thin film/NaCl) 3360(m), 3290 (m), 3110 (w), 2873 (m), 2114(w), 1621 (s), 1588 (m), 1336 (s), 1134 (m) cm−1; 1H-NMR (500 MHz, CDCl3) δ 9.13 (d, 1H, J=2.6 Hz), 8.80 (broad peak, 1H), 8.25 (dd, 1H, J=2.6, J=9.5 Hz), 6.94 (d, 1H, J=9.5 Hz), 4.18 (m, 2H), 3.83 (t, 2H, J=5.2 Hz), 3.67 (m, 12H), 3.60 (q, 2H), 2.41 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ 148.6, 136.2, 130.4, 124.4, 114.3, 79.8, 74.7, 70.8, 70.7, 70.5, 69.2, 68.7, 58.5, 43.4; HRMS (EI) calc'd for C17H23N3O8 (MH+) m/z 398.1558. Found 398.1557.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[C:33]([O:39][CH3:40])[CH:32]=1>>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[C:33]([O:39][CH3:40])[CH:32]=1
Reactant: COc1cc(Br)ccc1CBr
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: COc1cc(Br)ccc1COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-Bromo-1-bromomethyl-2-methoxy-benzene following the procedure of Example 478: MS (ES) m/z 592.1.
Reaction SMILES: [NH3:1].Br[C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].O>CS(C)=O>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([NH2:1])[CH:8]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 18 h

Procedure:
In a sealed reaction tube, add cautiously 6 mL of an aqueous solution of ammonia (32%) to a solution of 2,4-dibromonitrobenzene (1,6 g) in 2 mL of DMSO. Stir for 18 hours at 100° C. and cool to room temperature. Pour the heterogeneous mixture into water and filter the title compound (1.1 g, 92%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:28]1([CH2:34][C:35]([N:37]=[C:38]=[O:39])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.CCCCCC>[N:22]1([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[O:39])=[CH:27][CH:26]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:25][CH2:24][CH2:23]1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(azetidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (62.8 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.71 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (50.0 mg, 55%) as white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[N:4]([CH2:14][CH2:15][CH2:16][N:17]([CH3:35])[CH2:18][CH2:19][CH2:20][N:21]2[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:34])[C:3]1=[O:36].[Na].[CH2:39](I)[CH3:40]>C(O)C>[CH3:1][C:2]1([CH3:37])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:39][CH3:40])=[CH:9][CH:10]=2)[C:5](=[O:13])[N:4]([CH2:14][CH2:15][CH2:16][N:17]([CH3:35])[CH2:18][CH2:19][CH2:20][N:21]2[C:30](=[O:31])[C:29]([CH3:32])([CH3:33])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:34])[C:3]1=[O:36]
Reactant: CN(CCCN1C(=O)c2ccccc2C(C)(C)C1=O)CCCN1C(=O)c2cc(O)ccc2C(C)(C)C1=O
Reactant: CCI
Agent: [Na]
Solvent: CCO
Product: CCOc1ccc2c(c1)C(=O)N(CCCN(C)CCCN1C(=O)c3ccccc3C(C)(C)C1=O)C(=O)C2(C)C

Procedure:
1.3 gm of N-[3-(3,4-dihydro-4,4-dimethyl-7-hydroxy-1,3-dioxo-2(1H)-isoquinolyl)-propyl]-N-[3-(3,4-dihydro-4,4-dimethyl-1,3-dioxo-2(1H)-isoquinolyl)-propyl]-methylamine were dissolved in 10 ml of absolute ethanol, the resulting solution was added to a solution of 0.06 gm of sodium in 10 ml of absolute ethanol, and 0.42 gm of ethyl iodide was added to the mixed solution. The mixture was refluxed for 30 minutes, another 0.42 gm of ethyl iodide was added, and the mixture was refluxed again for 30 minutes. The product was purified on a silicagel column (eluant: chloroform/ethanol = 25:1), and the hydrochloride was precipitated from acetone with ethereal hydrochloric acid. The hydrochloride sintered above 45° C; yield: 0.5 gm (35% of theory).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[O:31]=[C:32]1[NH:37][CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:37]5[CH2:36][CH2:35][NH:34][CH2:33][C:32]5=[O:31])[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cc(-c3cccnc3)ncc21
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Product: O=C1CNCCN1c1cccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)n1
Yield: 20 %

Procedure:
Following the procedure of Example 224, 3-(6-bromopyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 3-oxopiperazine-1-carboxylate were reacted. The product was deprotected by the procedure of Example 225 and purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 8.0 mg (20%) of 301 over two steps. ESI MS m/z 372.1 (M+1). 1H NMR (400 MHz, DMSO); 14.08 (s, 1H), 9.29 (d, J=2.0 Hz, 1H), 9.25 (s, 1H), 8.94 (s, 1H), 8.61 (dd, J=4.7, 1.3 Hz, 1H), 8.47-8.40 (m, 1H), 8.07-7.92 (m, 3H), 7.56 (dd, J=7.9, 4.8 Hz, 1H), 6.48 (s, 1H), 4.22 (t, J=5.4 Hz, 2H), 3.56 (s, 2H), 3.18 (t, J=5.4 Hz, 2H). m/z 372.1 (M+1)
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[CH:14][CH:13]=1>CN(C=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:17]([N:16]1[C:12]([NH:11][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:13][CH:14]=[N:15]1)([CH3:19])[CH3:18]
Reactant: O=C(O)c1ccccc1I
Reactant: CC(C)n1nccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1nccc1Nc1ccccc1C(=O)O
Yield: 97.3 %

Procedure:
To 2-iodobenzoic acid (54 g, 0.218 mol) in DMF (570 ml) was added K2 CO3 (33.4 g, 0.242 mol), then 5-amino-1-isopropylpyrazole (27.3 g, 0.218 mol) and finally copper (II) acetate monohydrate (0.9 g, 4.5 mmol). The reaction mixture was refluxed overnight and then the DMF was evaporated. The residue was poured into ice/water and then the mixture was acidified with acetic acid and concentrated HCl to a pH of about 4. A precipitate formed which was collected by filtration, washed with water and dried in a vacuum oven at 40° C. to afford 52 g (97.2%) of N-(1-isopropylpyrazol-5-yl)anthranilic acid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[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](=[CH:5][CH:6]=[C:7]([F:14])[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)nc2ccc(F)cc2c1Cl
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)nc2ccc(F)cc2c1Cl

Procedure:
Prepared according to general Procedure F using 2,4-dichloro-6-fluoro-3-methylquinoline (300 mg, 1.3 mmol), 3-pyridylboronic acid (160 mg, 1.3 mmol), tetrakis(triphenylphosphine)palladium(0), sodium carbonate (242 mg, 2.28 mmol) in toluene:water (5 mL:2 mL) and heating at 130° C. overnight. After purification 4-chloro-6-fluoro-3-methyl-2-(pyridin-3-yl)quinoline was obtained as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>C(Cl)Cl>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:6]2[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1CNCCN1
Solvent: ClCCl
Product: CC1CN(Cc2ccc(F)cc2)CCN1
Reaction time: 15 h
Yield: 12 %

Procedure:
To a solution of 2-methylpiperazine (0.10 g, 1 mmol) in CH2Cl2 (2 mL) was added 4-fluorobenzyl bromide (0.125 mL, 1 mmol). The resultant mixture was stirred at ambient temperature. After 15 hours, the mixture was concentrated in vacuo to afford a solid. This solid was dissolved in CH2Cl2 and washed sequentially with water, aqueous NaHCO3 solution, then brine. The organic layer was dried over MgSO4, filtered, and concentrated to an oil. Purification by flash column chromatography afforded 0.025 g (12% yield) of 1-(4-fluorobenzyl)-3-methylpiperazine, a compound of formula (C), as a colorless oil; NMR (CDCl3) 7.3 (m, 2), 7.0 (m, 2), 3.4 (s, 2), 3.0-2.6 (m, 5), 2.0 (br s, 2), 1.6 (t, 1), 1.0 (d, 3) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:18]=[C:17]([N:19]2[C@H:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][C@H:21]([C:29]([NH:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:30])[CH2:20]2)[CH:16]=[C:15]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[C:40](F)[CH:39]=2)[N:14]=1.O.[NH2:48][NH2:49]>C(O)C>[NH2:45][C:44]1[C:41]2[C:40](=[CH:39][C:38]([C:15]3[N:14]=[C:13]([NH:12][CH2:11][C:4]4[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=4[O:2][CH3:1])[N:18]=[C:17]([N:19]4[C@H:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][C@H:21]([C:29]([NH:31][CH:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)=[O:30])[CH2:20]4)[CH:16]=3)=[CH:43][CH:42]=2)[NH:49][N:48]=1
Reactant: COc1ccc(CNc2nc(-c3ccc(C#N)c(F)c3)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(CNc2nc(-c3ccc4c(N)n[nH]c4c3)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To cis-1-[2-({[2,4-bis(methyloxy)phenyl]methyl}amino)-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (304 mg, 0.48 mmol) in ethanol (6 mL) was added hydrazine monohydrate (0.47 mL, 9.5 mmol), and the reaction mixture was stirred overnight at 100° C. into a sealed tube. The reaction was allowed to cool to room temperature and poured onto water (˜200 mL). A white precipitate was formed. The mixture was filtered, and the solid was air dried for 2 hours to afford the title compound (270 mg) as a white solid. LC-MS (ES) m/z=653 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (1.0 g, 0.0044 mole) in 140 ml of tetrahydrofuran was hydrogenated over 5% palladium on carbon (0.2 g) at room temperature for 4 hr. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. To this stirred solution was added triethylamine (0.6 g, 0.0059 mole) and benzoyl chloride (0.62 g, 0.0044 mole). The reaction mixture was allowed to stir at room temperature overnight. The triethylamine hydrochloride was filtered off and the filtrate was evaporated to dryness. The residue was taken up in ether-methylene chloride solution. Sodium sulfate was added to adsorb an immiscible dark oil. The filtrate was evaporated to dryness to give a residue which was recrystallized from ether. The precipitate was collected, washed with a solution of 75% hexanes/25% ether, and dried at room temperature under high vacuum to yield 1.1 g, of title compound, m.p. 115°-16° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:4][CH:5]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Reactant: C1CCNCC1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CN2CCCCC2)cc1

Procedure:
4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) was dissolved in DMSO (1 mL) and stirred for 1 h with piperidine. The reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((piperidin-1-yl)methyl)benzamide. MS (Q1) 406.4 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Cl:20][C:21]1[C:25]([Cl:26])=[C:24]([C:27](Cl)=[O:28])[S:23][N:22]=1.O>CN(C)C=O>[Cl:20][C:21]1[C:25]([Cl:26])=[C:24]([C:27]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[O:28])[S:23][N:22]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(C(=O)c2snc(Cl)c2Cl)c2ccc(Cl)cc2)cc1
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of N-(4-chlorophenyl)-4-methoxybenzenesulfonamide (1.98 g) in unhydrous N,N-dimethylformamide (20 ml) 60% sodium hydride (0.24 g) was added at room temperature. After stirring the reaction mixture at the same temperature for 1 hour, a solution of 3,4-dichloro-5-isothiazolecarbonyl chloride (1.1 g) in unhydrous N,N-dimethylformamide (10 ml) was added thereto dropwise. After finishing the addition, the reaction mixture was stirred at room temperature for 18 hours and poured into water. The mixture was extracted with ethyl acetate and the organic phase was washed with water and dried with unhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from ethanol to obtain N-(3,4-dichloro-5-isothiazolecarbonyl)-N-(4-chlorophenyl)-4-methoxybenzenesulfonamide (0.89 g). mp 154-158° C.