Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: OCc1ccccc1
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)c[nH]c1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
3-(2-Cyanophenyl)-5-(2-pyridyl)-2(1H)-pyridone (46 mg), 36 mg of benzyl alcohol and 88 mg of triphenylphosphine were dissolved in 2 ml of tetrahydrofuran, 147 mg of a 40% solution of diethylazo dicarboxylate in toluene were added with ice cooling and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo and purified by a silica gel chromatography (hexane-ethyl acetate system) to give 12 mg of the title compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:25]([O-])=O.[Na+].C([O-])(O)=O.[Na+].[ClH:34]>O>[ClH:34].[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:13]2[N:12]=[C:11]3[C:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:9])=[O:8])=[N:25][NH:17][C:16]3=[CH:15][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(c2ccc(N)c(CS(=O)(=O)c3ccccc3)n2)CC1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3n2)CC1
Reaction time: 1 h

Procedure:
A stirred solution of 2-[(phenylsulfonyl)methyl]-6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (1.20 g, 3.50 mmol) in 1.0 M aqueous hydrochloric acid (20 mL) is cooled in an ice bath, treated dropwise with NaNO2 (358 mg, 5.2 mmol) in water, stirred for 1 h, treated with aqueous saturated NaHCO3 and filtered. The brown solid filtercake is washed with water, dried in vacuo, triturated with acetone and filtered. The filtercake is washed with ether and air-dried to afford the free amine of the title compound as a tan solid, 0.50 g. This solid is dissolved in a mixture of ethanol and 4.0 M HCl in dioxane and concentrated in vacuo. The resultant residue is triturated with ether to afford the title compound as an off-white solid, mp>250° C., identified by mass spectral and NMR analyses.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[CH:7][N:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([SH:30])[CH3:29]>CN(C=O)C.O>[CH2:28]([S:30][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[CH:7][N:8]=2)[N:3]=1)[CH3:29]
Reactant: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)cnc2c1C
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(SCC)nc2cc(C(F)(F)F)cnc2c1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a solution of ethyl 2-chloro-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (0.97 g, 3.05 mmol, 1 eq.) in DMF (10 ml) were added K2CO3 (1.26 g, 9.15 mmol, 3 eq.) and ethanethiol (0.66 ml, 9.15 mmol, 3 eq.) at RT. The mixture was stirred at 60° C. for 16 h. Afterwards the mixture was diluted with water (80 ml) and was extracted with EtOAc (3×80 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na2SO4 and evaporated to provide the crude product, which is purified by CC (EtOAc/hexane 1:9) to yield ethyl 2-(ethylthio)-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (0.75 g, 2.18 mmol, 71%).
Reaction SMILES: Br[C:2]1[C:26]([Cl:27])=[CH:25][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:28])[CH:3]=1.[CH3:29][O:30][C:31](=[O:36])[CH2:32][CH2:33][C:34]#[CH:35].C(N(CC)CC)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH3:29][O:30][C:31](=[O:36])[CH2:32][CH2:33][C:34]#[C:35][C:2]1[CH:3]=[C:4]([Cl:28])[C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:25][C:26]=1[Cl:27]
Reactant: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCCc2ccccc21
Reactant: C#CCCC(=O)OC
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCC#Cc1cc(Cl)c(Oc2ncccc2C(=O)N2CCCc3ccccc32)cc1Cl
Temperature: 60 °C
Yield: 5.9 %

Procedure:
To a degassed suspension of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone (50 mg, 0.10 mmol, 1.0 equiv; Example 165) in THF (2 mL) under Ar was added pent-4-ynoic acid methyl ester (34 mg, 0.30 mmol, 3 equiv; [CAS RN 21565-82-2]), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (1 mg, 0.001 mmol, 0.01 equiv; [CAS RN 52522-40-4]), copper(I) iodide (0.2 mg, 0.001 mmol, 0.01 equiv; [CAS RN 7681-65-4]) and triethylamine (20 mg, 28 μL, 0.20 mmol, 2.0 equiv; [CAS RN 121-44-8]). The reaction mixture was stirred at 60° C. over the weekend. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 3 mg (6%) of the title compound as a light brown oil. MS (ISP): 509.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:10])([CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:5].[CH3:11]OS(OC)(=O)=O>O1CCCC1>[CH3:11][O:10][C:4]([CH3:5])([CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: C=CCCC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(C)(C)OC

Procedure:
To a stirred suspension of sodium hydride (46.8 g of a 60% oil dispersion, 1.15 mol) in tetrahydrofuran (240 mL) was added 2-methylhex-5-en-2-ol (120 g, 1.05 mol) in tetrahydrofuran (240 mL). Dimethylsulfate (75 mL, 0.79 mol) in tetrahydrofuran (120 mL) was added to the cooled (0~C) mixture. The mixture was heated at reflux for 6 hours. Workup yielded 2-methoxy-2-methylhex-5-ene, bp40 53-58~C (51.36 g); NMR(CDC13)δ1.1(s,6H), 1.5-1.6(m,2H), 2.0-2.2(m,2H), 3.2(s,3H), 4.8-5.1(m,2H),5.7-6.0(m,1H); IR(neat) 2960, 2925, 1640, 1460, 1360, 1300, 1085 cm-1 ; MS(m/e) 43, 55, 73, 81, 95, 97, 113, 114.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[C:9]([C:15]([O:17]C)=O)=[CH:8][CH:7]=1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[O:27][C@H:28]1[CH2:31][C@H:30]([NH2:32])[CH2:29]1.C1(C2CCCCCCCCC=2)CCCCCCNNN=1>C1COCC1.C(Cl)Cl>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[O:27][C@H:28]1[CH2:29][C@H:30]([NH:32][C:15]([C:9]2[C:10]3[N:11]([CH:12]=[CH:13][N:14]=3)[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)=[O:17])[CH2:31]1
Reactant: COCOCc1ccc(C(=O)OC)c2nccn12
Reactant: N[C@H]1C[C@H](Oc2cccc(Cl)c2Cl)C1
Agent: C1=C(C2=NNNCCCCCC2)CCCCCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCOCc1ccc(C(=O)N[C@H]2C[C@H](Oc3cccc(Cl)c3Cl)C2)c2nccn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of methyl 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carboxylate (438 mg, 1.75 mmol), trans-3-[(2,3-dichlorophenyl)oxy]cyclobutanamine (463 mg, 1.995 mmol) and triazabicyclodecene (75 mg, 0.539 mmol) in THF (0.5 mL) was stirred in a sealed tube at room temperature for 18 hours. The reaction mixture was then transferred to a round bottomed flask using DCM as solvent and evaporated in vacuo to give yellow/brown gum which solidified (1.5 g). This material was dissolved in DCM and purified on silica (70 g) using a 0-100% ethyl acetate-cyclohexane gradient over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound as yellow crystals (601 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]3)[N:9]=2)=[CH:4][CH:3]=1.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=1>C(Cl)Cl>[N:14]1([C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:36](=[O:42])[NH:51][C:52]4[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=4)=[CH:3][CH:4]=3)[N:9]=[C:10]([NH:20][CH:21]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]3)[N:11]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Nc1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CCOCC3)n2)C1
Reaction time: 0.25 h

Procedure:
To a stirred solution of tert-butyl 3-{[4-(4-aminophenyl)-6-morpholin-4-yl-1,3,5-triazin-2-yl]amino}azetidine-1-carboxylate (200 mg, 0.47 mmol) in DCM (100 ml) at 0° C., triphosgene (300 mg) and triethylamine (3 ml) was added slowly. The reaction mixture was stirred for 15 minutes and 4-aminopyridine (200 mg. 2.1 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours and concentrated. It was quenched with cold water and the separated solid was filtered and washed with water. It was dried and purified by Gilson HPLC. Yield 100 mg (40%); (M+H) 548.6
Reaction SMILES: [OH:1][C:2]1([CH3:20])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].O>N1C=CC=CC=1>[OH:1][C:2]1([CH3:20])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:21](=[O:23])[CH3:22])=[C:13]([O:18][CH3:19])[CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(CCC2CC(C)(O)CC(=O)O2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 100 mg of 3-hydroxy-3-methyl-7-(p-hydroxy-m-methoxyphenyl)-5-heptanolide in 1 ml of pyridine was added 1 ml of acetic anhydride and the mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. Evaporation of the solvent from the extract yielded the desired compound as a colorless oily substance,
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[S:5][CH:6]=1.CI.[C:18]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:18][O:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: O=C(Cc1nc(O)cs1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1csc(CC(=O)c2ccccc2)n1
Temperature: 25 °C
Yield: 8014 %

Procedure:
To a suspension of 2-(4-hydroxy-1,3-thiazol-2-yl)-1-phenylethan-1-one (0.5 g, 2.3 mmol) in acetone (10 mL) at r.t. was added MeI (0.17 mL, 2.7 mmol), followed by K2CO3 (315 mg, 2.3 mmol). After stirring ON at r.t., the solvent was removed and the residue was taken up in Et2O/H2O. The organic layer was dried (MgSO4), filtered, and evaporated to yield o.43 g of the title compound.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.[S:12]([O-])(=O)(=O)C.C(N(CC)CC)C.[C:24]([O:27][CH2:28]C)(=[O:26])C>C(Cl)Cl.C(Cl)CCl>[S:12]1[CH2:6][CH2:5][CH:4]=[C:3]([C:24]([O:27][CH3:28])=[O:26])[CH2:2]1
Reactant: CS(=O)(=O)[O-]
Reactant: c1ccncc1
Reactant: CCOC(C)=O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCCSC1
Temperature: 0 °C
Reaction time: 7.5 h
Yield: 63 %

Procedure:
To a solution of 4.93 gm (0.0279 mole) of methyl tetrahydro-2H-thiopyran-4-hydroxy-3-carboxylate from part B in anhydrous methylene chloride (25 mL) was added 6.77 mL (0.0837 mole) anhydrous pyridine. The solution was cooled to 0° C., upon which was added 3.25 mL (0.0420 mole) methanesulfonyl chloride, dropwise via syringe. The solution was allowed to warm to room temperature and stirred under N2 for 7.5 hrs. The reaction was then cooled to 0° C. and an additional 0.648 mL (0.00837 mole) of methanesulfonyl chloride was added. The solution was stirred at room temperature an additional 16 hrs. upon which ethyl acetate (125 mL) was added. The organic layer was washed with dilute HCl, saturated sodium bicarbonate, and saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a mixture of the cis and trans mesylate and unreacted methanesulfonyl chloride. The crude mesylate mixture was dissolved in anhydrous ethylene chloride (30 mL) upon which was added 12.68 mL (0.0911 mole) triethyl amine. The reaction was stirred under N2 for 7 hrs. upon which was added 8.5 mL (0.061 mole) triethyl amine and the solution stirred 17 more hrs. The organic layer was washed once with dilute acid and once with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on 300 gm silica gel with 4-25% ethyl acetate in hexane to give 2.76 gm (63%) of methyl 5,6-dihydro-2H-thiopyran-3-carboxylate as a clear oil; mass spectrum m/z=159 (CI,M+H)
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH3:25])[CH2:18][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCC(O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(O)CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 60.7 %

Procedure:
Diphenylmethylpiperazine (2.20 g) was dissolved in dimethylformamide (25 ml), and then 1-chloro-3-pentanol (1.78 g) and potassium carbonate (722 mg) were added thereto, followed by stirring the mixture at 80° C. for 15 hours. After evaporation of dimethylformamide, water was added to the residue and the resultant was extracted 3 times with ethyl acetate. Organic layers were combined and washed with brine. The resultant was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 1.79 g of amorphous 1-(4-(diphenylmethyl)piperazinyl)pentane-3-ol. Yield: 61%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH3:20])=[N:12][C:13]3[N:14]([N:17]=[CH:18][N:19]=3)[C:15]=2[NH2:16])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>CC#N>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:16][C:15]1[N:14]2[N:17]=[CH:18][N:19]=[C:13]2[N:12]=[C:11]([CH3:20])[C:10]=1[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=2)=[O:30])=[CH:3][CH:4]=1
Reactant: Cc1nc2ncnn2c(N)c1C#Cc1ccc(N)cc1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2ncnn2c(N)c1C#Cc1ccc(NC(=O)Nc2cccc(Cl)c2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of Example 1 (10 mg, 0.038 mmol) in 1.0 mL of CH3CN was added 3-chloro-phenyl isocyanate (6.4 mg, 0.046 mmol) and triethylamine (8 μL, 0.057 mmol). The resulting mixture was stirred for over night at room temperature. The resulting mixture was purified by reverse phase HPLC (C-18 column, eluting with a 5-100% CH3CN gradient in 0.1% trifluoroacetic acid) to the title compound as its trifluoroacetic acid salt (3.5 mg, 17.3% yield). MS (ESI) m/z 416, 418 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[S:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:13])=[O:12].O>ClCCl>[CH2:3]([N:2]([CH3:1])[S:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CNCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)CS(=O)(=O)N(C)Cc1ccccc1
Yield: 61 %

Procedure:
To a stirred solution of N-methyl benzylamine (7 ml, 54.2 mmol) in dichloromethane (10 ml) at 0-5° C. under an atmosphere of nitrogen was added dropwise a solution of methyl chlorosulfonylacetate (prepared by the method of M. J. Szymonifka and J. V. Heck, Tetrahedron Lett., 1989, 30, 22, 2869) (4.26 g, 24.7 mmol) in dichloromethane (5 ml), maintaining the temperature below 5° C. The yellow solution was then warmed to ambient temperature over a 2 hr period before water (30 ml) was added. The organic phase was partitioned and evaporated in vacuo to give a yellow oil. This was purified by flash column chromatography (diethyl ether:hexane 1:1 as eluant) to give the subtitle compound (3.9 g, 61%) as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:8]=1)[CH3:2].[C:19]([OH:22])(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:11][C:12]=1[O:22][C:19](=[O:21])[CH3:20])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(N(CC)CC)cc1
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(N(CC)CC)cc1OC(C)=O

Procedure:
3-(4-Diethylaminophenyl)-2-propenic acid ethyl ester (1 g, 3.80 mmol) was dissolved in 5 ml of pyridine. To this was added 0.8 ml of anhydrous acetic acid and it was allowed to react at room temperature for 24 h. After the solvent was removed in vacuo, purification was carried out by silica gel column chromatography (toluene/ethyl acetate 93:7 as a developing solvent) to give 1.2 g of the desired product in a quantitative yield.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:16](=[O:29])[C:15]=1[Cl:30].CN1CCOCC1.[CH2:43]([O:45][C:46](Cl)=[O:47])[CH3:44]>CC(N(C)C)=O>[Cl:30][C:15]1[C:16](=[O:29])[N:17]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[CH2:9][NH:8][C:46](=[O:47])[O:45][CH2:43][CH3:44]
Reactant: Cc1cc(OCc2ccc(F)cc2CN)c(Cl)c(=O)n1-c1c(F)cccc1F
Reactant: CCOC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: CCOC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2c(F)cccc2F)c(=O)c1Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one trifluoroacetate (0.3 g, 0.00057 mol) in dimethylacetamide (3.0 mL) was added N-methymorpholine (0.064 g, 0.00064 mol), followed by addition of ethylchloroformate (0.06 mL) and stirred at −10° C., for 30 min. The solvents were distilled in vacuo and the residue was purified by reverse-phase HPLC purification using 10-90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z=481 M+H) were combined and freeze-dried, and the residue was partitioned between 5% sod. bicarbonate (20 mL) and dichloromethane (20 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated to dryness under reduced pressure, to afford the title compound as a white amorphous powder (0.15 g, 55%): 1H NMR (CD3OD/400 MHz) δ7.61 (m, 1H), 7.52 (m, 1H), 7.26 (˜t, 2H, J=8.4 Hz), 7.12 (dd, 1H) 7.05 (3d, 1H, J=2.4 Hz), 6.74 (s, 1H), 5.40 (s, 2H), 4.42 (s, 2H), 4.05 (q, 2H, J=7.2 Hz), 2.12 (s, 3H), and 1.21 (t, 3H, J=7.2 Hz); ES-HRMS m/z 481.1118 (M+H C23H21N2O4F3Cl requires 481.1136).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1.[NH3:21].CO>C(Cl)Cl>[NH2:21][CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1
Reactant: N
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CBr)c2Cl)c1
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2Cl)c1
Yield: 100 %

Procedure:
The title compound was prepared as described herein using 3-{[3-(bromomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile (728 mg, 1.941 mmol) and NH3 in MeOH (27.7 ml, 194 mmol, 7.0 N) in CH2Cl2 (20 ml) to give the title compound as a white solid (602 mg, 100%) which was used for the next step without purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37-7.43 (1H, m) 7.34 (1H, s) 7.12-7.21 (2H, m) 6.99 (1H, br. s.) 3.98 (2H, br. s.) 1.65-1.89 (2H, m). LCMS: m/z 311 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[Si]([C:24]#[N:25])(C)C>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>[C:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[C:24]#[N:25])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2ncccc2c1
Reactant: C[Si](C)(C)C#N
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#CC1C=Cc2ccccc2N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
A mixture of quinoline (19.35 g), benzoyl chloride (28.1 g), aluminum chloride (1.0 g) and methylene chloride (500 mL) was stirred at ambient temperature for 10 minutes. Trimethyl silyl cyanide (20.0 g) was added dropwise. The stirring was continued for 4 hours. The mixture was washed twice with 1N HCl (500 mL) then with water (500 mL). The organic phase was dried over anhydrous magnesium sulfate then evaporated to dryness. The title compound (26.0 g) was obtained as a white solid, m.p. 153-154° C. This product was used for the preparation of the title compound described in step 2, and for preparation of the title compound described in Example 2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[NH2:11]
Reactant: Nc1cc(O)ccc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (4.76 g, 30 mmol) and 3-amino-4-chlorophenol (4.31 g, 30 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (4.15 g, 30 mmol), and the mixture was stirred at room temperature for 16 hr. Ethyl acetate (80 mL) was added to the reaction mixture, and the mixture was washed successively with water (50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual solid was recrystallized from ethyl acetate (15 mL)/n-hexane (15 mL), and the precipitated crystals were collected by filtration, washed with diisopropyl ether (20 mL) and dried under reduced pressure to give the title compound (6.74 g, 85%) as brownish-red crystals.