Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH2:9][C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[Cl:21][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH2:9][C:8]2=[O:19])=[CH:2][CH:3]=1
Reactant: O=C1CCCC(c2ccccc2)N1c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1CCCC(c2ccccc2)N1c1ccc(Cl)cc1
Yield: 73.9 %

Procedure:
To 0.25 g of 1,6-diphenyl-2-piperidone were added 0.30 g of phosphorus pentachloride, 0.5 ml of sulfuryl chloride and 5 ml of chloroform, and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure, made alkaline with an aqueous sodium hydrogen carbonate solution, and extracted with 30 ml of ethyl acetate. The ethyl acetate extract was washed with water, dried, and concentrated to give 0.21 g of 1-(4-chlorophenyl)-6-phenyl-2-piperidone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21]OS(C)(=O)=O)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:27][NH:28][CH3:29]>>[CH3:27][N:28]([CH2:21][C:12]1[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:11]=1)[CH3:29]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Reactant: CNC
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(CC(C)C)n2)cc1F
Yield: 88.6 %

Procedure:
Following the procedure of Example 7, 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 88.6%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([Cl:15])[N:12]=[N:11][C:10]=2[C:16]([OH:18])=[O:17])=[C:4]([F:19])[CH:3]=1.[C:20](OC(=NC(C)C)NC(C)C)([CH3:23])([CH3:22])[CH3:21]>C1COCC1.C(OCC)(=O)C>[C:20]([O:17][C:16]([C:10]1[N:11]=[N:12][C:13]([Cl:15])=[CH:14][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:19])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: O=C(O)c1nnc(Cl)cc1Nc1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1nnc(Cl)cc1Nc1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
To the stirred solution of 4-(4-bromo-2-fluoro-phenylamino)-6-chloro-pyridazine-3-carboxylic acid (516 gm, 1.49 mmol) in THF (10 ml) under argon at room temperature is added a solution of 2-tert-butyl-1,3-diisopropylisourea (1.49 g, 7.45 mmol) in THF (1.0 ml). The resulted mixture is refluxed for 6 hours. The reaction mixture is then cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with 10% K2CO3 (20 ml×2) and saturated NaCl (30 ml×3), dried over Na2SO4 and concentrated in vacuum. The residue is dissolved in 30 ml of dichloromethane and the resulting white solid (urea byproduct) is filtered out. The filtrate is concentrated under reduced pressure. The residue is purified by flash column chromatography to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:21][OH:22])[N:14]=2)[C:9](=[O:23])[C:8]([C:24]([O:26]CC)=[O:25])=[CH:7]1.[OH-].[Li+].Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:21][OH:22])[N:14]=2)[C:9](=[O:23])[C:8]([C:24]([OH:26])=[O:25])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC[C@H]3CO)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccc(N4CCC[C@H]4CO)nc32)c(OC)c1

Procedure:
A mixture of EXAMPLE 1C (2 g) and 0.1M lithium hydroxide (80 mL) in ethanol (100 mL) at 25° C. was stirred for 24 hours, adjusted to pH 3 with 1M hydrochloric acid, treated with water, and filtered.
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16](N)[C:15]=3[N:14]=[CH:13]2)[C@H:9]([OH:22])[C@@H:8]1[OH:23])([OH:4])([OH:3])=[O:2].C1N=C([Cl:30])C2N=CN([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)C=2N=1.O=P(Cl)(Cl)Cl>O>[CH:19]1[N:18]=[C:16]([Cl:30])[C:15]2[N:14]=[CH:13][N:12]([C@@H:10]3[O:11][C@H:7]([CH2:6][O:5][P:1]([OH:4])([OH:3])=[O:2])[C@@H:8]([OH:23])[C@H:9]3[OH:22])[C:21]=2[N:20]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=P(O)(O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O

Procedure:
N6-(ω-amino-linker) adenosine 5′-monophosphate can be prepared by contacting 6-chloropurine riboside first with POCl3 then water to produce 6-chloropurine riboside 5′-monophosphate. This intermediate can be reacted with a diamine to produce an N6-(ω-amino-linker) adenosine 5′-monophosphate. Diamines include ethylenediamine (EDA), 1,4-butanediamine (BDA), 1,6-hexanediamine (HDA), 2,2′-oxydiethylamine (ODEA), 2,2′-(ethylenedioxy)diethylamine (EDODEA), and 4,7,10-trioxa-1,13-tridecanediamine (TOTDDA). These diamines provide linkers of (CH2)2, (CH2)4, (CH2)6, C2H4OC2H4 and C3H6OC2H4OC2H4OC3H6, respectively. Additional diamines (and polyamines) such as spermidine (NH2(CH2)3NH(CH2)4NH2), spermine, (NH2(CH2)3NH(CH2)4NH(CH2)3NH2), polyethylene glycol diamines (H2N-PEG-NH2), 1,4-bis(3-aminopropoxy)butane (H2N(CH2)3O (CH2)4O(CH2)3NH2), bis(3-aminopropyl)amine(H2N(CH2)3NH(CH2)3NH2), tris(2-aminoethyl)amine(N(CH2CH2NH2)3), 1,8-diaminooctane (H2N(CH2)8NH2), 1,10-diaminodecane (H2N(CH2)10NH2), and 1,12-diaminododecane (H2N(CH2)12NH2), can also be used.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH3:33])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH3:33])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: CCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nc(-c2cnc3[nH]cc(C(=O)N[C@H](C)C(=O)N4CC(C#N)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.8 %

Procedure:
To a solution of 2-(6-chloro-1-ethyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (150 mg, 0.25 mmol) in CH2Cl2 (2 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 5 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with 0% to 5% MeOH/EtOAc followed by trituration with MeOH to afford 88 mg (75%) of 2-(6-chloro-1-ethyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white powder. MS: (M+Na)+=499; mp=248-255° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.92 (br. s., 1H), 9.14 (s, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.47 (dd, J=7.6, 3.4 Hz, 2H), 8.02 (s, 1H), 7.25 (d, J=8.7 Hz, 1H), 4.48-4.79 (m, 5H), 4.04-4.28 (m, 2H), 3.77-3.92 (m, 1H), 1.47 (t, J=7.2 Hz, 3H), 1.39 (dd, J=6.8, 4.5 Hz, 3H).
Reaction SMILES: [ClH:1].C(S[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[NH:11])C1C=CC=CC=1.[NH2:18][CH:19]([C:25]#[N:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)C>C(Cl)(Cl)Cl>[ClH:1].[NH2:26][C:25]1[NH:11][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(N)C#N
Reactant: N=C(SCc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccccc2)[nH]c1N
Reaction time: 8 h

Procedure:
Phenylformimino benzyl thioether hydrochloride (28.5gm) was refluxed in chloroform (200 ml) with ethyl aminocyanoacetate (17.0gm) for 1 hour. On standing for 8 hours the addition of dry diethyl ether (250 ml) caused the precipitation of the 5-amino-4-carbethoxy-2-phenylimidazole hydrochloride (24.5gm) m.p. 228° C after recrystallisation from ethanol.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1>>[NH:28]1[C:27]2[C:26](=[C:4]([C:2]3[N:3]=[C:4]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:5]4[S:10][C:9]([C:26]5[CH:30]=[N:29][NH:28][CH:27]=5)=[CH:8][C:6]=4[N:7]=3)[CH:5]=[CH:6][CH:8]=2)[CH:30]=[N:29]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Product: c1cc(-c2nc(N3CCOCC3)c3sc(-c4cn[nH]c4)cc3n2)c2cn[nH]c2c1

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) was coupled to 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane via General Procedure I. The product was purified by reverse phase HPLC to yield 18.1 mg of 203. MS (Q1) 404 (M)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:34]([F:35])([F:36])[F:37])[C:38]([F:41])([F:39])[F:40])=[CH:29][CH:28]=3)=[CH:14][CH:13]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: OC(c1ccc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(S(=O)(=O)c2ccc(-c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cn3)cc2)cn1
Temperature: 100 °C
Yield: 39.1 %

Procedure:
A glass microwave reaction vessel was charged with 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (381 mg, 1.06 mmol, Example 264, step 1), 2-(6-chloro-3-pyridinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (148 mg, 0.53 mmol), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (22 mg, 0.03 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (517 mg, 1.59 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1.5 mL), and water (0.15 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 3% 2M NH3/MeOH in DCM, to provide 2-(6-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-3-pyridinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (99 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:3]=1.[CH2:22]([Mg]Br)[CH3:23]>C1COCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:22][CH3:23])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:3]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Nc1ccccc1Cl
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
In a 500 mL round bottom flask, 4-chloro-2-(2-chloro-phenylamino)-N-methoxy-N-methyl-benzamide (1.0 g, 3.08 mmol) was added to THF (60 mL) to give a colorless solution. The reaction was cooled to 0° C. in an ice bath and ethyl magnesium bromide (3.0 M in THF, 3.59 mL, 10.8 mmol) was added slowly dropwise. The mixture was stirred at 0° C. for 1 hr. TLC and HPLC indicated the presence of starting material. The reaction was warmed to room temperature overnight. TLC the next day still showed the presence of starting material. The reaction was re-cooled to 0° C. and additional amount of ethylmagnesium bromide (3.59 mL, 10.8 mmol) was added. The reaction was stirred at 15° C. for 2.5 hr. TLC indicated complete consumption of starting material. The reaction mixture was quenched with cold water and extracted twice with ethyl acetate. The combined organic layers were washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography using 0-20% dichloromethane-hexanes to give 1-[4-chloro-2-(2-chloro-phenylamino)-phenyl]-propan-1-one (584 mg, 65% yield) as a yellow oil. 1H NMR (DMSO-d6) δ ppm 10.67 (s, 1H) 8.05 (d, J=8.7 Hz, 1H) 7.58 (ddd, J=12.8, 8.1, 1.1 Hz, 2H) 7.32-7.48 (m, 1H) 7.12-7.27 (m, 1H) 7.02 (d, J=2.0 Hz, 1H) 6.91 (dd, J=8.6, 1.9 Hz, 1H) 3.10 (q, J=7.3 Hz, 2H) 1.09 (t, J=7.2 Hz, 3H). MS calcd. for C15H13Cl2NO [(M+H)+] 295.0, obsd. 294.1.
Reaction SMILES: [Na].[CH3:2][C@H:3]([CH2:19][CH2:20][CH3:21])[CH2:4][C:5]([N:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:9][C:8]1=[O:18])=[O:6].[CH3:22]I>C1COCC1>[CH3:22][C@H:4]([C@H:3]([CH3:2])[CH2:19][CH2:20][CH3:21])[C:5]([N:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:9][C:8]1=[O:18])=[O:6]
Reactant: CCC[C@@H](C)CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Reactant: CI
Agent: [Na]
Solvent: C1CCOC1
Product: CCC[C@@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a 1M THF solution of Sodium hexamethyldisylamide (16.2 g, 88.3 mmol) at −78° C. was added via canular a 0° C. solution of (R)-3-((R)-3-methyl-hexanoyl)-4-phenyl-oxazolidin-2-one (18.7 g, 67.9 mmol) in 70 mL dry THF. The resulting solution was stirred at −78° C. for 30 minutes. Methyl Iodide (48.2 g, 339.5 mmol) was added and stirring at −78° C. was continued for 4 hours. The reaction was quenched with saturated ammonium chloride solution, extracted into CH2Cl2 and washed with 1M sodium Bisulfite. The solution was dried over MgSO4, concentrated and chromatographed in 10% ethylacetate in hexane to give the titled compound (11.1 g, 56.5% yield) as an oil. MS, m/z (relative intensity): 1H NMR (400 MHz, CDCl3) δ ppm 0.8 (t, J=7.0 Hz, 3H) 0.9 (d, J=6.6 Hz, 3H) 1.0 (d, J=6.8 Hz, 3H) 1.0 (d, J=8.5 Hz, 1H) 1.1 (m, 1H) 1.4 (m, 1H) 1.7 (m, 1H) 3.7 (m, 1H) 4.2 (dd, J=8.8, 3.4 Hz, 1H) 4.6 (t, J=8.7 Hz, 1H) 5.4 (dd, J=8.7, 3.3 Hz, 1H) 7.2 (m, 2H) 7.3 (m, 3H). MS, m/z (relative intensity):290 [M+1H, 100%].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)[CH:8]=2)[CH:3]=1.C([Li])(C)(C)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=1>O1CCCC1>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([OH:30])[C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:12]4([CH3:17])[O:16][CH2:15][CH2:14][O:13]4)[CH:8]=3)[CH:3]=2)[CH:24]=1
Reactant: CC1(c2ccc3cc(Br)ccc3c2)OCCO1
Reactant: O=Cc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1(c2ccc3cc(C(O)c4cccnc4)ccc3c2)OCCO1
Yield: 63 %

Procedure:
A solution of 4.5 g of 2-bromo-6-(2-methyl-1,3-dioxolan-2-yl)naphthalene in 30 ml of tetrahydrofuran was cooled to -78° C. under nitrogen, and 14.0 ml of 2.2M t-butyl lithium added dropwise. A solution of 1.64 g of 3-pyridinecarboxaldehyde in 15 ml of tetrahydrofuran was added over a period of 10 minutes, and the temperature was allowed to rise to -20° C. during the next 30 minutes. The reaction was quenched with 30 ml of water and the mixture extracted with methylene chloride. The organic layer was dried over sodium sulfate and solvent removed under reduced pressure to give a solid that was recrystallized from methylene chloride/diethyl ether to give 3.1 g of 2-[(3-pyridyl)hydroxymethyl]-6-(2-methyl-1,3-dioxolan-2-yl)naphthalene, m.p. 154°-156° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5](=[O:7])[N:6]=1.[Cl:8][C:9]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:10]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21]>>[NH2:1][C:2]1[S:3][C:4](=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][C:10]3[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:9]=3[Cl:8])=[C:13]([O:20][CH3:21])[CH:14]=2)[C:5](=[O:7])[N:6]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1Cl
Reactant: NC1=NC(=O)CS1
Product: COc1cc(C=C2SC(N)=NC2=O)ccc1Oc1ccc(C#N)cc1Cl

Procedure:
4-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-chloro-benzonitrile was prepared using 2-amino-thiazol-4-one and 4-(2-Chloro-4-cyanophenoxy)-3-methoxybenzaldehyde according to General Procedure B. 1H NMR (400 Hz, DMSO-d6) δ 9.47 (bs, NH), 9.21 (bs, NH), 8.17 (d, 1H), 7.70 (dd, 1H), 7.64 (s, 1H), 7.46 (d, 1H), 7.32 (d, 1H), 7.23 (dd, 1H), 6.81 (d, 1H), 3.79 (s, 3H); LC/MS (m/z) [M+1]+386.0 (calculated for C18H13ClN3O3S, 386.82).
Reaction SMILES: [OH:1][CH:2]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].[H-].[Na+].[CH3:15]I.O>CN(C)C=O>[CH3:15][O:1][CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3]
Reactant: CI
Reactant: CC(O)c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)c1nc2ccccc2[nH]1
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To a solution of 4.05 g of 1-hydroxyethylbenzimidazole in 25 ml of dimethylformamide was added 1.2 g of 50% sodium hydride in oil, and the mixture stirred for 30 minutes. Methyl iodide (3.55 g) was added and the reaction mixture stirred at room temperature overnight. Water (200 ml) was added and the product extracted with ethyl acetate. The extracts were combined, dried and concentrated to an oil which was chromatographed on 130 g of silica gel using 5% methanol in chloroform as the eluent to give 2.36 g of brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](O)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[F:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38].CCCP(=O)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:19]([C:15]2[C:16]3[C:11](=[CH:10][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=4)=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[O:20])=[CH:32][C:31]=1[C:37]([F:38])([F:39])[F:40]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1nccc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Reaction time: 1 h

Procedure:
To a suspension of 2.58 g (9.2 mMol) 6-(2-amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid in 50 ml DMF, 12.8 ml (92 mMol) Et3N, 490 mg (4.0 mMol) DMAP, 1.41 ml (11 mMol) 4-fluoro-3-trifluoromethyl-aniline and finally 11 ml propylphosphonic anhydride (50% in DMF; 19 mMol) are added. The mixture is stirred for 1 h and then concentrated in vacuo. The residue is diluted with water and EtOAc, the aq. phase is separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/EtOAc 2:1→1:1→1:2) and re-crystallization from CH3CN gives the title compound: m.p.: 205° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[N:26]=[C:25]([CH3:27])[C:24]([Cl:28])=[C:23]([CH3:29])[C:18]=1/[C:19](=[N:21]/O)/[NH2:20].N1C=CC=CC=1.Cl>S(Cl)(Cl)=O>[Cl:16][C:17]1[C:18]([C:19]2[N:20]=[C:6]([C:5]3[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([OH:1])=[C:3]([O:14][CH3:15])[CH:4]=3)[O:8][N:21]=2)=[C:23]([CH3:29])[C:24]([Cl:28])=[C:25]([CH3:27])[N:26]=1
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reactant: Cc1nc(Cl)c(/C(N)=N/O)c(C)c1Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2nc(-c3c(Cl)nc(C)c(Cl)c3C)no2)cc([N+](=O)[O-])c1O
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A stirred suspension of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (2.00 g, 9.38 mmol) in thionyl chloride (8.2 mL) was heated at 80° C. for two hours. The excess of thionyl chloride was removed under vacuum. The resulting yellow solid was dissolved in DMA (15.4 mL), then (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide (2.636 g, 11.26 mmol) and pyridine (6.2 mL) were added. The red solution was heated to 120° C. for 2.5 hours. The reaction mixture was cooled to room temperature and poured into a mixture of cc HCl (10 ml) and ice (80 g), then stirred for thirty minutes. The yellow precipitate was filtered off, washed with water and dried under vacuum. Recrystallization from dichloromethane-isopropanol mixture afforded 2.42 g (62%) of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol as yellow crystalline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccc(F)cc12
Product: Fc1ccc2nccc(Cl)c2c1

Procedure:
A mixture of 52 g (0.319 mol) of 6-fluoro-4-hydroxyquinoline and 100 ml of phosphorus oxychloride was stirred and heated under reflux for 3 hr. The reaction mixture was concentrated in vacuo. A slurry of the residue in methylene chloride was poured into ice-water, and the mixture neutralized with 3N sodium hydroxide. The organic phase was separated, and the aqueous phase was extracted with 250 ml of methylene chloride twice. The organic phases were combined, washed with water, dired over sodium sulfate, and concentrated in vacuo. The residue was crystallized from hexane to give 27.95 g of product, mp 71°-74°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH:13][CH2:14][CH2:15][OH:16])[CH3:12]>>[CH2:11]([N:13]([CH2:14][CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCNCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CCN(CCO)c1ccc([N+](=O)[O-])cc1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
To a pressure tube containing 1-fluoro-4-nitrobenzene (5.3 mL) and is added 2-(ethylamino)-1-ethanol (10.7 g). The reaction is tightly sealed and heated to 135° C. with stirring. After 1 hour, the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is dried in vacuo. The residue is chromatographed on silica eluting with ethyl acetate. The product-containing fractions are evaporated to give 10.1 g of 2-(ethyl-4-nitroanilino)-1-ethanol as an orange solid.
Reaction SMILES: [CH2:1]([C:15]1C=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:22]([O:21][CH2:17][CH2:18][CH2:19][CH2:20][CH2:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCc1cccc(O)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCOC(C)=O
Reaction time: 16 h

Procedure:
A mixture of 18.85 g of 3-tetradecylphenol, 20 ml of acetic anhydride and 60 ml of pyridine was stirred for 16 hours, then diluted with chloroform, washed with aqueous sodium bicarbonate, dried and the solvent removed by evaporation with toluene, giving 21 g of the desired compound.