Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:27](O)=[O:28])=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)[N:7]([CH3:25])[C:6]=2[CH:26]=1.C(O)(=O)C.[CH3:34][N:35]([CH3:40])[C:36](=[O:39])[CH2:37][NH2:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:34][N:35]([CH3:40])[C:36]([CH2:37][NH:38][C:27]([C:3]1[C:2]([F:1])=[CH:26][C:6]2[N:7]([CH3:25])[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[N:9][C:5]=2[CH:4]=1)=[O:28])=[O:39]
Reactant: CN(C)C(=O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F
Yield: 35.6 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (32 mg) was prepared by following General Procedure F starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), glycine dimethylamide acetate (32 mg), HBTU (80 mg), and DIEA (46 uL). LC/MS: m/z 511.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.19-8.00 (m, 2H), 7.93 (s, 1H), 7.74 (d, 1H), 7.54 (d, 1H), 7.36 (d, 1H), 4.18 (d, 2H), 3.61 (bs, 3H), 3.01 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:5]=[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:3]=1.[C:34]1([C:40]2[CH:46]=[C:45]([OH:47])[CH:44]=[C:43]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:41]=2[OH:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[Na+].Cl>O>[OH:42][C:41]1[C:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:46][C:45]([O:47][C:2]2[N:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:5]=[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:3]=2)=[CH:44][C:43]=1[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CCCCCCCCCCCCOc1nc(Cl)nc(OCCCCCCCCCCCC)n1
Reactant: Oc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCOc1nc(OCCCCCCCCCCCC)nc(Oc2cc(-c3ccccc3)c(O)c(-c3ccccc3)c2)n1
Temperature: 0 °C

Procedure:
In a 500 ml-three-necked flask 4.8 g (0.01 mole) of the 2-chloro-4,6-dilauroxy-s-triazine prepared above, were mixed with 2.6 g (0.01 mole) of 2,6-diphenyl hydroquinone. After rinsing with nitrogen, 150 ml of acetone were added, followied by adding dropwise, with vigorous stilling, 0.4 g (0.01 mole) of NaOH dissolved in 7 ml of water, at 20° C. The solution then assumed an orange-yellow color, which largely disappeared upon heating the reaction mixture for a longth of time under reflux. After completion of the reaction, the contents of the flask were poured into 100 ml of ice water containing 2 ml of hydrochloric acid. The organic layer was extracted three times with methylene chloride, after which the combined extracts were washed and dried. After concentration of the organic layer by evaporation a product was obtained which crystallized out after a length of time (melting point 18°-20° C).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[N:3][CH:2]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:20]([NH:27][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([NH:10][C:4]2[C:5]3[NH:9][CH:8]=[CH:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH:12]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cccc(Nc2ncnc3cc[nH]c23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.9 %

Procedure:
A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153 mg), benzylamine (96 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate containing tetrahydrofuran. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→50:50). Ethyl acetate and diethyl ether were added and the precipitate was collected by filtration to give the title compound (128 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:12]#[N:13])=[C:8]([C:10]#[N:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[CH2:1]([C:5]1[N:9]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[C:8]([C:10]#[N:11])=[C:7]([C:12]#[N:13])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C#N)c(C#N)[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: CCCCc1nc(C#N)c(C#N)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2-n-Butyl-4,5-dicyano-1-(4-nitrobenzyl)imidazole was prepared from 2-n-butyl-4,5-dicyanoimidazole by the procedure in Example 1, Part A using 4-nitrobenzyl bromide as the alkylating agent. The product was obtained as an oil. NMR (200 MHz, CDCl3) δ8.29 (d, 2H, J=10 Hz); 7.29 (d, 2H, J=10 Hz); 5.36 (s, 2H); 2.67 (t, 2H, J=7 Hz); 1.70 (t of t, 2H, J=7,7 Hz); 1.36 (t of q, 2H, J=7,7 Hz); 0.86 (t, 3H, J=7 Hz). Mass Calcd. for C16H15N5O2 : 309.1225. Found: 309.1211.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[C:19](Br)[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]=1[OH:22])(=[O:3])[CH3:2].C([O-])=O.[Na+]>CN(C=O)C.CCOC(C)=O.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>[C:1]([C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:11][CH2:12][C:6]=2[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Br)c2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Yield: 67.6 %

Procedure:
Mix 7-acetyl-9-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (833 mg, 2.2 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13 mmol) and sodium formate (224 mg, 3.3 mmol) in anhydrous DMF (15 mL). Degas twice then flush with argon. Keep the flask under argon and heat the reaction at 95° C. for 16 h. Dilute with EtOAc then wash with 1 N HCl. Separate the organic layer, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:100 to 20:80 EtOAc:hexanes) to give the title compound (448 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH3:12].CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[CH2:11]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[Cl:1])[CH3:12]
Reactant: CCO
Reactant: O=C(O)c1ccncc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A suspension of 3-chloro-isonicotinic acid (1.0 g, 6.35 mmol) in thionyl chloride (10 ml) was heated under reflux for 2.5 hours. After cooling to ambient temperature, the solution was concentrated to dryness and then azeotroped with toluene (10 ml) to afford an oil. The resultant oil was added dropwise over 10 minutes to a cooled (0° C.) solution of ethanol (15 ml) and DIPEA (5 ml). The reaction was stirred at room temperature for 18 hours then concentrated in vacuo before water (20 ml) was added. The solution was extracted with ethyl acetate (30 ml) and the organic phase was dried over sodium sulfate then concentrated to give the title compound as an orange oil (1.1 g, 94%). 1H NMR (CDCl3, 400 MHz) 8.72 (s, 1H), 8.59 (d, J=4.9 Hz, 1H), 7.63 (dd, J=4.9 Hz, 0.5 Hz, 1H), 4.44 (q, J=7.3 Hz, 2H), 1.42 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17](=[O:34])[C@H:18]([NH:29][C:30](=[O:33])[CH2:31]Cl)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([O:27][CH3:28])[CH:21]=1.Cl>CN(C)C=O.ClCCl>[CH3:15][O:16][C:17](=[O:34])[C@H:18]([NH:29][C:30](=[O:33])[CH2:31][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([O:27][CH3:28])[CH:21]=1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(OC)c1)NC(=O)CCl
Reactant: NCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(C)c(OC)c1)NC(=O)CNCc1ccccc1
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
Benzylamine (1.65 g) and potassium carbonate (1.28 g) were added successively to a solution of (2R)-2-[N-(chloroacetyl)amino]-3-(3-methoxy-4-methylphenyl)propionic acid methyl ester (1.85 g) in N,N-dimethylformamide (15 ml) at 20° C. After being stirred at 35° C. for 1.5 hours, the mixture was poured into a mixture of ice-water (20 ml) and dichloromethane (20 ml). After the mixture was adjusted to pH 9 with diluted aqueous hydrochloric acid under stirring, the organic layer was separated, washed with brine (20 ml), dried over magnesium sulfate and evaporated under reduced pressure to give an oil of (2R)-2-[N-(benzylaminoacetyl)-amino]-3-(3-methoxy-4-methylphenyl)propionic acid methyl ester. A solution of (2R)-2-[N-(benzylaminoacetyl)amino]-3-(3-methoxy-4-methylphenyl)propionic acid methyl ester obtained by above procedure and acetic acid (0.18 ml) in isopropyl alcohol (10 ml) was stirred for 12 hours under reflux.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>>[NH2:6][C:7]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:9][N:8]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 247 %

Procedure:
To ice-water bath cooled, conc. H2SO4 (10 mL) was added 2-amino-5-trifluoromethylpyridine (1.70 g, 10.5 mmol). The resulting solution was heated to 50° C. and 69-71% HNO3 (1.7 mL, 2.6 mmol) was added dropwise over 10 min with stirring. The resulting solution was stirred at 80° C. for 46 h, then allowed to cool to room temperature, poured into ice-water (100 mL) and basified to pH 9 with 40% aq NaOH. The resulting mixture was extracted with EtOAc (5×40 mL). The EtOAc solution was dried (MgSO4), and evaporated to give 1.33 g (61%) of 50 as a yellow powder, mp 191°-3° C. 1H NMR (CDCl3), 6.140 (bs, 1H), 7.916 (bs, 1H), 8.590 (s, 1H), 8.670 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]([C@:6](C(=O)C1C=CC=CC=1)([C@@:8](C(=O)C1C=CC=CC=1)([C@@H:10]([N:13]=[N+:14]=[N-:15])[CH2:11][OH:12])[OH:9])[OH:7])=[O:5])[CH:2]=[CH2:3].C1COCC1.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([C:4]([C@H:6]([C@@H:8]([C@@H:10]([N:13]=[N+:14]=[N-:15])[CH2:11][OH:12])[OH:9])[OH:7])=[O:5])[CH:2]=[CH2:3]
Reactant: C=CCC(=O)[C@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)c1ccccc1)[C@H](CO)N=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: C=CCC(=O)[C@@H](O)[C@H](O)[C@H](CO)N=[N+]=[N-]
Reaction time: 5 h

Procedure:
1-allyl-2,3-dibenzoyl-4-azido-4-deoxy-L-xylose 35 (12.0 g, 28.3 mmol) was dissolved in 5:1 methanol:THF (70 mL); to this solution was added sodium methoxide (650 μL of 25% solution, 2.83 mmol). The solution was stirred for 5 h, then to it was added acetic acid (175 μL, 3.11 mmol) and the reaction stirred for 1 min. The solvent was removed in vacuo to give 36 as a thick oil. The material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](O)=[O:8])=[C:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]=1.OC1C2N=N[NH:24]C=2C=CC=1.Cl.CN(C)CCCN=C=NCC.N>C(#N)C>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:24])=[O:8])=[C:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)sc1C(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cc(Br)sc1C(N)=O
Reaction time: 0.17 h

Procedure:
5-Bromo-3-[(t-butyloxycarbonyl)amino]thiophene-2-carboxylic acid (0.80 g) was stirred in acetonitrile (80 ml). Hydroxybenztriazole (1.41 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.62 g) were added and stirring continued at room temperature for 10 minutes. Concentrated aqueous ammonia solution (8 ml) was added and the reaction mixture was heated to reflux for 1 h. The acetonitrile was removed by evaporation. Water (100 ml) was added and the mixture was sonicated and triturated. The resultant off-white solid was then collected by filtration, washed with water and dried under vacuum (0.763 g).
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(OCC)(=O)C>C(O)(=O)C>[NH2:2][C:12]1([C:5]#[N:4])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:12]2([C:1]#[N:2])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=C1CCCCC1
Reactant: Cc1ccc(N)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(NC2(C#N)CCCCC2)cc1
Product: N#CC1(N)CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 186 %

Procedure:
Sodium cyanide (0.147 g, 3 mmol) was added to a mixture of p-toluidine (0.214 g, 2 mmol) and cyclohexanone (0.294 g, 3 mmol) in acetic acid 90% (3 ml). The reaction mixture was stirred at room temperature for 12 h and then 20 ml of ethyl acetate was added. The organic layer was washed with water (3×10 ml), dried over magnesium sulfate and concentrated under vacuum to dryness to yield 14-methylphenyl)aminocyclohexanenitrile, 9a (0.398 g, 1.86 mmol, 93%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:21]=[C:17]([C:18](O)=O)[C:16]([OH:22])=[CH:15][CH:14]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:18]([C:17]3[CH:21]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=3[OH:22])=[N:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: NC(=O)c1cc(Cl)ccc1O
Reactant: O=C(O)c1cc(Cl)ccc1O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Reaction time: 1 h

Procedure:
40.0 g of 5-chlorosalicyl-amide and 54.0 g of 5-chlorosalicylic acid are boiled under reflux in 400 ml of xylene after addition of 2.5 ml of pyridine. 38 ml of thionyl chloride are added in the course of 2 h, the mixture is stirred for a further 1 h and the solvent is then distilled off under reduced pressure. The residue is suspended in 200 ml of ethanol, filtered off and washed with ethanol. After drying, 6-chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one is obtained as slightly yellow crystals of m.p. 246-248 C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:17]1[CH:16]=[CH:15][N:14]2[C:10]([C:4]3[CH:3]=[C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=3)=[CH:11][N:12]=[C:13]2[CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: CNc1cc(-c2cnc3cc(Cl)ccn23)cc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNc1cc(-c2cnc3cc(Cl)ccn23)cc(-c2ccccc2)n1

Procedure:
[6-Chloro-4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-pyridin-2-yl]-methyl-amine (1 eq, 0.19 mmol, 56 mg) and phenylboronic acid (1.1 eq, 0.21 mmol, 25.6 mg) are dissolved in DME (2 ml) and water (0.5 ml) and Na2CO3 (1.5 eq, 0.29 mmol, 35.5 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.019 mmol, 13.4 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield [4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-6-phenyl-pyridin-2-yl]-methyl-amine as a brown solid; [M+H]+=335
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:21]([OH:23])=O)[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:2].[Cl-].[O:25]1[CH2:29][CH2:28][CH:27]([NH3+:30])[CH2:26]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[N:4]=[C:5]([C:21]([NH:30][CH:27]2[CH2:28][CH2:29][O:25][CH2:26]2)=[O:23])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:2]
Reactant: [NH3+]C1CCOC1
Reactant: COc1ccc2c(C(=O)O)nc(C#N)c(-c3ccccn3)c2c1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(C(=O)NC3CCOC3)nc(C#N)c(-c3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
DMF was added to a vial containing 3-cyano-6-methoxy-4-pyridin-2-ylisoquinoline-1-carboxylic acid (0.028 g, 0.092 mmol), tetrahydrofuran-3-aminium chloride ( 0.068 g, 0.550 mmol), EDC (0.105 g, 0.550 mmol) and HOAT (0.0437 g, 0.275 mmol). DIEA (0.071 g, 0.550 mmol) was added to this mixture and stirred at rt overnight. Partitioned between half-saturated bicarb and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated, then purified by reverse phase HPLC to give a tan solid (0.019 g, 55%).
Reaction SMILES: [CH2:1]=[C:2]1O[C:4](=[O:5])[CH2:3]1.[Cl:7][C:8]1[C:9]([OH:21])=[C:10]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14].CO>CS(O)(=O)=O>[Cl:7][C:8]1[C:9]([OH:21])=[C:10]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=[C:12]2[C:13]=1[O:14][C:4](=[O:5])[CH:3]=[C:2]2[CH3:1]
Reactant: COC(=O)CCc1ccc(O)c(Cl)c1O
Reactant: C=C1CC(=O)O1
Agent: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)CCc1cc2c(C)cc(=O)oc2c(Cl)c1O
Yield: 64.3 %

Procedure:
Diketene (0.7 ml, 9.1 mmol) was added dropwise to a stirred solution of 5a (1.0 g, 4.3 mmol) in 7 ml of methanesulfonic acid. The resultant solution was heated at 70° C. for 5 min and cooled. Methanol (20 ml) was added and the reaction was heated to boiling; this treatment esterified small amount of free acid formed during the cyclization step. Methanol was evaporated and water was added to precipitate the product. The crude material was chromatographed on silica eluting with ethyl acetate. Concentration of the pure product fractions and drying under vacuum afforded 0.82 g (64%) of the desired product as a pale yellow solid. 1H NMR (DMSO-d6): δ 10.45 (s, 1H), 7.50 (s, 1H), 6.24 (s, 1H), 3.59 (s, 2.93 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.38 (s, 3H).
Reaction SMILES: [PH4+].[Li]CCCC.[O:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.[CH2:14]1C[O:17][CH2:16][CH2:15]1>>[O:7]1[CH2:12][CH2:11][C:10](=[CH:14][CH2:15][CH2:16][OH:17])[CH2:9][CH2:8]1
Reactant: C1CCOC1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Agent: [PH4+]
Product: OCCC=C1CCOCC1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a suspension of the phosphonium salt (90.2 g, 1.5 eq) in dry THF (1100 mL) at 0° C. under nitrogen atmosphere was added n-BuLi (2.5 M, 216 mL, 0.54 mol). The solution was stirred for 1 h, followed by addition of dihydro-2H-pyran-4(3H)-one (15 g, 0.15 mol). Stirring was continued at rt overnight. The mixture was quenched with satd aq NH4Cl, and then filtered. The filtrate was dried over Na2SO4, and concentrated under vacuum to give the crude product, which was purified by column chromatography to give the product (13.1 g, 61%). 1H NMR (CD3OD) δ 2.1-2.3 (m, 6H), 2.5 (s, 1H), 3.5-3.7 (m, 6H), 5.1-5.2 (t, 1H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cnc(NCc3cccc(Cl)c3)nc2-c2ccc(Cl)cc2Cl)cc1
Temperature: 100 °C

Procedure:
To a 5 mL round bottom flask fitted with a stirrer bar and rubber septum was added 1 mL DMF and 2-methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (103 mg, 0.2 mmol) from Step A. Then 3-chlorobenzyl amine (2 eq, 50 μL, 0.4 mmol) was added vial syringe and the mixture heated at 100° C. for 4 h. HPLC/MS, showed that the starting material had been converted to the desired product. The product was extracted from 10 mL water with 20 mL ether, dried over MgSO4, filtered and the solvent removed under reduced pressure. Flash column chromatography on silica gel (eluted with 92/8 hexanes/ethyl acetate) afforded the desired product. HPLC/MS: m/e=476 (M+1); Rt=4.70 min; 1H-NMR 500 MHz (CDCl3): δ 5.46 (s, 2H), 7.08 (d, J=9 Hz, 2H), 7.31-7.4 (m, 5H), 7.41-7.53 (m, 4H), 9.00 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([OH:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:29][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(Cl)c1ccccc1I
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccccc1I

Procedure:
One ml of o-iodobenzoyl chloride was reacted with 2.7 g of 1-octadecanol in accordance with the procedure of Example 8. There was obtained 2.36 g of octadecyl o-iodobenzoate, mp 35°, Rf 0.66.