Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([N:12]2[CH2:18][CH2:17][C:16]3[S:19][C:20]([CH3:22])=[N:21][C:15]=3[CH2:14][CH2:13]2)[N:3]=1.[CH2:23](I)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:23]([O:8][C:6]1[N:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:12]2[CH2:18][CH2:17][C:16]3[S:19][C:20]([CH3:22])=[N:21][C:15]=3[CH2:14][CH2:13]2)[C:5]=1[N+:9]([O-:11])=[O:10])[CH3:24]
Reactant: Cc1nc(N2CCc3nc(C)sc3CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(C)nc(N2CCc3nc(C)sc3CC2)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 19.3 %

Procedure:
A suspension of 0.120 g (0.373 mmol) of 2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one (example 1), of 0.070 g (0.45 mmol) of the ethyl iodide and of 0.077 g (0.56 mmol) of potassium carbonate in 1.0 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture was then poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of ethylacetate. The combined ethylacetate phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was then chromatographed on silica gel using a 95:5 v/v mixture of dichloromethane and methanol as eluent giving in a first fraction 0.025 g (0.072 mmol, yield 19%) of the 6-(6-ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine as yellow amorphous solid; MS: [M+H]+=350.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.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.O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
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: C1CCOC1
Solvent: CCO
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc(Cl)c2)s1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and 3-chlorophenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by flash chromatography using a gradient of 5%-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent to give the title compound as a colourless solid; MS (ES+) 347 (MH+).
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:20][CH2:19][CH2:18]1.Cl>CN(C)C=O.O>[CH:17]1([O:2][C:3]2[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: OCc1ncccc1O
Reactant: BrC1CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ncccc1OC1CCC1
Yield: 27.3 %

Procedure:
3-Hydroxy-2-(hydroxymethyl)pyridine hydrochloride (1.57 g, 0.009 mol), potassium carbonate (8.09 g, 0.058 mol) and cyclobutyl bromide (5.0 g, 0.037 mol) were stirred together under nitrogen in N,N-dimethylformamide (20 ml) at 50° C. overnight. Water (40 ml) was added, and the resultant solution was acidified to pH 1 with hydrochloric acid (5 N). The solution was washed with dichloromethane (3×100 ml), basified to pH 14 with sodium hydroxide solution (4 N), and extracted with dichloromethane (3×100 ml). The organic layers from the extraction were combined, washed with water (1×100 ml), dried over magnesium sulfate and concentrated in uacuo to give a dark brown solid which was recrystallised from hexane to give the title compound (0.44 g). 1H NMR (250 MHz, CDCl3) δ 1.61-1.81 (1H, m), 1.86-1.91 (1H, m), 2.09-2.22 (2H, m), 2.39-2.51 (2H, m), 4.31 (1H, br s), 4.66 (1H, m), 4.74 (1H, s), 6.97 (1H, m), 7.07-7.17 (1H, m), 8.13 (1H, m); MS (ES+) m/e 180 [MH]+.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:3]1[OH:23].S(=O)(=O)(O)O.[CH3:29][S:30][CH2:31][CH2:32]O.[OH-].[Na+]>O1CCOCC1.CN(C)C=O>[CH3:15][C:13]1[N:14]=[C:7]2[C:6]3[NH:5][C@H:4]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C@@H:3]([OH:23])[C@H:2]([O:1][CH2:32][CH2:31][S:30][CH3:29])[C:11]=3[CH:10]=[CH:9][N:8]2[C:12]=1[CH3:16]
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Reactant: CSCCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CSCCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of (7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine, dissolved in 30 ml of dioxane and 5 ml of dimethyl-formamide, is admixed with 0.63 g of concentrated sulfuric acid and 1 g of 2-methylmercaptoethanol. The mixture is stirred at RT for 3 h, poured into ice-water (200 ml), adjusted to pH 8 using 2 N aqueous sodium hydroxide solution and extracted three times with methylene chloride. The solvent is stripped off under reduced pressure and the oily residue that remains is purified on silica gel (mobile phase: diethyl ether). This gives 80 mg of the title compound of m.p. 118-9° C. (diisopropyl ether).
Reaction SMILES: C(N[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)C.[CH:10]([N:13]([SiH3:17])C(C)C)(C)[CH3:11]>>[C:4]1([CH2:11][CH2:10][NH:13][SiH3:17])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCNc1ccccc1
Reactant: CC(C)N([SiH3])C(C)C
Product: [SiH3]NCCc1ccccc1
Reaction time: 24 h

Procedure:
In a 500 ml Schlenk flask, 60.5 g (0.5 mol) N-ethylaniline and 131 g (1.0 mol) di-isopropylaminosilane were stirred at ambient temperature under a nitrogen atmosphere for 24 hours. The relatively lower boiling point by-product di-isopropylamine was removed with vacuum at a pressure of 20 mmHg and room temperature (25° C.). The reaction mixture was stirred for another 24 hours. The end-product phenylethylaminosilane was obtained by vacuum distillation. The end-product was characterized by mass spectroscopy (MS) which is provided in FIG. 2 and shows, among other things, peaks at 151, 150, 136, 120, 106, 93, and 77. The molecular weight of the phenylethylaminosilane was 151.28.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2]>C(OC(=O)C)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:14])[O:15][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 8 h
Yield: 51.3 %

Procedure:
Next, 4-nitrophthalic acid (21.1 g, 0.1 mole) in a round-bottomed flask was admixed with acetic anhydride (40 ml) and refluxed for 1 hour. The mixture was brought to room temperature and acetic anhydride was removed under vacuum. The concentrated mixture was allowed to stand overnight, and the solid obtained was recrystallized using toluene to give 4-nitrophthalic anhydride ((9.9 g (51%), Mp 119° C.)).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C(N(CC)CC)C.O>CN(C)C=O>[C:14]([CH2:13][CH2:12][NH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])([OH:16])=[O:15]
Reactant: NCCC(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCNc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 10 h
Yield: 47.6 %

Procedure:
A mixture of 5.0 g (36 mmol) 2-fluoronitrobenzen, 6.3 g (71 mmol) β-alanin, 20 ml triethylamine, 50 ml water and 100 ml dimethylformamide was stirred at 80° C. for 10 h. After cooling to 25° C. the reaction mixture was evaporated in vacuo. The residue was stirred with IN hydrochloric acid, and the precipitate was filtered off and washed with water to give 3.6 g (48%) N- carboxyethyl-2-nitroaniline. M.p. 145° C., 1H-NMR (DMSO-d6): 8.2-6.2 (5H, m), 3.4 (2H, q), 2.5 (2H, t).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccc(Cl)c(Cl)c2)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:18][NH2:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.C[Si](C)(C)Cl.[S:34](Cl)(=[O:37])(=[O:36])[NH2:35].Cl>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:18][NH:19][S:34](=[O:37])(=[O:36])[NH2:35])=[O:11])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: NC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: NS(=O)(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)NC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
To a solution of crude (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-aminomethyl-4-mercaptopyrrolidine (3.3 g: 10.18 mmole) in dichloromethane (100 ml) at -78° C., triethylamine (2.84 ml: 2.2 eq.) and trimethylchlorosilane (3.12 ml: 2.2 eq.) are dropwise added. After stirring for 20 minutes, triethylamine (4.25 ml: 3 eq.) and 1M-sulfamoyl chloride in dichloromethane (25 ml: 2.5 eq.) are dropwise added to the mixture. After 20 minutes stirring, the reaction mixture is acidified with hydrochloric acid, warmed to room temperature, and extracted with dichloromethane. The extract is washed with water, and 1N-hydrochloric acid (10 ml) and methanol (30 ml) are added thereto. The solution is stirred at room temperature for 30 minutes. The reaction mixture is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate) to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-sulfamoylaminomethyl-4-mercaptopyrrolidine (2.65 g). Yield: 66.7%. NMR δ(CDCl3 -CD3OD) ppm: 1.42(t, J=7 Hz, 1H), 1.65 to 1.93(m, 1H), 2.48 to 2.70(m, 1H), 3.05 to 3.63(m, 4H), 3.93 to 4.16(m, 2H), 5.22(s, 2H), 7.53(d, J=8 Hz, 2H), 8.23(d, J=8 Hz, 2H). IR ν (CHCl3) cm-1 : 3276br, 1692, 1607.
Reaction SMILES: [CH:1]1([CH3:18])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][C:11](=[O:17])/[CH:12]=[CH:13]\[C:14]([OH:16])=[O:15])[CH2:2]1.[CH3:19][C:20](O)([CH3:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:20]([O:15][C:14](/[CH:13]=[CH:12]\[C:11]([O:10][CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:18])[CH2:2]1)=[O:17])=[O:16])([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)O
Reactant: CC1CCC(C(C)C)C(OC(=O)/C=C\C(=O)O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)/C=C\C(=O)OC(C)(C)C)C1
Temperature: 150 °C

Procedure:
2.5 g of maleic acid monomenthyl ester, 1 g of 2-methyl-2-propanol and 0.7 g of p-toluenesulfonic acid in 30 mL of toluene were heated to reflux at a oil temperature of 150° C. for 19 h. Subsequently, the reaction mixture was quenched by the addition of salt saturated sodium bicarbonate solution. The mixture was extracted with ether, the organic layers were combined and washed with salt saturated sodium bicarbonate solution and then with an aqueous solution of sodium hydroxide, salt saturated ammonium chloride solution, and then dried over salt saturated brine and sodium sulfate anhydrous. Finally, the resultant oily product was subjected to distillation under reduced pressure to obtain menthyl 3-t-butoxycarbonyl-2Z-propenoate.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH3:9][CH2:10][O:11][C:12]([CH:14](P(OCC)(OCC)=O)[CH3:15])=[O:13].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=O>O1CCCC1.O>[CH3:15][C:14](=[CH:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[C:12]([O:11][CH2:10][CH3:9])=[O:13]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)=Cc1cccs1
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a solution of 5.1 g of sodium hydride in oil (prewashed by decantation with hexane.) in 60 ml of dry tetrahydrofuran was added dropwise 30 g of triethyl 2-phosphonopropionate over a period of 30 minutes under dry argon atmosphere at room temperature. After the mixture was stirred for further 1 hour, a solution of 11.8 g of 2-thiophenealdehyde in 30 ml of tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate. Drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 11.0 g of ethyl 2-methyl-3-(2-thienyl)acrylate as a yellow oil. Next, 150 ml of ethanol and 60 ml of aqueous 2N sodium hydroxide were added to the oil, and the mixture was refluxed for 1 hour. After cooling, ethanol was removed under reduced pressure, and the residue was acidified with dilute hydrochloric acid. Crystalline precipitate was collected by filtration to give 8.2 g of 2-methyl-3-(2-thienyl)acrylic acid as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[OH:11].Cl.[CH3:13][NH:14][O:15][CH3:16]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([O:15][CH3:16])[CH3:13])=[O:8])=[CH:4][C:3]=1[OH:11]
Reactant: CNOC
Reactant: O=C(O)c1ccc(F)c(O)c1
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)c(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 4-fluoro-3-hydroxybenzoic acid (1.49 g, 9.55 mmol) in DCM (40 mL) was added TEA (1.2 mL, 8.61 mmol) followed by N,O-dimethylhydroxylamine hydrochloride (1.12 g, 11.5 mmol). The reaction mixture was stirred at room temperature for 3 h, then diluted with DCM, washed with water twice, dried over Na2SO4, filtered and concentrated to yield 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide as a colorless oil (1.90 g, 100% yield). LCMS: RT=0.89 min [M+H] 200.10 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: FC1C=CC(CN)=CC=1.[F:10][C:11]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=1[CH2:13][NH2:14].[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38](O)=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38]([NH:14][CH2:13][C:12]3[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:11]=3[F:10])=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cc(F)ccc1F
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1cc(F)ccc1F
Yield: 76 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 2,5-difluorobenzylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 76% yield: mp 176-177° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.37-6.87 (m, 8H), 6.06 (t, J=5.7 Hz, 1H), 4.56 (d, J=5.7 Hz, 2H), 4.46 (s, 2H), 4.05 (t, J=8.1 Hz, 2H), 3.44 (t, J=8.1 Hz, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.5, 158.4, 157.4, 155.3, 155.2, 153.5, 135.5, 128.9, 128.3, 128.0, 127.0, 126.8, 116.8, 115.4, 48.0, 42.0, 41.6, 37.6, 17.2; MS (ES+) m/z 443.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[C:21]([F:23])[N:20]=[CH:19][C:18]=4[CH2:24][N:25]([CH3:27])[CH3:26])=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:28])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][NH:41][C:40]1=[O:44]>C(O)CCC.C(OCC)(=O)C>[CH3:26][N:25]([CH2:24][C:18]1[C:17]([C:13]2[C:11]3[S:12][C:8]([C:6]4[C:5]([F:28])=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][N:39]5[CH2:43][CH2:42][NH:41][C:40]5=[O:44])[N:7]=4)=[CH:9][C:10]=3[CH:16]=[CH:15][CH:14]=2)=[CH:22][C:21]([F:23])=[N:20][CH:19]=1)[CH3:27]
Reactant: NCCN1CCNC1=O
Reactant: CN(C)Cc1cnc(F)cc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CN(C)Cc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Temperature: 120 °C
Yield: 63.2 %

Procedure:
Combine {4-[2-(2-chloro-5-fluoro-pyrimidin-4-yl)-benzo[b]thiophen-7-yl]-6-fluoro-pyridin-3-ylmethyl}-dimethyl-amine (0.25 g, 0.59 mmol) and triethylamine (0.25 mL, 1.78 mmol) in n-butanol (8.0 mL). Add 1-(2-aminoethyl) imidazolidin-2-one (0.23 g, 1.78 mmol). Heat the reaction mixture at 120° C. overnight (15 hours), then cool to room temperature. Dilute the reaction mixture with ethyl acetate, and wash with water and saturated aqueous sodium chloride. Separate the organic layer from aqueous layer and dry over MgSO4. After filtration, remove the organic solvent to give a crude. Purify the crude by column chromatography (0.5% to 10% 2 N NH3 in methanol solution/dichloromethane) to afford the title compound (0.19 g, 63%). MS (ES) m/z 510 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]([OH:21])[CH3:20].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:21][CH:19]([C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:20]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(O)c1ccncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(O)c1ccncc1-c1ccc(C#N)cc1
Temperature: 100 °C
Yield: 50.5 %

Procedure:
To the solution of 4-cyano phenylboronic acid (220 mg, 1.50 mmol), 1-(3-Bromo-pyridin-4-yl)-ethanol (303 mg, 1.50 mmol) and PdCl2(dppf). CH2Cl2 adduct (98 mg, 0.12 mmol) in DMF (6 mL) was added 2M Na2CO3 solution (1.50 ml, 3.00 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and sat. NH4Cl solution. After extraction with DCM and separation, the combined extracts were concentrated and purified by ISCO 12 g (10% MeOH/DCM=0-25%) to give 4-[4-(1-Hydroxy-ethyl)-pyridin-3-yl]-benzonitrile (18, 170 mg, 51%) as a white solid; ESI-MS m/z 225 [M+H]+, Retention time 0.97 min. 1H-NMR (MeOD, 400 MHz) δ 1.28 (d, J=6.4 Hz, 3H), 4.85 (q, J=6.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.73 (d, J=5.2 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 8.33 (s, 1H), 8.59 (d, J=5.2 Hz, 1H)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH2:23].C1COCC1>>[CH3:22][NH:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), 2.0 M methylamine in THF (2.0 ml, 4 mmol) by a procedure similar to that of Example 122 (53.7%). 1H NMR (CDCl3): 7.45 (d, J=7.8 Hz, 1H), 7.39-7.33 (m, 1H), 7.11-7.07 (m, 2H), 6.90-6.87 (m, 3H), 6.69-6.64 (m, 1H), 4.95 (brs, 1H), 3.82 (s, 3H), 3.50 (s, 3H), 3.11 (d, J=5.1 Hz, 3H).
Reaction SMILES: [OH-].[Na+].C(O)(=O)C(O)=O.[Cl:9][C:10]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:11]=1[CH:12]([S:19][C:20]([CH3:22])=O)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.[CH:28]1C(CCl)=[CH:32][CH:31]=[C:30]([Cl:36])[CH:29]=1>CO>[Cl:9][C:10]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:11]=1[CH:12]([S:19][CH2:20][C:22]1[CH:32]=[CH:31][C:30]([Cl:36])=[CH:29][CH:28]=1)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: CC(=O)SC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(CSC(Cn2ccnc2)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 330 mg sodium hydroxide in 30 ml methanol under nitrogen is added 810 mg of 1-[2,4-dichloro-β-(methylcarbonylthio)phenethyl]imidazole oxalate and the mixture is stirred at room temperature for ca. 30 minutes (until thin layer chromatography shows the disappearance of the ester). α,p-dichlorotoluene (350 mg) is then added, the solution stirred a further 15 minutes and the solvent removed under reduced pressure. Ether and water are then added to the residue and the ether extract washed with water, dried (MgSO4) and concentrated. Dropwise addition of nitric acid (d = 1.42) until precipitation is complete gives the nitrate salt of 1-[2,4-dichloro-β-(4-chlorobenzylthio)phenethyl]imidazole, recrystallized from acetone, mp 130.5°-132° C.