Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[BrH:12].N([O-])=O.[Na+]>O.O1CCOCC1>[Br:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cccc(O)c1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44.7 %

Procedure:
2-Amino-3-nitrophenol B1 (5 g; 32.4 mmol) was dissolved in H2O (29.5 mL) and 1,4-dioxane (14.7 mL). The mixture was heated to reflux and hydrobromic acid (48%; 16.7 mL; 147 mmol) was added dropwise over a period of 20 min. Upon completion of the addition, the reflux was maintained an additional 15 min. The reaction was cooled to 0° C. (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O (20 mL) was added over a period of 30 min. The stirring was continued for 15 min at 0° C., then the mixture was transferred to a jacketed dropping funnel (0° C.) and added dropwise to a stirred mixture of Cu(I)Br (5.34 g; 37.2 mmol) in H2O (29.5 mL) and HBr (48%; 16.7 mL; 147 mmol) at 0° C. The reaction was stirred for 15 min at 0° C., warmed to 60° C., stirred for an additional 15 min, cooled to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3×150 mL). The organic layers were combined, washed with brine (1×), dried (Na2SO4), filtered and concentrated to afford the crude product (7.99 g) as a red-brown oil. The crude material was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60 mm, 60 angstroms; CH2Cl2 as the solvent) to afford pure 2-bromo-3-nitrophenol B2 (45%; 3.16 g) as an orange-brown solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[CH3:2].Cl.[NH2:16][OH:17]>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCOCCCCN1CCC(=NO)CC1

Procedure:
1-(4-Ethoxybutyl)-4-piperidone oxime is prepared from 1-(4-ethoxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8][CH2:7]2.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=1)[CH2:8][CH2:7]2
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc2c(c1)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(Cc1ccc(-c3ccccc3)cc1)C2

Procedure:
4.0 g of 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, 4.1 g of 4-chloromethylbiphenyl and 6.0 g of finely powdered potassium carbonate in 50 ml of dimethylformamide are stirred at 80° for 5 hours. The solvent is removed in vacuo, the residue is taken up in water/methylene chloride, the organic phase is shaken twice with water, and the organic phase is dried with magnesium sulfate and evaporated in a rotary evaporator. The crude product, which is only slightly impure, can be reacted further without further purification. A sample recrystallized from ethyl acetate has a melting point of 120°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([I:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O:13][CH3:14])=[O:12]>C(Cl)Cl>[I:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:23])=[O:22])=[O:26])[N:7]=1
Reactant: COc1cc(I)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(I)cc(OC)n1
Reaction time: 20 h
Yield: 20.4 %

Procedure:
To a solution of 0.25 g of 2-amino-4-iodo-6-methoxypyrimidine in 5 mL of dry methylene chloride was added 0.30 g 2-carbomethoxybenzenesulfonyl isocyanate. The resulting solution was allowed to stand for 20 hours at ambient temperature. The solution was cooled in an ice bath and crystallization induced with scratching. The crystals were collected, washed with n-butylchloride and dried to afford 0.10 g of the title compound, m.p. b 194°-196° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14](F)=[C:13]([F:19])[CH:12]=3)[C:6]=2[N:7]=1.[CH3:21][NH2:22]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([F:19])[CH:14]=[C:15]([F:17])[CH:16]=3)[C:6]=2[N:7]=1
Reactant: CN
Reactant: Fc1cc(C2CCc3c(Cl)nc(Cl)nc32)cc(F)c1F
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1cc(F)cc(F)c1
Yield: 13 %

Procedure:
A solution of 2,4-dichloro-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (498 mg, 1.561 mmol) and methanamine (1.561 mL, 3.12 mmol) in MeOH (10 mL) was stirred at rt for 1 h. Incomplete reaction was observed. Additional portions of methanamine (1.561 mL, 3.12 mmol) were added to the reaction mixture until the reaction was complete. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-chloro-7-(3,5-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (60 mg, 0.203 mmol, 30.5% yield). LC-MS (M+H)+=314.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1(OC)[CH2:15][CH2:14][CH:13]([O:16]C)[O:12]1>Cl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[CH2:15][CH2:14][CH:13]=[O:16]
Reactant: COC(=O)CCCCCCCC1(OC)CCC(OC)O1
Agent: Cl
Product: COC(=O)CCCCCCCC(=O)CCC=O

Procedure:
10.0 g of the compound of step B was stirred for 30 minutes with 2100 ml of 1N hydrochloric acid at room temperature. The mixture was then extracted rapidly several times with ether.
Reaction SMILES: [Si]([O:8][CH2:9][C:10](=[CH2:42])[C:11]([N:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][C:29]=2[O:30][CH3:31])[N:26]=[CH:25][N:24]=[C:23]3[NH:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[C:34]=2[F:41])[CH2:15][CH2:14]1)=[O:12])(C(C)(C)C)(C)C>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:40][C:35]1[C:34]([F:41])=[C:33]([NH:32][C:23]2[C:22]3[C:27](=[CH:28][C:29]([O:30][CH3:31])=[C:20]([O:19][CH:16]4[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]([CH2:9][OH:8])=[CH2:42])[CH2:14][CH2:15]4)[CH:21]=3)[N:26]=[CH:25][N:24]=2)[CH:38]=[CH:37][C:36]=1[Cl:39]
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)N1CCC(Oc2cc3c(Nc4ccc(Cl)c(Cl)c4F)ncnc3cc2OC)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(CO)C(=O)N1CCC(Oc2cc3c(Nc4ccc(Cl)c(Cl)c4F)ncnc3cc2OC)CC1
Reaction time: 3 h
Yield: 50.5 %

Procedure:
140 mg of the compound obtained in step 3) was diluted with 3 ml of tetrahydrofuran, and 1.1 ml of a 1.0M tetra-n-butyl ammonium fluoride-containing tetrahydrofuran solution was added thereto. The resulting mixture was incubated at room temperature for three hours. After the reaction terminated, a saturated sodium hydrogen carbonate was added, and the resulting solution was extracted twice with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:methylene chloride:methanol=7:7:1) to obtain the title compound (58 mg, 51%).
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([C:29]([O:31]CC)=[O:30])[C:8]2[CH2:9][CH2:10][N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)[C:12](=[O:19])[C:13]=2[C:14]=1[O:15]C(=O)C)(=O)C.[OH-].[Li+]>C1COCC1.CO.O>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[C:14]([OH:15])[C:5](=[O:4])[NH:6][C:7]=2[C:29]([OH:31])=[O:30])[C:12]1=[O:19]
Reactant: CCOC(=O)c1nc(OC(C)=O)c(OC(C)=O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 90 °C

Procedure:
A solution of ethyl 3,4-bis(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-5-oxo-5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (1.00 g, 2.09 mmol; Example 12, step 8) and lithium hydroxide (0.70 g, 16.70 mmol) in a mixture of THF-methanol-water (30 mL, 1:1:1 by volume) was heated under reflux in an oil bath at 90° C. overnight. The product mixture was acidified and concentrated under vacuum. The residue was triturated with diethyl ether. The solid precipitated was filtered and washed with ether to provide the titled compound. ES MS M+1=367.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12](COCC[Si](C)(C)C)[CH:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(Sc5ccc(O)cc5)c34)n(-c3ccccc3)c(=O)c12
Yield: 47.1 %

Procedure:
(S)-2-(1-((5-((4-Methoxyphenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (65 mg, 0.10 mmol) was treated with boron tribromide (1M in dichloromethane, 894 μL, 0.99 mmol) in dichloromethane (1.3 mL) and then with a solution of ammonia (7N in methanol, 1.3 ml, 9.10 mmol) according to the method described in Example 41. The residue was purified using SP1® Purification System (0% to 100% dichloromethane ethyl acetate) to obtain 24 mg (48% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC.CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH:14]1([N:20]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=O)c1cccn1C
Reactant: NC1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Solvent: CCOCC
Product: CCOC(=O)C(=NC1CCCCC1)c1cccn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of 25 g ethyl 1-methylpyrrole-2-glyoxylate and 44.5 g cyclohexylamine in 700 ml ether under nitrogen at 0° C. is added 8.8 ml of titanium tetrachloride in 80 ml pentane. After stirring at room temperature overnight, the precipitate is removed by filtration. The filtrate is evaporated and the resulting oil distilled. The fraction collected at 111°-117° C. (5 millitorr) is crystallized from hexane to afford a 15% yield of ethyl α-cyclohexylimino-1-methylpyrrole-2-acetate, m.p. 35°-36° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[C@@H:14]([NH2:21])[C@H:12]1[OH:13].[C:22]([O:26][C:27]([NH:29][C@H:30]([C:44](O)=[O:45])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:34][CH:33]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[C@@H:14]([NH:21][C:44](=[O:45])[C@H:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:37]=2)[NH:29][C:27]([O:26][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:28])[C@H:12]1[OH:13]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Product: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)OC)cc1
Yield: 23.7 %

Procedure:
Methyl 1-(6-amino-9H-purin-9-yl)-3-[N-tert-butoxycarbonyl-O-methoxycarbonylmethyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronate (220 mg) was prepared by reacting methyl 1-(6-amino-9H-purin-9-yl)-3-amino-1,3-dideoxy-β-D-ribofuranuronate (577 mg) prepared in Example 62 with N-tert-butoxycarbonyl-O-methoxycarbonylmethyl-L-tyrosine (520 mg) prepared in Preparation 8 (2) according to a similar manner to that of Example 64, mp. 115°-120° (dec.).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1.[N:19]1([C:25]2[C:29]3[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=3[O:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C.[Br-].[Na+]>CN1CCCC1=O>[CH3:18][N:15]1[CH2:16][CH2:17][C:11]2[C:8]3[C:9](=[O:10])[N:4]([CH2:3][CH2:2][N:22]4[CH2:23][CH2:24][N:19]([C:25]5[C:29]6[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=6[O:27][N:26]=5)[CH2:20][CH2:21]4)[CH:5]=[N:6][C:7]=3[S:13][C:12]=2[CH2:14]1
Reactant: CN1CCc2c(sc3ncn(CCCl)c(=O)c23)C1
Reactant: Cc1ccc2onc(N3CCNCC3)c2c1
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc2onc(N3CCN(CCn4cnc5sc6c(c5c4=O)CCN(C)C6)CC3)c2c1
Yield: 16.9 %

Procedure:
3-(2-Chloroethyl)-7-methyl-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4(3H)-one (2.5 g, 8.81 mol; preparation: Example A3) was stirred together with 3-piperazin-1-yl-5-methyl-1,2-benzisoxazole (2.49 g, 11.45 mmol), diisopropylethylamine (15.4 ml, 88.1 mmol), sodium bromide (4.53 g, 44.05 mmol) and N-methyl-2-pyrrolidone (40 ml) at 70° C. for 4 days. After cooling, N-methyl-2-pyrrolidone and excess diisopropylethylamine were removed under high vacuum, the residue was added to water, the aqueous phase was extracted several times with ethyl acetate, and the organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. The very impure crude product was chromatographed on silica gel (eluent: methylene chloride with slowly increasing methanol content (0-50%)). This resulted in 0.9 g of 7-methyl-3-{2-[4-(5-methyl-1,2-benzisoxazol-3-yl)piperazin-1-yl]ethyl}-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4(3H)-one (yield: 22%) being obtained as a solid product which was converted into the corresponding dihydrochloride with ethereal hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c(OC)cc21
Yield: 56.7 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (59 mgs) and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (69 mgs) were converted to the title compound as an off-white solid (65 mgs, 57%). 1H-NMR (CDCl3): δ 8.33 (s, 1H), 7.94 (s, 1H), 7.50 (broad s, 1H), 6.80-6.77 (m, 1H), 6.72 (s, 1H), 6.34 (s, 2H), 5.62 (broad s, 1H), 5.45 (broad s, 1H), 4.47 (t, J=8.6 Hz, 1H), 3.92 (s, 3H), 3.10 (s, 1H), 2.90 (s, 1H), 2.69-2.59 (m, 1H), 2.55 (d, J=8.1 Hz, 1H), 2.30-2.15 (m, 4H), 1.68 (d, J=9.3 Hz, 1H), 1.32 (s, 2H), 1.60 (t, J=7.1 Hz, 3H), 0.99-0.92 (m, 2). MP: 145-153° C., LCMS, found 497 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.Cl.[CH2:9]([N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:9]([N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][C:1]#[N:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: ClCc1nccn1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CCc1nccn1Cc1ccccc1
Temperature: 23 °C
Yield: 70 %

Procedure:
Dry, powdered sodium cyanide (14 gm, 280 mmole) was added to 80 ml of dry dimethylsulfoxide with stirring at 23° C. Then 1-benzyl-2-chloromethylimidazole hydrochloride (14 gm, 63 mmole) was added portionwise over 10 minutes while maintaining the temperature below 40° C. After the addition was complete, the mixture was stirred at 40° C. for an additional hour. It was diluted with 250 ml methylene chloride and the resulting solution was washed with 4×200 ml of water, dried over MgSO4 and the solvent removed in vacuo. The residue was collected by filtration, dissolved in warm methanol and precipitated with ether to obtain needle-like crystals (8.7 g) of N-benzyl-2-cyanomethylimidazole. m.p. 102.5°-104° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:9](=[O:21])[C:8]=1[Br:22])(=O)=O.CCN(C(C)C)C(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[CH:42])=[CH:37][CH:36]=1>CN(C=O)C.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>[Br:22][C:8]1[C:9](=[O:21])[N:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]([CH3:13])=[CH:12][C:7]=1[C:42]#[C:41][C:38]1[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c(Br)c(=O)n1Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2ccc(F)cc2)c(Br)c(=O)n1Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a degassed solution of 3-bromo-6-methyl-2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (0.6675 g, 1.56 mmol) in DMF (9 mL), DIEA (0.35 mL, 2.03 mmol), 4-fluorophenylacetylene (0.235 mL, 1.95 mmol) and PdCl2(PPh3)2 (0.11 g) were added. The reaction mixture stirred at room temperature under nitrogen for 1 hour and then heated in an oil bath (65° C.) under nitrogen overnight. The solvents were distilled in vacuo and the residue was purified by flash column chromatography (5% methanol in ethyl acetate). The extracts were concentrated to afford the desired compound (0.432 g, 69%) after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.45 (s, 2H), 7.96 (s, 1H), 7.64 (m, 3H), 7.41 (dd, 1H, J=4.8 Hz, 4.8 Hz), 7.18 (t, 2H, J=8.8 Hz), 6.46 (s, 1H), 5.45 (s, 2H), 2.37 (s, 3H); ES-HRMS m/z 397.0361/399.0310 (M+H calculated for C20H15N2OFBr requires 397.0346/399.0328).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[C:8]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:27][C:28]1[CH:29]=[C:30]([NH:40][C:41]([NH2:43])=[NH:42])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1>>[F:27][C:28]1[CH:29]=[C:30]([NH:40][C:41]2[N:43]=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][C:8]([CH3:17])([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[N:42]=2)[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reactant: CN(C)C=C1CCCC(C)(c2ccccc2)C1=O
Solvent: O=[N+]([O-])O
Product: Cc1cn(-c2ccc(Nc3ncc4c(n3)C(C)(c3ccccc3)CCC4)cc2F)cn1

Procedure:
The title compound was prepared from 6-[1-dimethylamino-methylidene]-2-methyl-2-phenylcyclohexanone (117 mg, 0.48 mmol) and N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (130 mg, 0.36 mmol) using in analogous manner the procedure described in example 48b). Obtained as a pale-yellow solid (44 mg, 30%). MS ISP (m/e): 414.4 [(M+H)+]. mp 157-158° C.
Reaction SMILES: FC(F)(F)C([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][Br:21])=[CH:16][CH:15]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:5]=2)=[CH:15][CH:16]=1
Reactant: O=C(n1c(-c2ccc(CBr)cc2)nc2ccccc21)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: BrCc1ccc(-c2nc3ccccc3[nH]2)cc1

Procedure:
1-Trifluoroacetyl-2-(4-bromomethylphenyl)benzimidazole (229.9 g, 0.6 mole) is stirred for 5 hours at room temperature in a 7% solution of potassium carbonate in aqueous methanol The methanolic solution is evaporated to near dryness, and the aqueous residue is extracted with methylene chloride. The combined organics are washed with water, filtered through cotton, and evaporated to yield a solid product which is purified by recrystallization from benzene.
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.[CH2:15]([N:18]1[C@H:22]([CH2:23][CH2:24][CH3:25])[CH2:21]OS1(=O)=O)[CH2:16][CH3:17].[ClH:28]>O1CCCC1.C(OCC)C.COCCOC.CCCCCC>[ClH:28].[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[CH2:21][C@H:22]([NH:18][CH2:15][CH2:16][CH3:17])[CH2:23][CH2:24][CH3:25]
Reactant: c1ccc2sccc2c1
Reactant: CCC[C@@H]1COS(=O)(=O)N1CCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCN[C@H](CCC)Cc1cc2ccccc2s1
Yield: 70 %

Procedure:
Under an argon atmosphere, n-butyl lithium (a 1.56 mol/L hexane solution, 44.4 mL) and 1,2-dimethoxyethane (7.2 mL) were added to a solution of benzothiophene (8.45 g) in tetrahydrofuran (120 mL) under ice-cooling and stirring and then stirred under ice-cooling for 30 minutes. A solution of (R)-3,4-dipropyl-1,2,3-oxathiazolidine 2,2-dioxide (14.36 g) in tetrahydrofuran (43.0 mL) was added dropwise to the resulting solution and stirred under ice-cooling for 2.5 hours. Under ice-cooling and stirring, 1 mol/L hydrochloric acid (200 mL) was added to the resulting solution and stirred at room temperature for 1.5 hours. Diethyl ether (200 mL) was added to the solution, and the mixture was separated. The aqueous layer was neutralized with 1 mol/L sodium hydroxide and then extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Saturated hydrogen chloride in diethyl ether (10 mL) was added to a solution of the residue in diethyl ether (50 mL) under ice-cooling and stirring. After stirring at the same temperature for several minutes, the solvent was removed under reduced pressure. The residue was recrystallized from ethanol (100 mL) to give (R)-1-(2-benzothienyl)-2-propylaminopentane hydrochloride (13.17 g, 70% yield) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][C:19]([OH:21])=[O:20].C(OC(=O)C)(=O)C.C(N(CC)CC)C>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:18]([C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[Cl:10])[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Temperature: 110 °C
Yield: 52.9 %

Procedure:
Part A; To 4-bromobenzaldehyde (25 gram, 0.135 mol) is successively added 2,4-dichlorophenylacetic acid (27.7 gram, 0.135 mol), acetic anhydride (100 mL) and triethylamine (19 mL, 0.136 mol) and the resulting mixture is heated at reflux temperature for 90 minutes. The reaction mixture is cooled to 110° C. and water (100 mL) is slowly added. The resulting mixture is allowed to attain room temperature and ethyl acetate is added. The ethyl acetate layer is twice washed with water, dried over MgSO4, filtered and concentrated in vacuo. The resulting oil is crystallised from diisopropyl ether to give 3-(4-bromophenyl)-2-(2,4-dichlorophenyl)acrylic acid as a white solid (26.55 gram, 53% yield).