Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([O:15][C:16](=[O:22])[C:17](=O)[CH:18](Br)[CH3:19])[CH3:14]>O1CCOCC1>[CH2:13]([O:15][C:16]([C:17]1[N:1]=[C:2]2[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:10])[F:11])=[CH:4][N:3]2[C:18]=1[CH3:19])=[O:22])[CH3:14]
Reactant: Nc1ncc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C(=O)C(C)Br
Solvent: C1COCCO1
Product: CCOC(=O)c1nc2c(Cl)cc(C(F)(F)F)cn2c1C

Procedure:
To a solution of 2-amino-3-chloro-5-(trifluoromethyl)pyridine (11.3 g, 57.5 mmol) in dioxane (200 mL) at room temperature was added dropwise 3-bromo-2-oxo-butyric acid ethyl ester (12.017 g, 57.49 mmol, the product of Step A). The reaction mixture was heated to reflux for 24 h, cooled, and the dioxane was removed under reduced pressure. Chromatography on silica gel eluting with a hexane/ethyl acetate gradient afforded 17.3 g of 8-chloro-3-methyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester as a solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])[NH2:34].O1CCOCC1>O>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([N:8]=[CH:9][N:10]=4)[C:2]([C:39]4[CH:40]=[CH:41][C:36]([C:33]([NH2:34])=[O:35])=[CH:37][CH:38]=4)=[CH:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1)[CH2:25][CH3:26]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CCCN1CCN(c2ccc(Nc3ccc(Cl)n4ncnc34)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCN1CCN(c2ccc(Nc3ccc(-c4ccc(C(N)=O)cc4)n4ncnc34)cc2)CC1
Temperature: 107.5 °C
Yield: 42.2 %

Procedure:
To a reaction vial (40 mL), is added 5-chloro-N-(4-(4-propylpiperazin-1-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (55 mg, 0.15 mmol), potassium carbonate (104 mg, 0.75 mmol, 5 eq.), 4-carbamoylphenylboronic acid (50 mg, 0.30 mmol, 2 eq), PddppfCl2 (20 mg, 15%), dioxane (4.0 mL) and water (1.0 mL). The reaction mixture is degassed and filled with argon. The reaction is heated at 105-110° C. for 20 h. After cooling to rt, ethyl acetate (10 mL) is added to each reaction vial. The organic phase was filtered through a pat of celite and then is evaporated to give a dry residue that was purified by preparatory HPLC to give the title compound, 28.9 mg, yield 42.2%; LCMS-ESI (m/z): calcd for C26H29N7O, 455; [M+H]+ found, 456.
Reaction SMILES: C(ON=O)(C)(C)C.[C:8]([O:11][CH2:12][C:13]([CH2:15]Br)=[CH2:14])(=[O:10])[CH3:9].[N+:17]([C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)N)([O-:19])=[O:18]>CC#N>[C:8]([O:11][CH2:12][C:13](=[CH2:14])[CH2:15][C:22]1[CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=1)(=[O:10])[CH3:9]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C=C(CBr)COC(C)=O
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: C=C(COC(C)=O)Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of t-butylnitrite (0.47 ml, 4.0 mmol) and 2-acetoxymethyl-3-bromopropene (1.93 g, 10.0 mmol) in 1 ml CH3CN, 3,5-dinitroaniline (0.37 g, 2.0 mmol) was added, while maintaining the temperature between 18 and 24° C. The mixture was stirred for 1 h at room temperature. The volatile material in the solution was removed at reduced pressure. Flash chromatography (heptane/ethylacetate) gave 0.42 g 1-(2-acetoxymethyl-2-propenyl)-3,5-dinitrobenzene. 1H-NMR (CDCl3, 300 MHz) δ ppm: 8.94 (t, J=2.1 Hz, 1H), 8.42 (d, J=2.1 Hz, 2H), 5.33 (s, 1H), 5.05 (s, 1H), 4.52 (s, 2H), 3.64 (s, 2H), 2.08 (s, 3H). 13C-NMR (CDCl3, 75.43 MHz) δ ppm: 170.4, 148.5, 143.1, 140.7, 129.1, 117.5, 117.2, 65.9, 39.3, 20.7.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([SH:24])=[CH:21][CH:22]=2)[O:17][C:16](=[O:25])[CH:15]=1>>[C:7]([C:5]1[S:6][C:2]([S:24][C:20]2[CH:19]=[C:18]3[C:23]([C:14]([CH3:13])=[CH:15][C:16](=[O:25])[O:17]3)=[CH:22][CH:21]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)(=[O:9])[CH3:8]
Reactant: Cc1cc(=O)oc2cc(S)ccc12
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc3c(C)cc(=O)oc3c2)s1

Procedure:
Prepared according to the procedure described for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (200 mg, 0.98 mmol) and 4-methyl-7-sulfanyl-chromen-2-one (188 mg, 0.98 mmol). The title compound was obtained as a solid (80 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.52 (1H, s), 8.02 (1H, m), 7.92 (1H, m), 7.79 (1H, m), 6.58 (1H, s), 3.33 (3H, s), 2.50 (3H, s). MS m/z: 362.01 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]1([CH3:22])[NH:13][C:12](=O)[C:11]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:10]=2[O:9]1>P(Cl)(Cl)(Cl)=O>[Cl:2][C:12]1[C:11]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:10]=2[O:9][C:8]([CH3:22])([CH3:7])[N:13]=1
Reactant: CC1(C)NC(=O)c2ccc([N+](=O)[O-])cc2O1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)N=C(Cl)c2ccc([N+](=O)[O-])cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Phosphorus pentachloride (5.5 g) was added to a solution of 2,2-dimethyl-7-nitro-3,4-dihydro-2H-1,3-benzoxazine-4-one (4 g) in phosphoryl chloride (15 mL) at 0° C., and the mixture was stirred at room temperature for one hour. The mixture was heated to 60° C. and stirred at the same temperature overnight. After cooling to 0° C., the reaction mixture was poured into ice water (300 mL). After stirring for 30 minutes, the mixture was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine (100 mL×2), dried over sodium sulfate and concentrated in vacuo to give the titled compound (2.34 g) as a brown oil, which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH:6]=CC2C=CC(OC)=C(OC)C=2)[NH:2]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:19]1([C:18]([N:1]2[CH2:5][CH2:4][CH:3]([NH2:2])[CH2:6]2)=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C=CC2CCNN2)cc1OC
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: NC1CCN(C(=O)c2ccccc2)C1

Procedure:
4-(2-aza-2-pyrrolidin-3-ylvinyl)-1,2-dimethoxybenzene (3 mmol) and benzoyl chloride (3.5 mmol), a compound of formula (10), were added to a mixture of dry methylene chloride (15 mL) and sodium carbonate (600 mg). The mixture was stirred for hours and then filtered through a Celite™ bed. Solvent was removed from the filtrate by evaporation, and the residue was dissolved in a mixture of methanesulfonic acid (3.84 g) in 20 mL tetrahydrofuran:water (3:1), and stirred for 60 hours. The solution was neutralized with sodium carbonate, filtered, and solvent removed from the filtrate under reduced pressure. The residue was purified on a silica gel flash chromatography column, to obtain 3-aminopyrrolidinyl phenyl ketone as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:9][C:10](=[O:31])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:27]([F:30])([F:29])[F:28])=[N:18][C:19]([C:20]([N:22]3[CH2:26][CH2:25][S:24][CH2:23]3)=[O:21])=[C:13]2[CH2:12]1)(C)(C)C.[ClH:43]>C(OCC)(=O)C>[ClH:43].[NH2:7][C@H:8]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:9][C:10]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:27]([F:28])([F:30])[F:29])=[N:18][C:19]([C:20]([N:22]3[CH2:26][CH2:25][S:24][CH2:23]3)=[O:21])=[C:13]2[CH2:12]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCSC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCSC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 75 %

Procedure:
(R)-[3-Oxo-3-[1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 20a (0.15 g, 0.24 mmol) was added to a solution of 2.2 N hydrochloric acid in 5 mL of ethyl acetate. The reaction mixture was reacted at room temperature for 4 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-3-amino-1-[1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 20 (100 mg, yield 75%) as a light yellow solid.
Reaction SMILES: CS[C:3]1[C@@:8]([O:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][N:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[C:36]1[O:40][C:39]([CH3:41])=[N:38][CH:37]=1)[C:29]([NH:31][NH2:32])=O.C(O)(=O)C>C(OCC)(=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:29]2[N:4]3[CH2:5][CH2:6][CH2:7][C@:8]([O:14][C:15]4[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=4)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]3=[N:32][N:31]=2)[CH:33]=[CH:34][C:35]=1[C:36]1[O:40][C:39]([CH3:41])=[N:38][CH:37]=1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCN=C1SC
Reactant: COc1cc(C(=O)NN)ccc1-c1cnc(C)o1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To ethyl (3S)-2-(methylsulfanyl)-3-(3,4,5-trifluorophenoxy)-3,4,5,6-tetrahydropyridine-3-carboxylate (702 mg) and 3-methoxy-4-(2-methyl-1, 3-oxazol-5-yl)benzohydrazide (500 mg) was added acetic acid (3 mL), and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate). The crudely-purified product was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (933 mg).
Reaction SMILES: N1(CCN2C=C(C3C=NC=C(C(F)(F)F)C=3)N=C2C2CCN([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])CC2)CCC1.[N:37]1([CH2:41][CH2:42][N:43]2[CH:47]=[C:46]([C:48]3[CH:49]=[CH:50][C:51]([F:57])=[C:52]([CH:56]=3)[C:53]([NH2:55])=[O:54])[N:45]=[C:44]2[CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:40][CH2:39][CH2:38]1>>[NH2:34][C:30]1[N:31]=[CH:32][N:33]=[C:28]([N:61]2[CH2:60][CH2:59][CH:58]([C:44]3[N:43]([CH2:42][CH2:41][N:37]4[CH2:38][CH2:39][CH2:40]4)[CH:47]=[C:46]([C:48]4[CH:49]=[CH:50][C:51]([F:57])=[C:52]([CH:56]=4)[C:53]([NH2:55])=[O:54])[N:45]=3)[CH2:63][CH2:62]2)[C:29]=1[CH2:35][CH3:36]
Reactant: NC(=O)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(N)=O)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 5-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-fluorobenzamide instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=493, obsd.=493).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[N-:11]=[C:12]=[S:13].[K+].[Na+].[I-]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:11]=[C:12]=[S:13]
Reactant: [N-]=C=S
Reactant: Fc1c(Cl)cccc1CBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1c(Cl)cccc1CN=C=S

Procedure:
One molar equivalent of 3-chloro-2-fluoro-benzyl bromide (commercially available from e.g., Lancaster Synthesis, Ltd.) is permitted to react with 2 molar equivalents of potassium isothiocyanate in dimethylformamide (DMF) containing 0.5 molar equivalent of NaI at 90° C. for 5 hours with stirring to yield 3-chloro-2-fluorobenzyl isothiocyanate. The reaction mixture is permitted to cool to room temperature, and the solution is diluted with H20 and extracted with ether. The ether phase containing the product is removed and the reaction mixture extracted twice more with fresh ether. The ether phases are combined and the product is concentrated in a Speed Vac® vacuum centrifuge (using house vacuum) set in a water bath at about 45° C. When the ether has evaporated, the unpurified 3-chloro-2-fluorobenzyl isothiocyanate is a viscous liquid.
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[C:30](OS(C(F)(F)F)(=O)=O)[CH:29]=[CH:28][CH:27]=2.C(N(CC)CC)C>O1CCOCC1>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:30]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:31]=4[CH:32]=[C:24]([CH3:23])[NH:25]5)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Reactant: Cc1cc2c(OS(=O)(=O)C(F)(F)F)cccc2[nH]1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc2c(/C=C/S(=O)(=O)N3CCC4(CC3)N=C(C3CCCCC3)NC4=O)cccc2[nH]1
Temperature: 100 °C
Reaction time: 18 h
Yield: 13.8 %

Procedure:
A mixture of 2-cyclohexyl-8-ethenesulfonyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (100 mg, 0.307 mmol), trifluoro-methanesulfonic acid 2-methyl-1H-indol-4-yl ester (129 mg, 0.462 mmol), tetrakistriphenylphosphine palladium(0) (35 mg, 30.2 μmol) and triethylamine (130 μL, 0.933 mmol) in 1,4-dioxane (1.5 ml) was heated with stirring at 100° C. for 18 hours. The reaction mixture was cooled, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-cyclohexyl-8-[(E)-2-(2-methyl-1H-indol-4-yl)-ethenesulfonyl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (19.3 mg, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C=O.[C:34](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH:26]5[CH2:27][CH2:28][N:29]([CH3:34])[CH2:30][CH2:31]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: NC(=O)c1sc(-n2cnc3ccc(OC4CCNCC4)cc32)nc1-c1cccc(Cl)c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(Oc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a mixture of 0.041 g (0.09 mmole) 4-(3-chloro-phenyl)-2-[6-(piperidin-4-yloxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.21), 0.0135 mL of 37% aqueous formaldehyde solution, 0.0062 mL (0.11 mmole) of acetic acid and 2.1 mL of methanol-dichloromethane (2:5) was added 0.029 g (0.14 mmole) of sodium triacetoxy-borohydride. The mixture was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure. The residue was diluted with dichloromethane-ethyl acetate and washed with aqueous 1M sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 10:90-20:80) to give 0.034 g of 4-(3-chloro-phenyl)-2-[6-(1-methyl-piperidin-4-yloxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (1.22). MH+/Z=468
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH:23]=[CH:24][CH2:25][CH3:26])([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[C:5]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][CH2:25][CH3:26])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCC=Cc1ccc(OCc2ccccc2)cc1OC(C)(C)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCc1ccc(O)cc1OC(C)(C)C(=O)OCC
Yield: 90 %

Procedure:
A solution of 2-(5-Benzyloxy-2-but-1-enylphenoxy)-2-methylpropionic acid ethyl ester (0.76 g, 2.06 mmol) in ethanol (50 mL) was treated with 5% Pd/C (0.10 g) and hydrogen (60 psi) at ambient temperature for 6 h. The mixture was filtered and concentrated in vacuo to give a colorless oil (0.52 g, 90%). 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=7.8 Hz, 1H), 6.37 (dd, J=8.3, 2.4 Hz, 1H), 6.20 (s, 1H), 4.66 (br s, 1H), 4.24 (q, J=7.2 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 1.60 (s, 6H), 1.53 (quintet, J=7.6 Hz, 2H), 1.34 (sextet, J=7.3 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), MS (ES) m/e 281 (M+1).
Reaction SMILES: [OH-].[K+].[CH3:3]I.[NH2:5][C:6]1[NH:11][C:10](=[O:12])[CH:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1>CCO>[NH2:5][C:6]1[N:11]([CH3:3])[C:10](=[O:12])[CH:9]=[C:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:7]=1
Reactant: CI
Reactant: Nc1nc(-c2ccccc2)cc(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(N)nc(-c2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of KOH (1.22 g, 22 mmol), MeI (6.85 g, 48 mmol), and 2-amino-6-phenyl-3H-pyrimidin-4-one (2.62 g, 14 mmol) in EtOH (130 mL) was stirred at room temperature in a stoppered 250 mL roundbottom flask for 3 days. An additional 6.85 g (48 mmol) MeI was added and stirring was continued for 1 day. The solvent was removed under vacuum and the residue was dissolved in H2O (35mL), warmed to 50° C., and 1N HCl was added dropwise until the solid dissolved completely. The solution was cooled to room temperature, made slightly basic with saturated NaHCO3, and the resulting white solid was filtered and dried under vacuum. M+1: 202.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1I.[CH2:14]([O:21][CH2:22][C@@H:23]1[O:31][CH2:30][C:26]2=[N:27][O:28][CH2:29][C@@H:25]2[CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.B(F)(F)F.CCOCC>O1CCCC1.C1(C)C=CC=CC=1>[CH2:14]([O:21][CH2:22][C@@H:23]1[O:31][CH2:30][C@:26]2([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[F:6])[NH:27][O:28][CH2:29][C@@H:25]2[CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Reactant: Fc1ccccc1I
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccccc1[C@]12CO[C@@H](COCc3ccccc3)C[C@H]1CON2
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes, 11.3 mL, 28.3 mmol) was added in a drop-wise manner to a solution of 1-fluoro-2-iodobenzene (3.30 mL, 28.3 mmol) in a mixture of tetrahydrofuran (26 mL) and toluene (116 mL) at −78° C., and the reaction mixture was stirred at this temperature for 30 minutes. In a separate flask, a solution of (3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (P1) (3.50 g, 14.2 mmol) in toluene (116 mL) was cooled to −78° C. and treated with boron trifluoride diethyl etherate (3.49 mL, 28.3 mmol); this mixture was also allowed to stir at −78° C. for 30 minutes, and then added via cannula over three to four minutes to the aryllithium solution. The reaction mixture was stirred at −78° C. for approximately 30 minutes and was then quenched with saturated aqueous ammonium chloride solution. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 20% ethyl acetate in heptane) provided the product as a yellow oil. Yield: 4.39 g, 12.8 mmol, 90%. The stereochemical outcome of this reaction (cis ring fusion) was established via single crystal X-ray analysis of intermediate C17 (see data below). LCMS m/z 344.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.50-1.61 (m, 1H), 1.82-1.90 (m, 1H), 3.10-3.18 (m, 1H), 3.50 (dd, half of ABX pattern, J=10.3, 4.1 Hz, 1H), 3.55-3.60 (m, 2H), 3.72 (br d, J=7.2 Hz, 1H), 3.85-3.93 (m, 2H), 4.20 (dd, J=12.7, 1.8 Hz, 1H), 4.61 (AB quartet, JAB=12.1 Hz, ΔνAB=22.5 Hz, 2H), 7.04 (ddd, J=12.1, 8.2, 1.2 Hz, 1H), 7.17 (ddd, J=7.8, 7.4, 1.4 Hz, 1H), 7.26-7.40 (m, 6H), 7.95 (ddd, J=8.1, 8.0, 1.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+].[N+]([C:18]1[CH:19]=[C:20]2[C:25](=[O:26])[N:24]([CH3:27])[C:22](=[O:23])[C:21]2=[CH:28][CH:29]=1)([O-])=O>O.ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:25](=[O:26])[N:24]([CH3:27])[C:22](=[O:23])[C:21]3=[CH:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Clc1ccccc1
Solvent: O
Product: CN1C(=O)c2ccc(-c3ccc(Cl)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
In a 500 ml three-necked flask equipped with a mechanical stirrer, Dean-Stark trap/condenser, nitrogen inlet, and thermometer was added 25.71 grams (0.20 moles) of p-chlorophenol, 100 ml dimethylsulfoxide, and 150 ml of chlorobenzene. After stirring and nitrogen purging the mixture for 30 min., 15.80 grams of aqueous sodium hydroxide (50.62 wt. %; 0.20 moles) was added. The mixture was heated up to 150° C. with the azeotropic removal of the water of reaction. After the removal of water was complete the temperature was lowered to 60° C. and 41.23 grams (0.20 moles) of 4-nitro-N-methyl phthalimide was added. The mixture was stirred overnight. Upon cooling to room temperature the product precipitated from solution. Filtration, washing the precipitate with water, and recrystallization from isopropanol yielded 50.8 grams of 4-(p-chlorophenyl)-N-methyl phthalimide. The melting point was 131°-132° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[N:14]=[CH:15][N:16]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]=2[CH3:18])=[CH:7][C:6]=1[N+:38]([O-:40])=[O:39])(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[N:14]=[CH:15][N:16]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:17]=2[CH3:18])=[CH:7][C:6]=1[N+:38]([O-:40])=[O:39]
Reactant: CC(=O)Nc1ccc(C=Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C=Cc2ccc(N)c([N+](=O)[O-])c2)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 48.6 %

Procedure:
A mixture of 4-[2-(4-acetamido-3-nitrophenyl)vinyl]-5-methyl-1-tritylimidazole (6.3 g) in ethanol (60 ml) and 1N-sodium hydroxide (23.8 ml) was refluxed for 1 hour and the mixture was cooled. The isolated precipitate was collected by filtration and the precipitate was washed with aqueous ethanol to give 4-[2-(4-amino-3-nitrophenyl)vinyl]-5-methyl-1-tritylimidazole (2.82 g).