Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[F:30][CH2:31][CH2:32]O.C([C@@H](O)C1C=CC=C(OC2C=CC=CC=2)C=1)#N>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:32][CH2:31][F:30])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: OCCF
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Agent: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCCF

Procedure:
Using the procedure of Step F of Example 9, the ester of Step A of Example 31 after reaction with 2-fluoro-ethanol and (S)α-cyano-3-phenoxy-benzyl alcohol was reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl- 3-[(Z) 3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+48° (c=0.25% in benzene).
Reaction SMILES: [CH:1]1[NH:2][C:3](=[S:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl[CH2:12][C:13]#[N:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]1[N:2]=[C:3]([S:10][CH2:12][C:13]#[N:14])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: S=c1[nH]cc2ccccn12
Reactant: N#CCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CCSc1ncc2ccccn12
Temperature: 25 °C

Procedure:
51.0 g (0.315 m) imidazo[1,5-a]pyridine-3(2H)-thione, prepared according to Example 1, 27.6 g (0.365 m) chloroacetonitrile and 30.7 g triethylamine are dissolved in 600 ml of toluene and the solution is heated to reflux for 3 hr, then allowed to cool to room temperature. The toluene solution is washed with water, dried over anhydrous magnesium sulfate and treated with Darco. After the solvent is removed, the residual solid is recrystallized from cyclohexane. A total yield of 62 g is obtained. The recrystallized sample has a melting point of 120°-2° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([OH:45])=[C:39]([S:41]([OH:44])(=[O:43])=[O:42])[CH:40]=1>C(Cl)Cl.C1COCC1>[OH:45][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])=[CH:40][C:39]=1[S:41]([OH:44])(=[O:42])=[O:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ccc(O)c(S(=O)(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N[C@@H](CCC(=O)Nc1ccc(O)c(S(=O)(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boc-Glu-OtBu (100 mg, 0.33 mmol) was dissolved in methylene chloride (1 mL) and THF (1 mL). CDI (65 mg, 1.1 mmol) was added thereto and stirred at room temperature for 30 minutes. Then, 5-amino-2-hydroxybenzene sulfonic acid salt (77 mg, 0.33 mmol) was added thereto and stirred overnight at room temperature. After removing a solvent, purification was conducted in accordance with the purification process A. The obtained intermediate was dissolved in 2 mL of TFA and stirred at room temperature for 3 hours, and a solvent was removed therefrom. The obtained product was purified in accordance with the purification process A to obtain a title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C3CCCCO3)[CH:8]=2)[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])O.[Na+]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc2cc(OC3CCCCO3)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(O)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chloro-6-(tetrahydropyran-2-yloxy)quinoline (1.00 g) and piperazine-1-carboxylic acid tert-butyl ester (0.76 g) were heated to 140° C. in the absence of solvent under an argon atmosphere and stirred for 2 hours. After cooling the reaction mixture to room temperature, a sodium hydrogen carbonate aqueous solution was added thereto, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The result was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25→67:33). The result was concentrated to dryness under reduced pressure to afford the title compound as a pale yellow amorphous compound (0.55 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]([O:22][C:23]3[C:32]([N+:33]([O-])=O)=[CH:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[CH:24]=3)[C:18]([O:20]C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(O)(=O)C.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[O:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][C:32]=4[NH:33][C:18]3=[O:20])[CH2:29][CH2:28][CH2:27][CH2:26]5)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(CCCN1CCN(c2ccc(F)cc2)CC1)Oc1cc2c(cc1[N+](=O)[O-])CCCC2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Nc2cc3c(cc2OC1CCCN1CCN(c2ccc(F)cc2)CC1)CCCC3
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
In a mixture of acetic acid (15 ml) and water (2.5 ml) was dissolved methyl 5-[4-(4-fluorophenyl)-1-piperazinyl]-2-(5,6,7,8-tetrahydro-3-nitro-2-naphthyloxy)valerate (4.1 g). To the solution was added little by little iron powder (1.9 g) whil stirring. The reaction was allowed to proceed for 30 minutes, followed by stirring at 80° C. for further 15 minutes. The resultant precipitate was filtered off, and the filtrate was concentrated. To the concentrate was added water, which was neutralized with an aqueous solution of sodium carbonate, followed by extraction with chloroform (then precipitated inorganic substances were filtered off). The chloroform layer was washed with water and dried (MgSO4). The concentrate was recrystallized from chloroform--ethyl acetate to give 1.54 g (43.1%) of 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one as crystals, m.p. 164°-165° C. This product was in good agreement with the authentic sample obtained by Method A.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1.[C:19](Cl)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1)([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:25]
Reactant: COC(=O)c1cn2c(n1)COc1ccc(N)cc1-2
Reactant: CCOC(=O)C(=O)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)Nc1ccc2c(c1)-n1cc(C(=O)OC)nc1CO2
Yield: 65 %

Procedure:
By the procedure of Step C in Example 1, methyl 8-amino-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate and ethyl chlorooxalate were reacted in dimethylformamide as solvent to obtain a 65% yield of methyl 8-(ethoxalylamino)-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate with a melting point of 186°-8° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([CH:24]4[CH2:29][CH2:28][CH:27]([O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:26][CH2:25]4)[C:20]3=[O:48])=[C:13]([Cl:49])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.C(OCC)(=O)C>[C:44]([Si:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[O:30][CH:27]1[CH2:28][CH2:29][CH:24]([CH:21]2[CH2:22][CH2:23][N:19]([CH2:18][C:14]3[C:15]([Cl:17])=[CH:16][C:11]([C:8]4[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=4)=[CH:12][C:13]=3[Cl:49])[C:20]2=[O:48])[CH2:25][CH2:26]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC(C4CCC(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC4)C3=O)c(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](OC1CCC(C2CCN(Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
Treat a solution of 4′-{3-[4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-1-ylmethyl}-3′,5′-dichloro-biphenyl-4-carboxylic acid methyl ester (0.56 g) in THF (5 mL ) and methanol (1 mL) with 2N LiOH (5 mL) and stir at 50° C. for 2 hours. Cool the reaction, dilute with ethyl acetate (25 mL), and wash with 1 N HCl (10 mL). Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford 0.55 g (99%) of the title compound. MS (m/z): 700 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20]3)[O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:29][O:30][CH2:31][CH2:32]O>C(OCC)(=O)C>[CH3:29][O:30][CH2:31][CH2:32][O:23][C:22]([C:19]1([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:21][CH2:20]1)=[O:24]
Reactant: O=C(O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Reactant: COCCO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COCCOC(=O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Temperature: 60 °C

Procedure:
To a solution consisting of the product of Example 87 (0.50 g) in 2-methoxyethanol (5 mL) is added thionyl chloride (1.0 mL.) The mixture is heated to 60° C. for 18 h is and is subsequently cooled, diluted with ethyl acetate, washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with a gradient (0 to 50% ethyl acetate in hexanes) afforded the title compound (0.37 g); MS (APCI+) m/z 380 (MH+.)
Reaction SMILES: C(O)(=O)C(O)=[O:3].[C:7]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:31][CH:30]=2)=[CH:15][CH:14]=1)#[N:8].[ClH:43]>>[ClH:43].[NH2:8][C:7](=[O:3])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:33][CH:34]=2)=[CH:17][CH:18]=1
Reactant: O=C(O)C(=O)O
Reactant: N#CCCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Agent: Cl
Product: NC(=O)CCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
The free base of the above nitrile (Example 34, Part D) (0.15 g; 0.3 mmol) was combined with 7 mL of conc HCl and stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure, and the product (0.16 g; 100% yield) was dried in vacuo overnight.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27](Cl)(=O)C.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([NH:34][CH:31]1[CH2:33][CH2:32]1)=[O:26])(=[O:7])[CH3:27]
Reactant: NC1CC1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Product: CC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)NC1CC1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, acetyl chloride, and cyclopropylamine the title compound was obtained in 52% purity by LC/MS. MS(ESI+): m/z=384.4.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([CH3:26])([CH3:25])[C:15]([N:17]3[CH2:22][CH:21]4[CH2:23][CH2:24][CH:18]3[CH2:19][CH2:20]4)=[O:16])[CH:12]=2)[NH:7][C:6]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH3:4].[C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:38])[CH:36]=[CH2:37]>>[C:40]([O:39][C:35](=[O:38])[CH2:36][CH2:37][NH:1][CH2:2][C@H:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([CH3:26])([CH3:25])[C:15]([N:17]3[CH2:22][CH:21]4[CH2:23][CH2:24][CH:18]3[CH2:19][CH2:20]4)=[O:16])[CH:12]=2)[NH:7][C:6]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH3:4])([CH3:43])([CH3:42])[CH3:41]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4CC5CCC4CC5)cc3c2[C@H](C)CN)c1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4CC5CCC4CC5)cc3c2[C@H](C)CNCCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H -indol-5-yl]-1-(2-aza-bicyclo[2.2.2]oct-2-yl)-2-methylpropan-1-one (248.6 mg in 2.0 mL absolute ethanol) was added 0.080 mL tert-butyl acrylate and the mixtureheated to 70° C. on an oil bath. After 3 hours, the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (methylene chloride:methanol, 94:6) to give the title compound (232 mg).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].O>CN(C)C(=O)C>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: Nc1ccc(S(=O)(=O)c2cccs2)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2cccs2)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.50 g, 3.1 mmol) in N,N-dimethylacetamide (7 mL) was added thionyl chloride (0.37 g, 3.1 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4-(2-Thienylsulfonyl)benzenamine (0.50 g, 2.1 mmol) was added in one portion to the orange solution and the mixture stirred at room temperature overnight. The brown solution was poured into water and the aqueous solution extracted with ethyl acetate (2×50 mL). The organics were combined, dried (MgSO4), filtered and the solvent distilled to yield a tan solid. Flash chromatography of the solid (eluted with 5% v/v ethyl acetate in methylene chloride) and evaporation of the eluent yielded the title propanamide (0.61 g, 77%) as an off-white solid; mp 158°-161° C. 1H-NMR (250 MHz, d6 -DMSO): 1.57 (s, 3H, CH3), 7.21 (dd, 1H, J=4.9, 4.0 Hz, aromatic), 7.56 (s, 1H, OH), 7.81 (dd, 1H, J=3.8, 1.5 Hz, aromatic), 8.00 (m, 5H, aromatic), 10.43 (s, 1H, NH). MS (CI, CH4): 380(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[C:9]#[CH:10])=[CH:4][CH:3]=1.C[Si]([N:34]=[N+:35]=[N-:36])(C)C>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([C:11]2[CH:12]=[N:36][NH:35][N:34]=2)[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCC(c1ccc(Cl)cc1)(c1cn[nH]n1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21

Procedure:
A solution of tert-butyl 1-(3-(4-chlorophenyl)pent-1-yn-3-yl)-1H-indol-4-ylcarbamate (200 mg, 0.5 mmol) in trimethylsilyl azide (3 mL) was heated at 100° C. under microwave for 3 h. The resulting mixture was diluted with brine (10 mL) and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo to afford the crude product. The product was purified via column chromatography (75% EtOAc/hexanes) to provide the title product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH:23]([NH2:26])([CH3:25])[CH3:24]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:26][CH:23]([CH3:25])[CH3:24])=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NC(C)C)c(Br)c2)c(SC)s1
Temperature: 70 °C

Procedure:
To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.226 mmol), (Example 2: step c), isopropylamine (0.012 g, 0.204 mmol), THF [2.0 mL]. Reaction vessel was sealed and heated to 70° C. for 72 hours. Removal of the solvents in vacuo followed by chromatography (0%–15% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. for C15H17BrN2O4S3: 466.41 (M+H); found 466.9.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[C:23]([O:30][CH2:31][CH2:32][Cl:33])(=[O:29])[CH2:24][CH2:25][C:26]([O-])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:26]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])[C:4]([F:22])=[CH:3][C:2]=1[Cl:1])(=[O:27])[CH2:25][CH2:24][C:23]([O:30][CH2:31][CH2:32][Cl:33])=[O:29]
Reactant: O=C([O-])CCC(=O)OCCCl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(=O)CCC(=O)OCCCl)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and mono (2-chloroethyl) succinate with N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine as the catalyst in methylene chloride there is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H) -pyrimidinyl]-4-fluorophenyl 2-chloroethyl succinate. m.p. 94°-96° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:24][C:23](=O)[C:22]3[C:17](=[CH:18][C:19]([O:31][CH3:32])=[C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:36])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([Cl:36])[C:22]3[C:17](=[CH:18][C:19]([O:31][CH3:32])=[C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCOc1cc2c(=O)[nH]c(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCOc1cc2c(Cl)nc(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
To a suspension of 2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one (3.28 g, 7.58 mmol) in CH2Cl2 (100 mL) was added oxalyl chloride (2.20 mL, 24.8 mmol) and 2 drops of DMF. The mixture was stirred at RT for 6 h. An additional aliquot of oxalyl chloride (1.20 mL, 13.5 mmol) was added. Stirring was continued at RT overnight, upon which the mixture was concentrated in vacuo, taken up in CHCl3 (100 mL) and washed with sat. NaHCO3 (3×50 mL), water (2×50 mL) and brine (1×50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (1.52 g, 3.37 mmol, 45%). MS 451 (M+1 Cl isotope pattern). HPLC retention time 10.84 mins. (10-95-13 method).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[C:7]12(C(O)=O)[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][CH2:8]2.NC1C=CC(C2[NH:25][C:26]3[CH:32]=[CH:31][C:30](N)=[CH:29][C:27]=3[N:28]=2)=CC=1>CN(C=O)C.N1C=CC=CC=1>[CH3:11][CH:12]([C:1]([C:2]1[NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[N:25]=1)=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:13]
Reactant: O=C(O)C12CCC(CC1)C2
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCC(C)C(=O)c1nc2ccccc2[nH]1
Temperature: 60 °C

Procedure:
Bis-bicyclo[2:2:1]heptane-2-carbonyl benzimidazole was prepared as follows: oxalyl chloride (1.07 ml, 2 M in CH2Cl2) was added to bicyclo[2.2.1]heptane carboxylic acid (0.305 g, 2.14 mmole) followed by one drop DMF. The mixture was allowed to react at RT for 1.0 hour. To the above solution was added 2-(4-aminophenyl)-6-amino-benzimidazole (0.200 g, 0.89 mmole) in pyridine (2 ml). The reaction was heated to 60° C. overnight. The reaction was cooled and the precipitate filtered and washed with NaHCO3 and hexanes. The resulting solid was purified by preparative HPLC to give a solid that was 68% pure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:26])=[C:18]([CH:25]=1)[C:19](N(OC)C)=[O:20]>O1CCCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:26])=[C:18]([C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:20])[CH:25]=1
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)c1cc(Br)ccc1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ccccn1)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An oven-dried flask was cooled under argon, then charged with anhydrous THF (40 mL) and 2-bromopyridine (1.76 mL, 18 mmol). Isopropylmagnesium chloride in tetrahydrofuran (2.0 M in THF, 11 mL) was then added dropwise at room temperature. The mixture was then stirred at room temperature for 2 hours, then cooled to 0° C., whereupon a THF solution (5 mL) of 5-bromo-2-fluoro-N-methoxy-N-methylbenzamide (3.93 g, 15 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with saturated NH4Cl, extracted with EtOAc, washed with 10% HCl, dried over Na2SO4, and purified by column chromatography (gradient 0 to 10% EtOAc/hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J=4.6 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.79 (dd, J=5.8, 1.4 Hz, 1H), 7.67-7.59 (m, 1H), 7.52 (dd, J=7.4, 4.9 Hz, 1H), 7.04 (t, J=9.0 Hz, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([NH:27][C:28]1[CH:29]=[C:30](I)[CH:31]=[CH:32][CH:33]=1)(=[O:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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.[Cu]I>[C:24]([NH:27][C:28]1[CH:33]=[C:32]([C:23]#[C:22][C:15]2([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Nc1cccc(I)c1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(NC(C)=O)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 59.6 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and 3-acetamido-1-iodobenzene (0.17 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.3 h, was cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, to provide the title compound as tan solid (0.17 g, 60%), m.p. 58-60° C.