Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:45]=[CH:44][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4C(OC(C)(C)C)=O)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)CCC(OC)=O)N(COCC[Si](C)(C)C)C=2C=1)#N.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([C:3]1[CH:45]=[CH:44][C:6]2[NH:7][C:8]([CH:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)CCC(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COC(=O)CCC(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCC(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-4-methoxy-4-oxobutyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-4-methoxy-4-oxobutyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 146-A) (0.21 g, 0.332 mmol) in DCM (3.32 ml) was added tin(IV) chloride (3.32 ml, 3.32 mmol) at 0° C. The solution was stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. The reaction was concentrated and absorbed onto silica to purify via FCC (0-50% EtOAc:heptanes) to obtain the title compound. MS (ESI+) m/z 403.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=3)[N:12]=2)[CH2:6]1)=[O:4].C(Cl)Cl.B(Br)(Br)Br>CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=3)[N:12]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCN(Cc2ncc3cc(OC)ccc3n2)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1CCN(Cc2ncc3cc(O)ccc3n2)C1
Temperature: -78 °C
Reaction time: 15 h
Yield: 94.4 %

Procedure:
(R)-1-(6-Methoxy-quinazolin-2-ylmethyl)-pyrrolidine-3-carboxylic acid methyl ester (600.00 mg, 1.9911 mmol) was dissolved in Methylene chloride (20 mL, 300 mmol), and cooled to at −78° C. A solution of 1.0 M of Boron tribromide in Methylene chloride (11.947 mL, 11.947 mmol) was then added dropwsie. The reaction mixture was then warmed up to 23° C. gradually and then heated at 50° C. for 3 hours. The reaction mixture was then cooled to −78° C., and cold MeOH (30 mL) was added. The mixture was then left standing for for 15 hours at 23° C. Solvent was removed under vacuum, and the residue was treated with K2CO3 (sat) to pH˜9, and then adjusted to pH˜7.5. Extracted with DCM (100×2 mL). Organic layers were washed with water, brine and dried over Na2SO4. The crude product was purified via chromatography (SiO2, 40 g, 0-10% MeOH/DCM) to give a pure product (540 mg, 94%). 1H NMR (MeOD) δ ppm: 9.26 (s, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.55 (dd, J=9.2, 2.6 Hz, 1H), 7.23 (d, J=2.5 Hz, 1H), 4.00 (d, J=3.0 Hz, 2H), 3.67 (s, 3H), 3.04-3.18 (m, 2H), 2.86 (d, J=2.5 Hz, 2H), 2.66-2.77 (m, 1H), 2.10 (s, 2H). MS (ESI, M+1): 288.10.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[Cl:10].[CH3:11][N:12](C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[Cl:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([CH3:8])=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: Cc1cc(Br)c(Cl)cc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)c(Cl)cc1F
Temperature: 110 °C
Reaction time: 13 h

Procedure:
Under an argon atmosphere, to a solution (20 mL) of 1-bromo-2-chloro-4-fluoro-5-methylbenzene (4.47 g) in N,N-dimethylformamide were added tetrakis(triphenylphosphine)palladium(0) (0.78 g) and zinc cyanide (1.23 g). The mixture was stirred at 110° C. for 13 hr and partitioned between ethyl acetate-water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate) and crystallized from ethyl acetate-hexane to give the title compound as a colorless solid (yield: 2.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH:16]=[CH:17][N+:18]([O-:20])=[O:19])=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+].C(O)(=O)C>O1CCOCC1.C(O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1COc2cc(C=C[N+](=O)[O-])ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1COc2cc(CC[N+](=O)[O-])ccc2O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of 6-(2-nitrovinyl)-2,3-dihydro-1,4-benzodioxine-2-carboxylic acid ethyl ester (3.7 mmol) in dioxane (10 mL) and ethanol (10 mL) was added dropwise a suspension of NaBH4 (140 mg) in dioxane (4 mL) and ethanol (4 mL) under cooling to −10° C. This solution was stirred at −5° C. for 1 hour and then acetic acid was added. It was concentrated under reduced pressure. To the residue were added water and a 1N aqueous solution of sodium hydroxide, and the mixture was extracted with ethyl acetate. The oily phase was washed with saturated aqueous ammonia and brine in turn, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and the title compound (790 mg) was obtained from the effluent with hexane/ethyl acetate=30/10 (v/v).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([CH:10](O)[C:11]([F:14])([F:13])[F:12])[N:4]([CH3:16])[C:3]=1[CH3:17].[N:18]1[CH:23]=CC=C[CH:19]=1.S(Cl)(Cl)=O.CNC>C(#N)C>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([CH:10]([N:18]([CH3:23])[CH3:19])[C:11]([F:14])([F:13])[F:12])[N:4]([CH3:16])[C:3]=1[CH3:17]
Reactant: c1ccncc1
Reactant: Cc1c(Cl)c(=O)c(O)c(C(O)C(F)(F)F)n1C
Agent: CNC
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1c(Cl)c(=O)c(O)c(C(N(C)C)C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
3-Chloro-5-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (618 mg, 2.3 mmol) was mixed with pyridine (276 μL, 3.4 mmol) in acetonitrile (10 mL) at room temperature. Thionyl chloride (249 μL, 3.41 mmol) was added dropwise. After being stirred at room temperature for 30 minutes, the reaction mixture was concentrated by rotary evaporation. The residue was dried under vacuum and then mixed with ethanol (20 mL) under ice-water bath. An ethanolic dimethylamine (5.6 M, 4.06 mL, 22.8 mmol) solution was added at about 5° C. and the mixture was stirred for 20 minutes. The reaction mixture was concentrated by rotary evaporation. The residue was mixed with water (10 mL) and the pH of the solution was adjusted to 5.5. The precipitated solid was collected by suction filtration, and washed with water, then triturated with ether/hexanes to give 3-chloro-6-[1-(dimethylamino)-2,2,2-trifluoroethyl]-5-hydroxy-1,2-dimethylpyridin-4(1H)-one (380 mg) as an off-white solid. Yield=56%; 1H NMR (CDCl3, 90 MHz) δ (ppm): 4.88 (q, J=8.6 Hz, 1H), 4.08 (s, 3H), 2.65-2.81 (m, 3H) and 2.39 (s, 6H); MS m/z 299 [M+1]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:7]=1[Cl:18])(=O)C.[OH-].[K+]>C(O)C>[Cl:18][C:7]1[C:8]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1cccc(C2CCCCC2)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCc1cccc(C2CCCCC2)c1Cl
Reaction time: 6 h
Yield: 78.2 %

Procedure:
26.4 g (99 millimoles) of 2-chloro-3-cyclohexylbenzyl acetate are added dropwise to a mixture of 150 ml of ethanol and 8.4 g (150 millimoles) of potassium hydroxide. After 6 hours at 50° C., the mixture is evaporated down under reduced pressure, water is added to the residue and the mixture is extracted with dichloromethane. After the organic phase has been worked up by a conventional method, it is subjected to fractional distillation under reduced pressure. 17.4 g (78%) of 2-chloro-3-cyclohexylbenzyl alcohol of boiling point 133°-135° C./0.5 mbar and nD20 =1.5593 are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[O:26])=[C:2]([Cl:1])[CH:3]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
67 mL of 2-chloro-1,4-dimethylbenzene and 356 g of Potassium Permanganate were refluxed in 1.5 L of H2O for several hours and monitored for disappearance of starting material by TLC. The Potassium Permanganate was filtered and the reaction mixture was acidified and filtered to yield 2-chloroterephthalic acid. 46.8 g of 2-chloroterephthalic acid was treated with a saturated HCl gas solution in MeOH overnight at room temperature. The reaction mixture was concentrated, subjected to basic workup and dried to yield the dimethyl 2-chloroterephthalate. 20 g of dimethyl 2-chloroterephthalate was cooled to 0° C. in DCM and 87 mL of a 1M in DCM solution of BBr3 was added dropwise over several hours. The reaction mixture was subsequently warmed to room temperature and stirred until complete. Following basic workup, 2-chloro-4-(methoxycarbonyl)benzoic acid was purified by ISCO Combi-Flash. 959 mg of 2-chloro-4-(methoxycarbonyl)benzoic acid was coupled to 750 mg of 4-chloro-3-(pyridin-2-yl)aniline via procedure G. 1 g of methyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was hydrolyzed via Procedure M to give 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to tert-butylamine via Procedure G. The product was purified on reverse phase HPLC to yield N4-tert-butyl-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 443.2 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:13])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:24][O:25][CH2:26][CH2:27]Br>O>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:27][CH2:26][O:25][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:13])[NH:7]2
Reactant: O=C1CCc2c(O)ccc(O)c2N1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1ccc(O)c2c1NC(=O)CC2
Yield: 52.4 %

Procedure:
21.6 g of 5,8-dihydroxy-3,4-dihydrocarbostyril and 19.9 g of potassium carbonate were added to a mixture comprising 480 ml of acetone and 120 ml of water, and the resulting mixture was stirred while refluxing for 30 minutes. 76 g of 2-methoxyethyl bromide was then added thereto followed by stirring while refluxing for 8 hours. The solvent was evaporated, and water was added to the residue. The mixture was extracted with diethyl ether. The aqueous layer was rendered acidic with hydrochloric acid and then extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the chloroform evaporated to obtain 15 g of 5-hydroxy-8-(2-methoxyethoxy)-3,4-dihydrocarbostyril as a black oily substance.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=2[CH3:35])=[C:20]([C:36]([F:37])([F:38])[F:39])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: Cc1cccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)c1C
Agent: Cl
Solvent: CCO
Product: Cc1cccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)c1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Compound 49-4 (670 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (490 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH3:26])[CH:17]=1
Reactant: CC(Oc1cc(F)ccc1CO)c1ccccc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CC(Oc1cc(F)ccc1COc1ccnn1-c1cc(C#N)ccn1)c1ccccc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-(1-phenylethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C24H19FN4O2, 415. Found, 415.
Reaction SMILES: CC([O-])(C)C.[Na+].[CH:7]1([N:12]2[C:16]3[N:17]=[C:18]([NH2:21])[N:19]=[CH:20][C:15]=3[C:14]3[CH:22]=[CH:23][N:24]=[CH:25][C:13]2=3)[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[C:27]1[C:32]([CH3:33])=[CH:31][C:30]([Br:34])=[CH:29][N:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[NH4+].[Cl-]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:34][C:30]1[CH:31]=[C:32]([CH3:33])[C:27]([NH:21][C:18]2[N:19]=[CH:20][C:15]3[C:14]4[CH:22]=[CH:23][N:24]=[CH:25][C:13]=4[N:12]([CH:7]4[CH2:8][CH2:9][CH2:10][CH2:11]4)[C:16]=3[N:17]=2)=[N:28][CH:29]=1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: Cc1cc(Br)cnc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cc(Br)cnc1Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Temperature: 140 °C

Procedure:
Sodium 2-methylpropan-2-olate (0.142 g, 1.48 mmol) was combined with compound 4 (0.125 g, 0.493 mmol) and 2,5-dibromo-3-methylpyridine (0.149 g, 0.592 mmol) in 1,4-dioxane (3 ml). The reaction mixture was degassed by bubbling nitrogen through the solution for ˜1 mM, followed by the addition of XANTPHOS (0.0428 g, 0.0740 mmol) and Pd2(dba)3 (0.0339 g, 0.0370 mmol). The reaction was heated to 140° C. using microwave irradiation for 1 hour. The reaction mixture was poured into sat. NH4Cl and extracted with 10% isopropanol/DCM. The organic layer was dried with MgSO4 and concentrated in vacuum. Purification by flash column chromatography, eluting with a gradient of DCM-5% methanol/DCM provided compound 77 as a yellow solid (150 mg, 71%). LCMS-ESI (POS), M/Z, M+1: Found 423.1
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:36].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][C:45]#[N:46]>CN(C=O)C.C(OCC)(=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:5]4[N:4]([CH2:44][C:45]#[N:46])[C:3](=[O:36])[CH:2]([CH3:1])[O:7][C:6]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.3 %

Procedure:
A solution of tert-butyl 1-(4-(3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.103 mmol) in DMF (2 ml) was added potassium carbonate (42.7 mg) and 2-bromoacetonitrile (22 μl, 0.309 mmol). The reaction mixture was stirred at room temperature for 48 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give crude product which was purified by column (biotage, 25 g) eluted with ethyl acetate and cyclohexane to afford product (45 mg). 1H NMR (500 MHz, CDCl3): 7.35 (s, 1H), 7.20-7.32 (m, 9H), 4.98 (q, 1H), 4.87 (dd, 2H), 2.44-2.49 (m, 4H), 2.06 (m, 1H), 1.80 (m, 1H), 1.75 (d, 3H), 1.24-1.36 (br, 9H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=[O:15])[NH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[Cl:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:17][C:9]1[C:10]2[NH:14][C:13](=[O:15])[N:12]([CH3:16])[C:11]=2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(CC)c1cccc2[nH]c(=O)n(C)c12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(CC)c1ccc(Cl)c2[nH]c(=O)n(C)c12
Temperature: 70 °C
Reaction time: 48 h
Yield: 67.8 %

Procedure:
2,2′-Azobisisobutyronitrile (AIBN) (94 mg, 0.57 mmol) was added to a mixture of 7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (2.90 g, 13.3 mmol) and N-chlorosuccinimide (1.95 g, 14.6 mmol) in carbon tetrachloride (250 mL). The mixture was stirred at 70° C. for 2 days. The reaction was concentrated in vacuo, extracted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give residue. The residue was crystallized from ethanol/iso-propanol to afford the title compound as colorless crystals (2.28 g, 68%). mp 165-166° C.
Reaction SMILES: Cl.[C:2]1([S:8]([N:11]2[C:23]3[CH2:22][N:21]([CH2:24][CH:25]([CH:27]4[CH2:36][CH2:35][C:30]5(OCC[O:31]5)[CH2:29][CH2:28]4)[OH:26])[CH2:20][CH2:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[C:2]1([S:8]([N:11]2[C:23]3[CH2:22][N:21]([CH2:24][CH:25]([CH:27]4[CH2:28][CH2:29][C:30](=[O:31])[CH2:35][CH2:36]4)[OH:26])[CH2:20][CH2:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)(=[O:10])=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)n1c2c(c3ccccc31)CCN(CC(O)C1CCC3(CC1)OCCO3)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCC(C(O)CN2CCc3c(n(S(=O)(=O)c4ccccc4)c4ccccc34)C2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 M hydrochloric acid (30 ml) was added to a solution of the product from stage 4 (748 mg, 1.50 mmol) in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 16 h. The mixture was rendered alkaline with 4 M sodium hydroxide solution and extracted with ethyl acetate (3×35 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18]1([NH:24][C:25]([NH2:27])=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([NH:24][C:25]2[S:26][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=3)[N:27]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Solvent: CCO
Product: CCOC(=O)c1sc(Nc2ccccc2)nc1-c1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (0.60 g, 2.03 mmol) in 20 mL of absolute ethanol was added N-phenylthiourea (0.31 g, 2.03 mmol). The resulting mixture was stirred at 80° C. for 3 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with hexanes/ethyl ether left the title compound as an off-white solid (0.35 g, 49%). MS(NH3—CI) 350 (M+H)+.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C@H:9]2[O:13][C:12](=[O:14])[NH:11][C@@H:10]2[C:15]2[CH:20]=[CH:19]C=[C:17]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[CH:6]=[CH:7][CH:8]=1.BrC1C=C([C@@H]2[C@@H](C3C=CC=CC=3)OC(=O)N2)C=C[N:31]=1.C1(C#C)C=CC=CC=1>>[C:5]1([C@H:9]2[O:13][C:12](=[O:14])[NH:11][C@@H:10]2[C:15]2[CH:20]=[CH:19][N:31]=[C:17]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1N[C@H](c2ccnc(Br)c2)[C@@H](c2ccccc2)O1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Solvent: C#Cc1ccccc1
Product: O=C1N[C@H](c2ccnc(C#Cc3ccccc3)c2)[C@@H](c2ccccc2)O1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with (4R,5R)-4-(2-bromopyridin-4-yl)-5-phenyloxazolidin-2-one and phenylacetylene. 1H-NMR (CDCl3, 500 MHz) δ 8.64 (d, J=4.9, 1H), 7.60 (m, 2H), 7.50 (m, 1H), 7.45 (m, 3H), 7.40 (m, 3H), 7.34 (m, 2H), 7.17 (dd, J=5.2, 1.5, 1H), 6.73 (bs, 1H), 5.25 (d, J=7.3, 1H), 4.82 (d, J=7.3, 1H). 13C-NMR (CDCl3, 126 MHz) δ 158.8, 151.0, 148.1, 144.6, 136.7, 132.2, 129.7, 129.4, 129.3, 128.6, 126.2, 124.4, 121.9, 120.2, 90.5, 88.2, 85.4, 63.7. Mass spec.: 341.2 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([O:25]C)[CH:19]=[C:18]3[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH3:35])[CH:28]=2)([C:9]2[N:10]([CH3:14])[CH:11]=[N:12][CH:13]=2)[OH:8])=[CH:4][CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:8])([C:9]2[N:10]([CH3:14])[CH:11]=[N:12][CH:13]=2)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[C:18]3[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH3:35])[CH:28]=2)=[CH:4][CH:3]=1
Reactant: CCOc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Yield: 73.4 %

Procedure:
Following the same procedure as described in example 1F, (5-chloro-thiophen-2-yl)-[4-(3-ethoxy-phenyl)-2-methoxy-quinolin-6-yl]-(3-methyl-3H-imidazol-4-yl)-methanol (810 mg, 1.60 mmol) was treated with HCl in aqueous THF to yield the title compound (578 mg, 74% yield).