Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH2:2]([Br:4])[CH3:3].[Cl:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:7]=1[NH2:8].[NH2:14][C:15]1[S:16][C:17]([C:20](OCC)=[O:21])=[CH:18][N:19]=1.[Cl-].[NH4+]>O1CCCC1.II>[CH2:2]([Br:4])[CH3:3].[NH2:14][C:15]1[S:16][C:17]([C:20]([NH:8][C:7]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:6]=2[Cl:5])=[O:21])=[CH:18][N:19]=1
Reactant: Cc1cccc(Cl)c1N
Reactant: CCOC(=O)c1cnc(N)s1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Magnesium turnings (12.16 g) were charged into a round bottom flask. Tetrahydrofuran (50 mL) was added to the flask. A solution of ethyl bromide (50.2 g in 200 mL tetrahydrofuran) was prepared and 20 mL of this solution was slowly charged to the round bottom flask. Iodine (30 mg) was added. The reaction mixture was stirred at 20° C. to 22° C. for 10 minutes and the remaining amount of ethyl bromide was added slowly over 30 minutes. The reaction mixture was heated to gentle reflux for 30 minutes and cooled to 0° C. to −10° C. 2-Chloro-6-methylaniline (72.4 g) was added drop-wise at 0° C. and the temperature of the reaction mixture was slowly raised to 20° C. Ethyl 2-amino-1,3-thiazole-5-carboxylate (20 g) dissolved in tetrahydrofuran (200 mL) was slowly added to the reaction mixture over 60 minutes. The reaction mixture was stirred for 3 hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was further stirred for 16 hours and then poured slowly into 25% ammonium chloride solution (200 mL) with stirring. The oily layer was separated, diluted with ethyl acetate (200 mL), and washed with 2 N hydrochloric acid (200 mL). The layers were separated and the pH of the aqueous layer was adjusted to between 8 and 9 with saturated sodium bicarbonate solution (300 ml) and extracted with ethyl acetate (2×100 mL). The oily layer was collected, concentrated, and further purified by column chromatography to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=S.[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[NH2:23])[C:16]([O:18][CH3:19])=[O:17]>>[CH3:19][O:18][C:16]([C:15]1[CH:20]=[CH:21][C:22]2[N:23]=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[NH:12][C:13]=2[CH:14]=1)=[O:17]
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(N)c(N)c1
Product: COC(=O)c1ccc2nc(Nc3ccc(Cl)cc3Cl)[nH]c2c1

Procedure:
2,4-Dichloro-1-isothiocyanatobenzene (5 mmol) and methyl 3,4-diaminobenzoate (5 mmol) were reacted, following general procedure B, to yield 2-(2,4-dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid methyl ester, which was purified by silica gel chromatography using DCM/ethyl acetate as eluent.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][CH:13]([Cl:32])[C:14]([N:16]1[C@H:20]([CH2:21][F:22])[C@@H:19]([C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)[O:18][C:17]1([CH3:31])[CH3:30])=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[Cl:32][CH:13]([Cl:12])[C:14]([N:16]1[C@H:20]([CH2:21][F:22])[C@@H:19]([C:23]2[CH:28]=[CH:27][C:26]([C:6]3[CH:7]=[N:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)=[CH:25][CH:24]=2)[O:18][C:17]1([CH3:30])[CH3:31])=[O:15]
Reactant: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Reactant: OCc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CO)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Temperature: 80 °C
Yield: 41.8 %

Procedure:
A mixture of commercially available (6-(hydroxymethyl)pyridin-3-yl)boronic acid (1.020 g, 5.38 mmol), 2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidin-3-yl)ethanone (2.0 g mg, 4.48 mmol), Cs2CO3 (4.38 g, 13.4 mmol) in dioxane (40 mL) and water (25 mL) is bubbled with nitrogen gas for 2 minutes. To this mixture is added Pd(PPh3)4 (518 mg, 0.44 mmol) and the resulting reaction mixture heated to 80° C. in microwave reactor for 6 hours. The reaction is diluted with water (20 ml) and extracted with ethyl acetate (3×20 mL). The combined organic solution is dried over Na2SO4 and concentrated. The crude product is adsorbed on celite, and purified on silica gel column using 0 to 50% EtOAC/heptane to give the title compound (800 mg): LCMS m/z (Cl): 427 [M+H].
Reaction SMILES: [BH4-].[Li+].[CH3:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]=1/[CH:12]=[CH:13]/[C:14](/[CH3:23])=[CH:15]/[CH:16]=[CH:17]/[C:18](/[CH3:22])=[CH:19]/[CH:20]=O.Cl>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]=1/[CH:12]=[CH:13]/[C:14](/[CH3:23])=[CH:15]/[CH:16]=[CH:17]/[C:18](/[CH3:22])=[CH:19]/[CH:20]=[CH:20]/[CH:19]=[C:18](\[CH3:22])/[CH:17]=[CH:16]/[CH:15]=[C:14](\[CH3:23])/[CH:13]=[CH:12]/[C:5]1[C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][CH2:9][C:4]=1[CH3:3]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Reaction time: 2 h
Yield: 59.6 %

Procedure:
A solution was prepared by dissolving titanium tetrachloride (1.10 ml, 10.0 mmol) in 25 ml dry tetrahydrofuran under an inert atmosphere. Lithium Borohydride (110 mg, 5.0 mmol) was added, and the resulting solution was stirred at 50° for two hours. A solution of retinal (1.42 gm, 5.0 mmol) 5 ml dry tetrahydrofuran was added, and the reaction was refluxed for four hours. After this, the solution was poured into 50 ml 2 N aqueous hydrochloric acid, and was extracted several times with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated by solvent removal at the rotary evaporator. The residue was further purified by chromatography on silica gel. Elution with hexane gave 0.8 gm (60%) beta-carotene, identified by comparison with an authentic sample; mp 180°-182°.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16](Br)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][C:20](=[O:26])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)(=O)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>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:16]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][C:20](=[O:26])[CH:19]=[CH:18]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc2[nH]c(=O)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 100 °C

Procedure:
The mixture of (S)-2-(5-bromo-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethyl pivalate (34 mg, 0.078 mmol), Pd(PPh3)4 (9 mg), 4-chlorophenylboronic acid (16 mg, 0.1 mmol), aqueous K2CO3 solution (0.15 mL, 2 M, 0.3 mmol) in 1,2-dimethoxyethane (2 mL) was heated at 100° C. for 90 minutes. The residue was diluted with ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4. Concentration and purification gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): 470.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:25])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:26]#[C:27]Br>C(O)C>[NH2:26][C:27]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([Cl:25])[C:2]=2[N:1]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)c(Cl)nc2ccccc12
Reactant: N#CBr
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCn1c(N)nc2c(Cl)nc3ccccc3c21
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl 4-[(3-amino-2-chloroquinolin-4-yl)amino]butylcarbamate (Nanba et al, U.S. Pat. No. 6,069,149, Example 14, 9.5 g, 26 mmol) in ethanol (100 mL) was heated to 110° C.; cyanogen bromide (2.98 g, 28.6 mmol) was added. The reaction was stirred for three hours at 110° C., and an analysis by LC/MS indicated the presence of starting material. Additional cyanogen bromide (0.55 equivalent) was added, and the reaction was stirred for three days at 110° C. and allowed to cool to room temperature. Most of the solvent was removed under reduced pressure, and 2 N aqueous sodium hydroxide (500 mL) was added. The mixture was stirred for 30 minutes, and ethyl acetate (400 mL) was added. A precipitate formed and was isolated by filtration to provide 7.188 g of tert-butyl 4-(2-amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)butylcarbamate as a cream-colored solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].C>C1COCC1.O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2nc3ccc(C(=O)O)cc3[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc3ccc(C(=O)O)cc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-methoxycarbonyl-phenyl)-3H-benzoimidazole-5-carboxylic acid (4.1 g) in THF (15 mL) and water (18 mL) and LiOH (1.74 g) was stirred for 16 hours at room temperature and then mixed with hot water (100 mL) and charcoal. The mixture was filtered and the filtrate was diluted with ice and water (100 mL) and acidified with conc. HCl. The crude diacid was filtered, washed with water and ether and then recrystallized from THF and MeOH. Yield 3.3 g; TLC single spot [CH2Cl2—CH3OH (9:1)].
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[N:11][S:12][C:13]=1[NH:14][C@H:15]([C:20]([OH:22])=O)[CH2:16][CH:17]([CH3:19])[CH3:18].Cl.[NH2:24][CH2:25][C:26]#[N:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O.O>[Br:8][C:9]1[CH:10]=[N:11][S:12][C:13]=1[NH:14][C@H:15]([C:20]([NH:27][CH2:26][C:25]#[N:24])=[O:22])[CH2:16][CH:17]([CH3:18])[CH3:19]
Reactant: N#CCN
Reactant: CC(C)C[C@H](Nc1sncc1Br)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C[C@H](Nc1sncc1Br)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Triethylamine (0.16 mL, 1.1 mmol) was added dropwise to a solution of N-(4-bromoisothiazol-5-yl)leucine (92 mg, 0.31 mmol), aminoacetonitrile hydrochloride (58 mg, 0.63 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (180 mg, 0.35 mmol) in N, N-dimethylformamide (1.0 mL) at 0° C. After stirring at rt for 3 h, the reaction vessel contents were poured into water and extracted with a 1:1 mixture of ether and ethyl acetate (3×). The combined extracts were washed with saturated sodium bicarbonate solution, then with saturated sodium chloride solution, and dried (Na2SO4). Concentration under reduced pressure and flash chromatography of the residue on silica gel eluting with a mixture of ethyl acetate and hexanes (2:3) afforded 91 mg of N2-(4-bromoisothiazol-5-yl)-N1-(cyanomethyl)leucinamide as a colorless foam.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])[C:4](=[O:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][OH:44])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>C(OCC)(=O)C.O.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].CO>[OH:44][CH2:43][CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[O:12])[C:4](=[O:26])[CH:3]=2)=[CH:36][CH:37]=1
Reactant: CC1(C)OB(c2ccc(CCCO)cc2)OC1(C)C
Reactant: CC(CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(CCn1ccc(-c2ccc(CCCO)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C
Yield: 65.6 %

Procedure:
4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be prepared as in Preparation 2A (320 mg, 0.640 mmol), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-1-ol (202 mg, 0.770 mmol) (See Takashima, H. et. al. WO 2008105515), potassium carbonate (448 mg, 3.20 mmol), and tris(dibenzylideneacetone)dipalladium(0) (56.8 mg, 0.064 mmol) were combined into a flask, placed under vacuum and opened to nitrogen. Degassed dimethoxyethane (2.0 mL) and methanol (2.0 mL) were added and the reaction was heated at 80° C. under nitrogen for 16 hours. The reaction was cooled and then diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered and evaporated in vacuo onto silica gel. Chromatography on silica gel with a dichloromethane-methanol gradient (1%-25%) gave 4-{4-[4-(3-hydroxypropyl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a white foam (213.3 mg, 65.6%). LCMS 507.5 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC(S(O)(=O)=[O:21])=CC=1.O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:21][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 95.9 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 46.2 g (0.24 mol) of p-chlorobenzenesulfonic acid (produced by Tokyo Chemical Industry Co., Ltd.), 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.8 g of 1-benzyl-3,4-epoxypyrrolidine (yield 95.9%) was obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:27]=[C:26](/[CH:28]=[CH:29]/[CH:30]([C:35]2[CH:40]=[C:39]([Cl:41])[C:38]([Cl:42])=[C:37]([Cl:43])[CH:36]=2)[C:31]([F:34])([F:33])[F:32])[CH:25]=[CH:24][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)=[O:12]>C(Cl)Cl>[NH2:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[C:10]1[CH:24]=[CH:25][C:26](/[CH:28]=[CH:29]/[CH:30]([C:35]2[CH:40]=[C:39]([Cl:41])[C:38]([Cl:42])=[C:37]([Cl:43])[CH:36]=2)[C:31]([F:34])([F:32])[F:33])=[CH:27][C:9]=1[Br:8]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.4 %

Procedure:
TFA (0.5 mL) was added to a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)ethylcarbamate (200 mg, 0.31 mmol) in CH2Cl2 (10 mL) at 0° C. and the reaction mixture was then stirred at ambient temperature for 18 h. The volatiles were evaporated under reduced pressure; water was added to the residue and the mixture extracted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 1-5% MeOH in CH2Cl2 to afford the title compound as a brown solid (50 mg, 31%): 1H NMR (400 MHz, DMSO-d6) δ 8.56 (bs, 1H), 7.70 (bs, 2H), 7.94-7.91 (m, 3H), 7.62-7.59 (m, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.00 (dd, J=15.6, 9.2 Hz, 1H), 6.77 (d, J=15.6 Hz, 1H), 4.84-4.81 (m, 1H), 3.46-3.41 (m, 2H), 2.95-2.92 (m, 2H); ESIMS m/z 528.72 ([M+H]+); IR (thin film) 3435, 1671, 1113, 722, 555 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=2[CH2:18][C:19]([OH:21])=O)=[CH:4][CH:3]=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:8][C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=3[CH2:18][C:19](=[O:21])[C:6]=2[CH:7]=1
Reactant: O=C(O)Cc1ccc(C(=O)O)cc1Sc1ccc(F)cc1
Solvent: O
Product: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C(=O)C2
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
Heat to 120° C. with stirring 450 gm of commercial polyphosphoric acid and add 35.9 gm of crude diacid from Step A. Stir under a nitrogen atmosphere at 120° C. for 90 minutes. Cool and slowly add 1.5 liters of ice and water. Separate the solids by filtration. Stir the residue in 500 ml of refluxing ethyl acetate for 90 minutes and filter while hot to obtain a first crop. Concentrate the filtrate until solids appear, allow to stand overnight and filter to obtain a second crop. Combine the crops (18.26 gm-54% crude) which may be used in the next step as such. Purify by boiling in ethyl acetate for 15 minutes, hold at room temperature overnight and filter (m.p. 289°-291° C.)
Reaction SMILES: N1CCC(CC2NC3=NC=CC=C3C=2)C1.C(OC(N1CCCC(C2C3C(=NC=CC=3)NC=2)C1)=O)(C)(C)C.CCOCC.[CH3:43][N:44]1[CH2:49][CH2:48][CH2:47][CH:46]([C:50]2[NH:58][C:53]3=[N:54][CH:55]=[CH:56][CH:57]=[C:52]3[CH:51]=2)[CH2:45]1>CO.C(N(CC)CC)C>[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([CH2:46][C:50]2[NH:58][C:53]3=[N:54][CH:55]=[CH:56][CH:57]=[C:52]3[CH:51]=2)[CH2:45]1
Reactant: CN1CCCC(c2cc3cccnc3[nH]2)C1
Agent: CC(C)(C)OC(=O)N1CCCC(c2c[nH]c3ncccc23)C1
Agent: c1cnc2[nH]c(CC3CCNC3)cc2c1
Solvent: CCOCC
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCC(Cc2cc3cccnc3[nH]2)C1

Procedure:
Compound 66 (0.3 g, 1.49 mmol) was converted to compound 67, using the methodology described for compound 9. Yield 0.362 g (80.7%). (TLC ether Rf 0.11), which was used as such to generate the title compound (68) using the methodology as described for compound 28. (Yield 0.17 g, 65%), mp 96-97° C. 1H-NMR (400 MHz, CDCl3): δ N1—H invisible, 8.16 (dd, J=5 Hz, 2 Hz, 1H), 7.77 (dd, J=8 Hz, 2 Hz, 1H), 6.98 (dd, J=8 Hz, 5 Hz, 1H), 6.16 (bs, 1H), 2.92-2.84 (m, 2H), 2.76-2.64 (m, 2H), 2.62-2.50 (m, 2H), 2.34 (s, 3H), 2.40-2.31 (m, 1H), 2.11-2.01 (m, 1H), 1.63-1.53 (m, 1H). (TLC MeOH/triethylamine (97/3) Rf 0.2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH:5]=[C:6]1[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]1=[O:15].[CH:19]1([Mg]Br)[CH2:21][CH2:20]1.Cl.O>C1COCC1>[CH:19]1([CH:5]([C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([OH:1])[CH:3]=2)[CH:6]2[C:7](=[O:15])[O:8][C:9]([CH3:14])([CH3:13])[O:10][C:11]2=[O:12])[CH2:21][CH2:20]1
Reactant: Br[Mg]C1CC1
Reactant: CC1(C)OC(=O)C(=Cc2cccc(O)c2)C(=O)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(=O)C(C(c2cccc(O)c2)C2CC2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-(3-hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (65.0 g) in THF (1.30 L) was added dropwise a 10% solution of cyclopropylmagnesium bromide in THF (2.20 kg) at −11° C. to −1° C. over 1.6 hr, and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid was added to the reaction mixture at 2° C. to 17° C. to adjust the solution to pH 3. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (76.0 g) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])#[N:2].C([Sn](=O)CCCC)CCC.C[Si]([N:24]=[N+:25]=[N-:26])(C)C>C1(C)C=CC=CC=1>[NH2:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:1]1[NH:26][N:25]=[N:24][N:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccccc1N
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Nc1ccccc1-c1nnn[nH]1
Temperature: 25 °C
Yield: 17.6 %

Procedure:
To 2-cyanoaniline (5.00 g, 42.3 mmol) and dibutyltin oxide (520 mg, 2.1 mmol) dissolved in toluene (40 mL) was added trimethylsilyl azide (6.40 mL, 47 mmol). The reaction mixture was heated at ~95° C. for 70 hours, cooled to ambient temperature, concentrated under reduced pressure and partitioned between water (50 mL) and saturated sodium carbonate solution (50 mL). The organic phase was extracted with another aliquot (25 mL) of saturated sodium carbonate solution. The combined aqueous extracts were washed with ether (2×25 mL), acidified with solid citric acid to pH 4-5, and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, decolorized with Norite, filtered and concentrated under reduced pressure to give the title compound as a solid (1.20 g). 1H NMR (DMSO-d6, 300 MHz) δ3.4 (br s, 1H), 6.68 (dt, J=1 Hz, 8 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 7.25 (d,t J=1 Hz, 8 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 9.0-11.0 (br, 2H). MS (DCl/NH3) m/e 162 (M+H)+, 179 (M+H+NH3)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:37][CH3:38])=[C:7]([C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[C:12]3[CH:17]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=4[CH3:36])[N:18]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[C:19](=[O:20])[C:11]=3[N:10]=2)[CH:8]=1.[C:39](Cl)(=[O:41])[CH3:40]>C1COCC1>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([CH3:28])=[C:21]([N:18]2[C:19](=[O:20])[C:11]3[N:10]=[C:9]([C:7]4[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=4[O:37][CH3:38])[CH2:2][NH:1][C:39](=[O:41])[CH3:40])[N:13]([CH:14]([CH3:15])[CH3:16])[C:12]=3[CH:17]2[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[CH3:36])[CH:26]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(CN)cc1-c1nc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)ccc1C)C2=O
Solvent: C1CCOC1
Product: COc1ccc(CNC(C)=O)cc1-c1nc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)ccc1C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from example 16 (30 mg, 0.05 mmol) was dissolved in THF (0.7 mL) and TEA (10 mL, 0.07 mmol) was added. The reaction was cooled in an ice bath and acetyl chloride (5 mL, 0.06 mmol) was added. The cooling bath was removed and the reaction mixture allowed to stir at rt for 0.5 h. It was then diluted with EtOAc and brine and the aqueous phase extracted with EtOAc. The combined extracts were dried (Na2SO4) and concentrated. The remaining crude product was triturated with acetonitrile to give the title compound as a white solid, which was isolated by filtration and dried under reduced pressure. tR: 1.18/1.21 min (LC-MS 2); ESI-MS: 591.2/593.2 [M+H]+ (LC-MS 2).