Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([OH:12])[CH:4]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O.O>[CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:12][C:13](=[O:15])[CH3:14])[CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1ccc(C(=O)O)c(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CSc1ccc(C(=O)O)c(OC(C)=O)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a mixture of 4-methylthio-2-hydroxybenzoic acid (50.0 g, 272 mmol) and acetic anhydride (77.0 mL, 815 mmol) was added 36 N sulfuric acid (0.45 mL, 8.16 mmol) and the mixture was heated to 75° C. for 1 h. To the reaction mixture was added H2O (200 mL), and it was stirred for 18 h. A white precipitate was collected, triturated with dichloromethane, (100 mL), diluted with 20% Et2O/hexanes (300 mL), and filtered to give the title compound as a white solid (49 g, 80%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[Br-].[CH3:19][O:20][N:21]1[CH2:25][CH2:24][CH:23]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:22]1=[O:45].C(N(CC)CC)C>C(O)C>[CH3:19][O:20][N:21]1[CH2:25][CH2:24][C:23](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:12]([OH:13])=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[CH:10]=2)[C:22]1=[O:45]
Reactant: CON1CCC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 67.9 %

Procedure:
27.6 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 54.0 g of (N-methoxy-2-pyrrolidone-3-yl)triphenylphosphonium bromide and 33.0 ml of triethylamine were heated at 50° C. in ethanol for four hours. After distilling the ethanol off, the residue was dissolved in chloroform, washed with water and then a saturated saline solution and dried over anhydrous magnesium sulfate. After distilling the chloroform off, the residue was treated with the column chromatography, using silica gel and a carrier liquid of benzene and acetone and recrystallized with a mixture of ethyl acetate and hexane to give 26.5 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Br:8][C:4]1[N:3]=[C:2]([C:18]2[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cccc(-c2cccc(Br)n2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 19.3 %

Procedure:
Part A. A solution of 2,6-dibromopyridine (6.16 g, 26 mmol) and 3-carboethoxybenzeneboronic acid (0.5 g, 2.6 mmol) in acetonitrile (20 mL) is treated with a solution of sodium carbonate (0.88 g) in water (5 mL). The mixture is degassed twice, and a catalytic amount of tetrakis(triphenylphosphine)palladium is added. The reaction mixture is heated to 80° C. and stirred for 12 h., then cooled, filtered and evaporated. The residue is partitioned between water and ethyl acetate, and the organic phase is washed with satd. aq. brine, dried over sodium sulfate, filtered and evaporated. The residual material is separated by column chromatography to give ethyl 3-(6-bromo-pyridin-2-yl)-benzoate (154 mg, 20%).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)=[CH:6][N:7]=1)[CH3:2].[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C1(C)C=CC=CC=1>[CH2:24]([NH:26][C:27]([NH:17][C:15]1[N:16]=[C:12]2[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=[C:8]([C:5]3[S:4][C:3]([CH2:1][CH3:2])=[N:7][CH:6]=3)[N:13]2[N:14]=1)=[O:28])[CH3:25]
Reactant: CCN=C=O
Reactant: CCc1ncc(-c2cc(-c3cccnc3)cc3nc(N)nn23)s1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cnc(CC)s3)n2n1
Temperature: 125 °C

Procedure:
A suspension of the product of Step 1 (75 mg, 0.23 mmol), ethylisocyanate (92 μL, 1.17 mmol), and dibutyltin diacetate (2 drops) in dry toluene (5 mL) was heated at 125° C. in a microwave reactor for 1 h. After being cooled to room temperature, the precipitated solid was filtered, and washed with chloroform to give 1-ethyl-3-[5-(2-ethyl-thiazol-5-yl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea as solid. MS m/z 394 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH2:10](Cl)Cl>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1
Reactant: COc1cncc(Br)c1
Reactant: ClCCl
Product: CCOc1cncc(Br)c1
Reaction time: 8 h

Procedure:
As shown in step 2-iii of Scheme 2,3-chloroperoxybenzoic acid (9.426 g, 42.06 mmol) was added to 3-bromo-5-methoxypyridine (4.25 g, 21 mmol) in 200 mL of DCM at RT. The reaction was stirred overnight and the mixture was washed with 200 mL of 2 N NaOH and 2×200 mL brine. The organic phase was dried over MgSO4, filtered and the volatiles removed under reduced pressure to provide 3-bromo-5-ethoxypyridine, 1-oxide (Compound 2002, 4.4 g): 1H NMR (CDCl3): δ 8.05 (s, 1H), 7.9 (s, 1H), 7.0 (s, 1H), 4.12 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][C:4]2([C:9]([O:11][CH3:12])=[O:10])[CH2:3][NH:2]1.CCN(C(C)C)C(C)C.[Br:22][C:23]1[CH:24]=[N:25][C:26](Cl)=[N:27][CH:28]=1>CCO>[Br:22][C:23]1[CH:24]=[N:25][C:26]([N:2]2[CH2:3][C:4]3([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH:5]3[CH2:1]2)=[N:27][CH:28]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COC(=O)C12CCCC1CNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)C12CCCC1CN(c1ncc(Br)cn1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
To the solution of methyl octahydrocyclopenta[c]pyrrole-3a-carboxylate (1.0 g, 5.91 mmol) in EtOH (10.0 mL) was added DIPEA (2.80 mL, 16.12 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (1.10 g, 5.37 mmol). The reaction was heated up to 70° C. for 2 h. After completion (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 7.0% EtOAc:hexane to obtain the desired product as a white solid (0.80 g, 45%). MS: 326.19 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[C:4]([F:11])[C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[C:4]([F:11])=[CH:5][C:6]2[S:7][CH:8]=[CH:9][C:10]=2[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(F)cc2sccc2c1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc2sccc2c(F)c1CBr

Procedure:
To a solution of 0.48 g of 4,6-difluoro-5-methylbenzo[b]thiophene in 5 ml of carbon tetrachloride are added 0.92 g of N-bromosuccinimide and 0.01 g of 2,2'-azobisisobutylonitrile, and the resulting mixture is refluxed for 16 hours. After cooling, insolubles are removed from the thus cooled mixture by filtration, and the filtrate obtained is concentrated under reduced pressure. The residue obtained is purified by a column chromatography [eluent:hexane], to obtain 0.18 g of colorless, solid 5-bromomethyl-4,6-difluorobenzo[b]thiophene.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:29][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][CH:13]([CH2:12][NH:31][CH3:30])[O:14][C:15]=2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(F)c(-c4ccccc4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2ccc(F)c(-c3ccccc3C)c2O1

Procedure:
The title compound was prepared (0.053 g, 72%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.1 g, 0.24 mmol) and methylamine (0.31 g, 10.0 mmol). mp 200-202° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1
Reactant: COc1ccccc1B(O)O
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Agent: O=Cc1cccc(B(O)O)c1
Product: COc1ccccc1C1=NCC(=O)N(C)c2ccc(-c3ccccc3)cc21
Yield: 58 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 2-methoxyphenyl boronic acid. The title compound (87 mg) was obtained as a beige solid, (yield=58%).
Reaction SMILES: [NH3:1].CO.Cl[C:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([CH3:12])[N:6]=1.C1(C)C=CC=CC=1>>[Cl:11][C:9]1[N:8]=[C:7]([CH3:12])[N:6]=[C:5]([NH2:1])[N:10]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: N
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc(Cl)n1
Reaction time: 2.5 h
Yield: 73 %

Procedure:
A solution of ammonia, 2.0M methyl alcohol (Aldrich, St. Louis, Mo.) (36.0 mL, 72 mmol) was added dropwise at room temperature (slightly exothermic) to a stirred yellow suspension of 2,4-dichloro-6-methyl-1,3,5-triazine (from Example 7) (2.94 g, 18 mmol) in toluene (20.0 mL, 188 mmol) over 1.5 h. The resulting mixture was stirred for an additional 2.5 h, concentrated and purified (ISCO, DCM to 10% MeOH in DCM) to give the desired product 4-chloro-6-methyl-1,3,5-triazin-2-amine (1.88 g, 73%) as a yellow solid. MS (API-ES) m/z 145 (M+H)+; 1H NMR (CD3OD, 300 MHz) δ 2.32 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[C:13]1([CH:19](O)[CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CCCCC(O)c1ccccc1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCCC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
To a flame-dried flask containing a mixture of 811 mg of 4-hydroxycoumarin and 985 mg of 1-phenyl-1-pentanol in 30 mL of dioxane under an argon atmosphere is added 3.0 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether, acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 40% to 50% ethyl acetate in hexane to yield 193 mg of the title product as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[Li+].[OH-].[ClH:21].[Cl:22][CH2:23][C:24]1[C:25]([NH:37][CH3:38])=[N:26][C:27]2[CH:28]=[C:29]3[O:36][CH2:35][O:34][C:30]3=[CH:31][C:32]=2[CH:33]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:22].[ClH:21].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:23][C:24]1[C:25]([NH:37][CH3:38])=[N:26][C:27]2[CH:28]=[C:29]3[O:36][CH2:35][O:34][C:30]3=[CH:31][C:32]=2[CH:33]=1
Reactant: CNc1nc2cc3c(cc2cc1CCl)OCO3
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2cc3cc4c(cc3nc2NC)OCO4)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (245 mg, 0.99 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. LiOH solution (1.00 mL, 2.00 mmol) at RT followed by 7-(chloromethyl)-N-methyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride CCH 34158B (284 mg, 0.99 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) gave, after evaporation, 6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-1-propylisoquinolin-3-ol. This free base was dissolved in MeOH (3 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.19 M HCl solution in MeOH (2 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 62 as a beige solid (46 mg, 9% yield).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]=O)[N:4]([CH3:9])[N:3]=1.[Cl-].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]2[N:19]=[C:20]([CH2:22][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=[C:14]2[N:13]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5]([CH:7]=[CH:22][C:20]2[N:21]=[C:14]3[N:13]=[C:12]([CH3:11])[CH:17]=[C:16]([CH3:18])[N:15]3[N:19]=2)[N:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2n1
Reactant: Cn1nc(Br)nc1C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(C)n2nc(C=Cc3nc(Br)nn3C)nc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A mixture of 3-bromo-1-methyl-1H-1,2,4-triazole-5-carbaldehyde (193 mg, 1.02 mmol, Eq: 1.00), ((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (466 mg, 1.02 mmol, Eq: 1.00) and DBU (387 mg, 383 μl, 2.54 mmol, Eq: 2.5) in tetrahydrofuran (12 ml) was stirred for 18 hours at 25° C. under argon atmosphere. Chromatography afforded) 2-[2-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (161 mg/47.4%) as a white solid. MS: m/z=334336 (M+H+), mp: 277.4° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[CH3:10][C:11]1([CH3:18])[C:15]([CH3:17])([CH3:16])[O:14][BH:13][O:12]1.C(N(CC)CC)C>O1CCCC1.[H-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])/[CH:5]=[CH:6]/[B:13]1[O:14][C:15]([CH3:17])([CH3:16])[C:11]([CH3:18])([CH3:10])[O:12]1)[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: C#CC(OCC)OCC
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Temperature: 50 °C
Yield: 43.1 %

Procedure:
A mixture of 3,3-diethoxy-1-propyne (18.5 g, 0.144 mol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.6 g, 0.216 mol) and bis(cyclopentadienyl)zirconium chloride hydride (1.9 g, 0.007 mol) in tetrahydrofuran (75 mL) was heated at 50° C. for 2 days. Triethylamine (2 mL) was added and the solvent was removed in vacuo. The residue was distilled at 90° C. at 10 torr. The residue was purified by column chromatography on neutral alumina using 89:10:1 dichloromethane: ethyl acetate: triethylamine as an eluent. The solvent was removed in vacuo to give the title compound (15.9 g, 53%) as a brown oil. 1H NMR (DMSO-d6, 400 MHz) δ 6.48 (dd, 1H), 5.75 (d, 1H), 4.85 (d, 1H), 3.55-3.67 (m, 2H), 3.40-3.52 (m, 2H), 1.22 (s, 12H), 1.17 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52]([O:54]C(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:59][O:60][C:61]([NH:63][C@H:64]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)C(O)=O)=[O:62].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>Cl.CCO>[CH3:59][O:60][C:61]([NH:63][C@H:64]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:52]([N:45]1[CH2:46][C@@H:47]([CH2:49][O:50][CH3:51])[CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:34]2[CH:35]=[C:36]3[CH2:37][O:38][C:25]4[CH:24]=[C:23]5[C:28]([CH:29]=[CH:30][C:20]6[N:19]=[C:18]([C@@H:13]7[CH2:14][CH2:15][C@H:16]([CH3:17])[N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])[NH:22][C:21]=65)=[CH:27][C:26]=4[C:31]3=[CH:32][CH:33]=2)=[CH:40][N:41]=1)=[O:54])=[O:62]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@H](NC(=O)OC)c2ccccc2)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A solution of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (150 mg, 0.19 mmol) in 1.25 N HCl in EtOH (3 mL) was stirred overnight then heated to 50° C. for 3 h. The reaction was concentrated and the crude material dissolved in DMF (2 mL). To this solution was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (52 mg, 0.25 mmol) and COMU (90 mg, 0.21 mmol). To the resulting solution was added diisopropylethylamine (0.099 mL, 0.57 mmol). After stirring for 2 h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (65 mg, 39%). LCMS-ESI+: calculated for C49H54N8O8: 882.4; observed [M+1]+: 884.1. Diagnostic peaks in NMR ′H NMR (CD3OD): 8.28 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.91-7.01 (m, 10H), 3.62 (s, 3H), 3.34 (s, 3H), 3.23 (s, 3H), 1.56 (d, 3H), 1.03 (d, 3H), 0.94 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:14][CH:13](OS(C)(=O)=O)[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CN(C)C=O>[C:20]([S:22][CH:13]1[CH2:12][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:14]1)(=[O:23])[CH3:21]
Reactant: CC([O-])=S
Reactant: CCOC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CC(SC(C)=O)C2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 71.3 %

Procedure:
To a solution of 1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (742 mg, 2.42 mmol) (obtained as described in Reference Example 1(3)) in dimethylformamide (37 ml) was added potassium thioacetate (1.11 g, 9.72 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1) as the eluant to afford 3-acetylthio-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (494 mg, yield 71%) as a pale brown solid.
Reaction SMILES: CN1CCOCC1.Cl.[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13].C1C=CC2N(O)N=NC=2C=1.[C:26]([NH:33][C@@H:34]([C:39](O)=[O:40])[CH2:35][CH2:36][S:37][CH3:38])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[NH:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:34]([C:39]([NH:13][C@H:12]([C:11]([O:10][CH3:9])=[O:15])[CH3:14])=[O:40])[CH2:35][CH2:36][S:37][CH3:38]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
N-methylmorpholine (5.6 g), L-alanine methyl ester hydrochloride (3.9 g), HOBt (4.6 g) and 1-(3-dimethlylaminopropyl)-3-ethylcarbodiimide (5.3 g) was added to a solution of Boc-(D)-Methionine (7 g, 0.028 mol) in dry DMF (50 ml). The mixture was stirred overnight. Solvent was removed by evaporation and the residue was partitioned between dichloromethane (100 ml) and 5% aqueous acetic acid (5 ml). On standing HOBt crystallised and was removed by filtration, and the organic layer was separated and washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated. The residue (8.5 g) was purified by flash chromatography in a sinter funnel eluting with a mixture of dichloromethane and ether (0% to 100% ether). The fractions containing product were combined and evaporated to give Boc-(D)-Met-(L)-Ala-OMe (7.2 g) as a gum which crystallised on standing; NMR (CDCl3): 1.4 (d, 3H), 1.45 (s, 9H), 1.95 (m, 1H), 2.1 (s, 3H), 2.1 (m, 1H), 2.6 (m, 2H), 3.75 (s, 3H), 4.3 (bs, 1H), 4.6 (m, 1H), 5.3 (m, 1H), 6.9 (bs, 1H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:17]1[NH:22][C:21](=[O:23])[C:20]([C:24]#[N:25])=[CH:19][C:18]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>>[CH2:1]([O:23][C:21]1[C:20]([C:24]#[N:25])=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[C:17]([C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[Cl:9])[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccccc1

Procedure:
In the following Examples 20-24, the procedure described in Example 19, Step C was repeated but substituting the appropriately substituted benzyl halide for benzyl bromide in the reaction with 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-nitrile to afford the following compounds:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]OS(C)(=O)=O)=[CH:5][CH:4]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:17]=[N+:18]=[N-:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1ccc(CCCN=[N+]=[N-])cc1
Yield: 75 %

Procedure:
Azide 12 was prepared according to procedure C from 11 (8.8 g, 0.036 mol) and sodium azide (3 g, 0.045 mol) in 75% yield. 1H NMR (300 MHz, CDCl3) δ 1.90 (m, 2H), 2.65 (t, 2H), 3.28 (m, 2H), 3.80 (s, 3H), 6.85 (d, 2H), 7.10 (d, 2H).