Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH3:9])[OH:8])[OH:6])[OH:4].[C:10](OC(=O)C)(=O)C.C(O[C@@H]1O[C@H](C)[C@@H](OC(=O)C)[C@H]1OC(=O)C)(=O)C.[Cl:35][C:36]1[NH:37][C:38]2[CH:44]=[C:43]([Cl:45])[C:42]([Cl:46])=[CH:41][C:39]=2[N:40]=1.C(O[C@@H]1O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H]1OC(=O)C)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>>[CH3:10][CH2:9][C@H:7]1[O:8][C@@H:2]([N:40]2[C:36]([Cl:35])=[N:37][C:38]3[C:39]2=[CH:41][C:42]([Cl:46])=[C:43]([Cl:45])[CH:44]=3)[C@H:3]([OH:4])[C@@H:5]1[OH:6]
Reactant: C[C@@H](O)[C@@H](O)[C@@H](O)C=O
Reactant: CC(=O)OC(C)=O
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: CC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O

Procedure:
Treatment of 205 with dilute acid liberated 5-deoxy-D-ribose which was immediately acetylated in the presence of acetic anhydride, giving an anomeric mixture of 5-deoxy-1,2,3-tri-O-acetyl-β-D-ribofuranose (206). The 5-deoxy-1,2,3-tri-O-acetyl sugar was used as an anomeric mixture for ribosylation of 2,5,6-trichlorobenzimidazole in a manner similar to its 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose counterpart. Thus, silylation of the chlorinated heterocycle (207) was followed by the addition of TMSOTf and 5-deoxy-1,2,3-tri-O-acetyl-β-D-ribofuranose (206) to afford a mixture of the α and β anomers of 2,5,6-trichloro-1-(5'-deoxy-2,3-di-O-acetyl-D-ribofuranosyl)benzimidazole. Separation of these anomers was achieved by chromatography, and deprotection of the β anomer gave the 5'-deoxy TCRB (210).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1)=[O:2].[CH2:13]([O:15][C:16](=[O:19])[CH2:17]Cl)[CH3:14].CC[O-].[Na+].O>C1C=CC=CC=1.C(O)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[O:2][CH:17]2[C:16]([O:15][CH2:13][CH3:14])=[O:19])=[CH:4][C:5]=1[O:11][CH3:12])#[N:8]
Reactant: COc1cc(C=O)ccc1C#N
Reactant: CCOC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1OC1c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-formyl-2-methoxybenzonitrile (383 mg, 2.38 mmol) and chloroacetic acid ethyl ester (291 mg, 2.38 mmol) were dissolved in 10 mL of dry benzene. Freshly prepared EtONa (3.09 mmol) in 2.5 mL of ethanol was added, and the mixture were stirred at room temperature for 2 hours. The mixture was added water, then extracted with EtOAc. The organic layers were dried over Na2SO4 and concentrated to afford ethyl 3-(4-cyano-3-methoxyphenyl)oxirane-2-carboxylate. MS m/z: 248 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6](O)[C:7](=[CH2:14])[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2].S(Br)([Br:22])=O.O>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6]=[C:7]([CH2:14][Br:22])[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCOC(C)=O)C(O)C(NC=O)C(=O)OCC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C=C(CBr)CCOC(C)=O)NC=O
Reaction time: 1 h

Procedure:
9.19 g (35.9 mmol) of 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 100 ml of dichloromethane, and 3.34 ml (43.1 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 10 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, saturated potassium hydrogen carbonate solution and again with water, dried over magnesium sulfate, filtered and concentrated by evaporation. 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brownish oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH2:6].[C:12]([O-:15])(O)=O.[Na+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1.[CH:28]([NH:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])([CH3:30])[CH3:29]>C1COCC1.CCOC(C)=O>[CH:28]([N:31]([CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[C:12]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:15])([CH3:30])[CH3:29]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: C=CCCCNC(C)C
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCCN(C(=O)N[C@H](C(=O)OC)C(C)(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
To a solution (60 nM) of L-tert-leucine methyl-ester hydrochloride and NaHCO3 (8 eq) in dry THF, a solution 20% w/w of phosgene in toluene (5 eq) was added dropwise at 0° C. and the reaction mixture was stirred at that temperature for 30 minutes. Then the solid was filtered-off and the filtrate evaporated at reduced pressure. The resulting crude yellow oil was taken-up in dry THF (0.3 M) and added dropwise to a stirred solution (0.2 M) of N-isopropylpent-4-en-1-amine and THF (1 eq). The reaction mixture was stirred at room temperature overnight. Then the mixture was taken-up in EtOAc and washed twice with water and brine. The organic phase was dried over Na2SO4 and the volatiles evaporated at reduced pressure. The crude was purified by flash chromatography eluting with petroleum ether (8) EtOAc (2) using Nynhydrin as stain. Methyl N-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valinate was obtained as light yellow oil (43%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([F:16])[CH:5]=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>O1CCCC1>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:27]=[CH:28][C:29]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]([F:16])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:9]=2[F:10])=[O:30])=[CH:25][CH:26]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Reactant: CS(=O)(=O)Nc1cc(F)c(CN)cc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C=CC(=O)NCc2cc(F)c(NS(C)(=O)=O)cc2F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.6 %

Procedure:
To the 25 ml round bottom flask were put N-(4-aminomethyl-2,5-difluoro-phenyl)-methanesulfonamide hydrochloride (125 mg, 0.46 mmol), 3-(4-t-butylphenyl)acrylic acid (1.2 eq, 112 mg), and DMTMM (1.2 eq, 152 mg). And to this mixture was poured 15 ml tetrahydrofuran and stirred 12 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, washed 1N HCl solution. And the combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=1/1) to yield a solid (147 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][C@H:12]1[CH2:22][OH:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:25].[Na+].O1CCOCC1.O=O>[Pt].O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:13][C@H:12]1[C:22]([OH:25])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H](C2CCCCC2)C[C@H]1CO
Reactant: O=C([O-])O
Agent: [Pt]
Agent: O=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1C(=O)OCc1ccccc1

Procedure:
To a mixture of (2S-trans)-1-[(benzyloxy)-carbonyl]-4-cyclohexyl-2-pyrrolidinemethanol (0.65 g), sodium bicarbonate (0.5 g), dioxane (20 ml), and water (20 ml) was added freshly prepared platinum black (prepared by hydrogenating 0.3 g of platinum oxide). Oxygen was passed through the solution at room temperature for 16 hours with vigorous stirring. Filtration and acidification, followed by extractive work-up yielded (trans)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-L-proline as a glassy solid. This compound can be deprotected using catalytic hydrogenation as described in Method I.
Reaction SMILES: C(OC([NH:7][C@H:8]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([CH2:25][C@@H:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24])=[O:16])[CH:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])=O)C=C.CC1(C)CC(=O)CC(=O)C1>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.C1COCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:25][C@@H:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19][C:18]=1[NH:17][C:15](=[O:16])[C@H:8]([CH:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])[NH2:7]
Reactant: C=CCOC(=O)N[C@H](C(=O)Nc1cc(C[C@@H](C)C(=O)OCC)ccc1Cl)C(C)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)Cc1ccc(Cl)c(NC(=O)[C@@H](N)C(C)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.40 g (2.92 mmol) of ethyl (2R)-3-[3-({N-[(allyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-chlorophenyl]-2-methylpropanoate (Example 38A, mixture of 4 isomers) and 3.28 g (23.4 mmol) of dimedone were initially charged in 10 ml of abs. THF. At RT, the solution was deoxygenated by passing through argon for 30 min. Subsequently 67.6 mg (0.058 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at RT overnight. After dilution with ethyl acetate, the mixture was washed twice with sat. sodium bicarbonate solution and once with sat. sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1→20:1) and separated. This gave 844 mg of the target compound as diastereomer mixture 1 (73.1% of theory).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1OC)[CH:8]([CH2:14][N:15](C)[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:7]2.[CH3:36][O:37]C1C=C2C(=CC=1OC)C(CNC)C2>>[ClH:1].[CH3:36][O:37][C:5]1[C:4]([O:3][CH3:2])=[CH:11][CH:10]=[C:9]2[C:6]=1[CH2:7][CH:8]2[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=2[CH2:22][CH2:21]1)=[O:19]
Reactant: CNCC1Cc2cc(OC)c(OC)cc21
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Agent: Cl
Product: COc1cc2c(cc1OC)CCN(C(=O)CCNCC1Cc3c1ccc(OC)c3OC)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement of the [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine in Step 4 by the product of Preparation 10.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1.CCN(CC)CC.CC(N(C)C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8]3)(=[O:32])=[O:33])=[CH:27][CH:26]=2)=[CH:35][CH:36]=1
Reactant: c1ccc(C2CNc3ccccc32)cc1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)N2CC(c3ccccc3)c3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
Stir 3-phenyl-2,3-dihydro-1H indole (0.233 g, 1.19 mmol), 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (1 equiv.), Et3N (0.50 mL, 0.36 g, 3.57 mmol), DMA (0.015 g, 0.123 mmol) in CH2Cl2 (45 mL) overnight under N2. Dilute the CH2Cl2 to 150 mL and pour into a saturated solution of NaHCO3 (50 mL) and stir for 15 minutes. Separate the organic layer and wash with H2O (100 mL), extract with 1N HCl (2×75 mL), wash with brine, separate and dry (MgSO4). Filter and evaporate followed by chromatography on the ISCO using a 40 g silica gel column and elute with EtOAc-hexane 90-100%) to give 0.33 g of the racemic compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][CH2:17][C:18](=O)[CH2:19][CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:17]([C:18]1([CH2:19][CH2:20][CH3:21])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH3:16]
Reactant: CCCC(=O)CC
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCC1(CC)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 3-hexanone (2.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred overnight at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol), then recrystallized from methanol, and the precipitate was collected by filtration. This yellow solid contained methanol, so it was stirred in ethyl acetate (5.0 mL) for 30 min at 70° C. After cooling, the precipitate was collected by filtration to afford the title compound (0.0334 g, 22%) as a yellow solid:
Reaction SMILES: [P:1](=[O:9])([N:6]=[C:7]=[O:8])([S:4][CH3:5])[O:2][CH3:3].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CCOCC>[N:10]1([C:7]([NH:6][P:1](=[O:9])([S:4][CH3:5])[O:2][CH3:3])=[O:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: COP(=O)(N=C=O)SC
Solvent: CCOCC
Product: COP(=O)(NC(=O)N1CCCCC1)SC

Procedure:
A solution of 6.0 grams (g) of O,S-dimethyl phosphoroisocyanatidothioate in 100 milliliters (ml) of ether was cooled to 0° C. and to this was added dropwise with stirring 3.1 g of piperidine. A precipitate began to form almost immediately and after one hour this precipitate was collected by filtration and extracted with ether. It was then recrystallized from toluene-hexane to obtain the title compound as white crystals melting at 96° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]1[CH2:25][CH2:24][C:12]2[N:13]([CH:21]=[CH:22][CH3:23])[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]=2[CH2:10]1.O>N(CCO)(CCO)CCO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][N:9]1[CH2:25][CH2:24][C:12]2[N:13](/[C:21](/[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:22]\[CH3:23])[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]=2[CH2:10]1
Reactant: Ic1ccccc1
Reactant: CC=Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: OCCN(CCO)CCO
Product: C/C=C(/c1ccccc1)n1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 100 °C
Reaction time: 14 h
Yield: 39.5 %

Procedure:
Iodo benzene (0.5 g, 2.4 mmol) and 2,8-dimethyl-5-(prop-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (588 mg, 2.4 mmol) were charged in triethanolamine (4 mL). Palladium (II)acetate (5 mg, 0.024 mmol) was added and stirred at 100° C. for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added. The desired compound was extracted with diethyl ether twice. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford 0.3 g of product. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.24 (s, 1H), 7.18 (m, 3H), 6.96-6.82 (m, 4H), 6.62 (m, 1H), 4.66 (m, 1H), 4.30 (m, 1H), 3.64 (m, 1H), 3.42 (m, 1H), 3.0 (s, 1H), 2.80 (m, 1H), 2.60 (m, 1H), 2.36 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@@:26]3([CH2:47][C@H:21]2[C:20](=[O:48])[NH:19][C@:18]2([C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:49][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[O:45][C:30]1[C:31]([C:41]([F:44])([F:43])[F:42])=[N:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][C:38]=2[C:29]=1[C:28](=[O:46])[CH2:27]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:55][Mg+].[Br-]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@@:26]3([CH2:47][C@H:21]2[C:20](=[O:48])[NH:19][C@:18]2([C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:49][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[O:45][C:30]1[C:31]([C:41]([F:44])([F:42])[F:43])=[N:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][C:38]=2[C:29]=1[C:28]([OH:46])([CH3:55])[CH2:27]3)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[Mg+]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@]3(CC(=O)c4c(c(C(F)(F)F)nc5ccc(OC)cc45)O3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@]3(CC(=O)c4c(c(C(F)(F)F)nc5ccc(OC)cc45)O3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@]3(C[C@H]1C(=O)N2)CC(C)(O)c1c(c(C(F)(F)F)nc2ccc(OC)cc12)O3
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@]3(C[C@H]1C(=O)N2)CC(C)(O)c1c(c(C(F)(F)F)nc2ccc(OC)cc12)O3
Temperature: -25 °C
Reaction time: 0.33 h

Procedure:
To the solution of (2S,6S,13aS,14aR,16aS,Z)-ethyl 6-((tert-butoxycarbonyl) amino)-9′-methoxy-1′,5,16-trioxo-5′-(trifluoromethyl)-1′,2′,3,5,6,7,8,9,10,11,13a,14,14a,15, 16,16a-hexadecahydro-1H-spiro[cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2,3′-pyrano[2,3-c]quinoline]-14a-carboxylate (2923 mg, 3.85 mmol) in THF (26 ml) was added 1.4M of MeMgBr solution in THF (11.01 ml, 15.41 mmol) at −25° C. and stirred at −25° C. for 20 min. TLC and LC-MS indicated that the major was product (about 50%) and starting material. Then the reaction was quenched with 1N HCl to pH=5-6 (about 12 ml 1N HCl), and diluted with EtOAc (40 ml). The layers were separated, and the aq. layer was extracted again with EtOAc (25 ml×2). The organic layers were combined and washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (120 g, gold column), eluting with 100% hexane for 400 ml, gradient to 35% of acetone to give 1430 mg of starting material and 1130 mg of (2S,6S,13aS,14aR,16aS,Z)-ethyl 6-((tert -butoxycarbonyl)amino)-1′-hydroxy-9′-methoxy-1′-methyl-5,16-dioxo-5′-(trifluoromethyl)-1′,2′,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydro-1H-spiro[cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2,3′-pyrano[2,3-c]quinoline]-14a-carboxylate as a light yellow solid. m/z=775.4 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C[Si]([N:14]=[N+:15]=[N-:16])(C)C.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:14]=[N:15][NH:16][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc(Br)cc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Brc1ccc(-c2c[nH]nn2)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
1-Bromo-4-ethynylbenzene (650 mg, 3.59 mmol) and trimethylsilyl azide (3.57 mL, 26.9 mmol) were combined in t-BuOH (5.0 mL) and water (3.0 mL) CuSO4.5H2O (90 mg, 0.36 mmol) in water (1.0 mL) and sodium ascorbate (285 mg, 1.44 mmol) in water (1.0 mL) were added, and the sealed reaction mixture was stirred at 100° C. for 48 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (dry load, 0-50% EtOAc/hexanes) afforded the title compound as a colorless solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20](O)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH2:27][OH:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[C:14]([Si:1]([O:18][CH2:19][C@@H:20]1[O:28][CH2:27][C:23]2=[N:24][CH:25]=[CH:26][N:22]2[CH2:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](OC[C@H](O)Cn1ccnc1CO)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@H]1Cn2ccnc2CO1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Separately, prepare a −78° C. solution of (2R)-1-[tert-butyl(diphenyl)silyl]oxy-3-[2-(hydroxymethyl)imidazol-1-yl]propan-2-ol (5.3 g; 1.0 equiv; 12.91 mmoles) in dichloromethane (25 mL). Add the in situ prepared iodinating reagent dropwise to the solution of (2R)-1-[tert-butyl(diphenyl)silyl]oxy-3-[2-(hydroxymethyl)imidazol-1-yl]propan-2-ol, with the orange color quickly fading to nearly colorless. Maintain the solution at −78° C. for 30 minutes, then allow it to warm to 0° C. and maintain for 10 minutes. Re-cool the solution to −78° C., and add tetrahydrofuran (100 mL) followed by 60% sodium hydride (1.14 g; 2.2 equiv; 28.40 mmoles). Slowly warm the solution to 0° C. over 30 minutes, and then to ambient temperature for 1 hour. Pour the mixture slowly into 50% saturated sodium bicarbonate solution and extract with dichloromethane (4×100 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate. Purify the crude product by column chromatography (10 to 100% ethyl acetate in hexanes) to afford the desired product contaminated with triphenylphosphine oxide. Further purify by SCX ion-exchange chromatography (10% methanol in dichloromethane to 10% (4N ammonia in methanol) in dichloromethane) to afford the desired tert-butyl-[[(6R)-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-yl]methoxy]-diphenyl-silane (1.86 g; 37%). MS (m/z): 393(M+1).
Reaction SMILES: CN(C)CCCN(C)C.[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=2)=[C:13]([CH3:28])[N:12]=1.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:31]=1[S:38](Cl)(=[O:40])=[O:39].Cl>C1COCC1.O.C(#N)C>[NH2:10][C:11]1[N:16]=[C:15]([O:17][S:38]([C:31]2[C:32]([CH3:37])=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=2[CH3:29])(=[O:40])=[O:39])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=2)=[C:13]([CH3:28])[N:12]=1
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)CCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)Oc2nc(N)nc(C)c2Cc2ccc(CC#N)cc2)c(C)c1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
N,N,N′,N′-Tetramethyl-1,3-propanediamine (56.7 g) was added dropwise to a suspension of the product from step (ii) (85.0 g) and 2,4,6-trimethylbenzenesulfonyl chloride (87.8 g) in THF (452.9 g), and the mixture was heated at 45° C. for 7 hours. 2.5% HCl in water (1291 g) was added to the mixture, and the mixture was stirred at 5° C. for 30 minutes. The resulting precipitate was collected by filtration, washed with acetonitrile (2×68.0 g), and dried to give the crude subtitle compound as a solid. A stirred suspension of the solid in acetonitrile (654.5 g) was heated at 70° C. for 30 minutes, cooled to 5° C. and stirred at 5° C. for 30 minutes. The resulting precipitate was collected by filtration, washed with acetonitrile (2×68.0 g) and dried to give the subtitle compound as a solid, 113.1 g; 1H NMR CDCl3: δ 7.24 (d, 2H), 7.11 (d, 2H), 6.96 (s, 2H), 4.71 (s, 2H), 3.90 (s, 2H), 3.71 (s, 2H), 2.59 (s, 6H), 2.32 (s, 3H), 2.27 (s, 3H).