Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:21]3[CH2:22][CH:20]3[CH2:19][C:8]=2[N:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[N:10]=1)=[O:5])C.COC(C1C2C3CC3CC=2N(C2C=CC(F)=CC=2F)N=1)=O.[OH-].[Na+]>CO.C1COCC1>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[N:9]1[C:8]2[CH2:19][CH:20]3[CH2:22][CH:21]3[C:7]=2[C:6]([C:4]([OH:5])=[O:3])=[N:10]1
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2F)c2c1C1CC1C2
Agent: COC(=O)c1nn(-c2ccc(F)cc2F)c2c1C1CC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C1CC1C2
Temperature: 20 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 1-(2,4-difluoro-phenyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylic acid ethyl ester (0.66 g, 2.169 mmol) and 1-(2,4-difluoro-phenyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylic acid methyl ester (0.08 g, 0.276 mmol) in methanol (6 mL) and THF (6.00 mL) was added a 2.0 M aqueous solution of sodium hydroxide (3.25 mL, 6.51 mmol). The resulting yellow solution was stirred at 20° C. for 16 h. The organic solvents were removed under reduced pressure. The remaining aqueous solution was diluted with water (25 mL) then acidified to pH 2 by addition of 6 M HCl. The resulting precipitate was collected by filtration, rinsed with water, and then dried under reduced pressure to give the title compound as a tan solid (0.575 g). LCMS m/z=277.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.28 (td, J=4.4, 3.8 Hz, 1H), 1.12 (td, J=7.6, 4.7 Hz, 1H), 2.10-2.15 (m, 1H), 2.19-2.23 (m, 1H), 2.79 (d, J=17.0 Hz, 1H), 2.98 (dd, J=17.0, 6.6 Hz, 1H), 7.25-7.29 (m, 1H), 7.56-7.60 (m, 1H), 7.72 (td, J=8.8, 6.2 Hz, 1H), 12.83 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[N:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1)[C:6]1[CH:11]=[C:10]([Br:12])[N:9]=[C:8](Br)[C:7]=1[N+:14]([O-:16])=[O:15])[CH3:2].[NH3:27]>>[CH2:1]([O:3][C:4](=[O:26])[N:5]([C:6]1[CH:11]=[C:10]([Br:12])[N:9]=[C:8]([NH2:27])[C:7]=1[N+:14]([O-:16])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1)[CH3:2]
Reactant: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Reactant: N
Product: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(Br)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 68 using (3-cyano-benzyl)-(2,6-dibromo-3-nitro-pyridin-4-yl)-carbamic acid ethyl ester (2.32 g), aqueous ammonia (10.2 ml), and 2-methyl-THF (10.2 ml). This gave the product (1.51 g) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]([N:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:21])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.[H-].[Na+]>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[C@@H:7]([N:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([Cl:23])[CH:25]=2)[C:12]1=[O:21])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@@H](C(=O)OC(C)(C)C)N1Cc2ccccc2NC1=O
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)[C@@H](C(=O)OC(C)(C)C)N1Cc2ccccc2N(Cc2cccc(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of (2S)-3-methyl-2-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-butyric acid tert-butyl ester (633 mg, 2.08 mmol) and 3-chlorobenzyl bromide (470 mg, 2.29 mmol) in DMSO (10 mL) was added sodium hydride (75 mg, 1.87 mmol) and the reaction mixture was stirred at room temperature for 40 hours. To this reaction was then added sat. aq. NH4Cl and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and evaporated.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5](/[CH:14]=[CH:15]/[CH:16]=[O:17])[C@@H:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:3]1>CC(C)=O.[Pd]>[CH3:1][C:2]1([CH3:24])[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:5]([CH2:14][CH2:15][CH:16]=[O:17])[C@@H:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1[C@H](/C=C/C=O)[C@@H](c2ccccc2)OC1(C)C
Agent: [Pd]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1[C@H](CCC=O)[C@@H](c2ccccc2)OC1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.4 %

Procedure:
To a solution of tert-butyl (4R,5R)-2,2-dimethyl-4-[(1E)-3-oxoprop-1-en-1-yl]-5-phenyl-1,3-oxazolidine-3-carboxylate (19.6 g, 59.1 mmol) (from Step A) in acetone (150 mL) was added 1.9 g of 10% Pd/C and the resulting suspension was stirred under a hydrogen balloon at ambient temperature for 24 h. The solid was filtered off on celite and the filtrate concentrated under vacuum. The residue was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 20% ethyl acetate in hexanes gradient then 20% ethyl acetate in hexanes) to afford 11.5 g (58%) of the title compound as a colorless oil. LC/MS 356.3 (M+23).
Reaction SMILES: CC1C=CC=CC=1C.N[C:10]1[CH:21]=[CH:20][CH:19]=[C:12]2[C:13](N(O)[C:16](=O)[C:11]=12)=[O:14].CC1C=CC=CC=1CO>>[CH3:16][C:11]1[CH:10]=[CH:21][CH:20]=[CH:19][C:12]=1[CH:13]=[O:14]
Reactant: Nc1cccc2c1C(=O)N(O)C2=O
Agent: Cc1ccccc1CO
Solvent: Cc1ccccc1C
Product: Cc1ccccc1C=O
Yield: 30 %

Procedure:
170 mg (1.60 mmol) of o-xylene were reacted analogously to Example 1 in the presence of 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide. After a reaction time of 4 hours and 18 hours, a further 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide were added in each case, and, after a total of 30 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy. Yield 30% of 2-methylbenzaldehyde and 7% of 2-methylbenzyl alcohol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]2[N:17]=[C:16]([N:18]3[C@@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][O:20][C:19]3=[O:26])[CH:15]=[CH:14][N:13]=2)[CH3:10])=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:23]([C@H:22]1[CH2:21][O:20][C:19](=[O:26])[N:18]1[C:16]1[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:8][CH:7]=2)[CH3:10])[N:17]=1)([CH3:24])[CH3:25]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CO)cc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C=O)cc2)n1

Procedure:
A solution of (S)-3-(2-((S)-1-(4-(hydroxymethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (285 mg, 0.8 mmol) and manganese dioxide (2.78 g, 32 mmol, 40 equiv) in DCM (16 mL) was stirred at room temperature for 30 min. The solution was filtered through a pad of celite and washed with DCM. The filtrated was concentrated and used to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21]>>[O:21]=[S:20]1(=[O:22])[CH2:19][CH2:18][CH2:17][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(N)cc1S(C)(=O)=O
Product: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O

Procedure:
To 4-bromo-2-methanesulfonylbenzoic acid (5 g) were added methanol (45 mL) and concentrated sulfuric acid (1.8 mL), and the mixture was stirred with heating under reflux. After completion of the reaction, the solvent was evaporated, and the residue was neutralized with 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give methyl 4-bromo-2-methanesulfonylbenzoate (3.34 g). To a mixture of the obtained methyl 4-bromo-2-methanesulfonylbenzoate (3.34 g), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (295 mg), 2-(dicyclohexylphosphino)biphenyl (399 mg), tripotassium phosphate (3.39 g) and benzophenonimine (2.5 mL) was added 1,2-dimethoxyethane (25 mL), and the mixture was stirred with heating under reflux. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in tetrahydrofuran (26 mL), 1N hydrochloric acid (100 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give methyl 4-amino-2-methanesulfonylbenzoate (1.46 g). Using the obtained methyl 4-amino-2-methanesulfonylbenzoate (1.46 g) and 3-chloropropane-1-sulfonyl chloride (1.03 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (0.53 g) was obtained.
Reaction SMILES: [C:1]([C:5]1([CH2:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([O:3]C)=[O:2].[OH-].[Li+]>CO>[C:1]([C:5]1([CH2:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1(CSC(C)(C)C)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)SCC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Dissolve 2-carbomethoxy-2-(t-butyl)thiomethyl-indan (557 mg, 2.0 mmol) in methanol (15 mL) and add 1N lithium hydroxide (3.5 mL). Warm briefly to effect solution then stir at room temperature under an argon atmosphere for 1 hour. Reflux for 6 hours, concentrate in vacuo to a volume of 3 mL and dilute to a volume of 15 mL with water. Wash with methylene chloride and acidify and aqueous phase with excess 2N hydrochloric acid. After 5 minutes, collect the resulting white precipitate by filtration and dry to give 2-carboxy-2-(t-butyl)thiomethyl-indan (506 mg, 96%); mp 158°-163° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[N:8]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][NH:9]1.N1C=CC=CC=1>O1CCCC1>[N:9]1([C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3])[CH2:10][CH2:11][CH:12]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)C1CCNN1C(=O)OC(C)(C)C
Reactant: C=CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CCOC(=O)N1CCC(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
Allyl chloroformate (0.488 ml, 4.59 mmol) was added dropwise to the solution of di-tert-butyl pyrazolidine-1,5-dicarboxylate (1 g, 3.67 mmol) and pyridine (0.371 ml, 4.59 mmol) in tetrahydrofuran (THF) (1.79 ml) at 0° C. The resulting solution was allowed to warm up to ambient temperature and stirred for 30 min. The reaction was filtered, and to the filtrate was added EtOAc. The solution was washed with brine. The organic layers were separated and dried over anhydrous Na2SO4. The crude product was purified by RP-HPLC to give 2,3-bis(1,1-dimethylethyl) 1-(2-propen-1-yl) 1,2,3-pyrazolidinetricarboxylate (749 mg, 2.101 mmol, 57% yield). MS (ES+) m/z 357.3 (MH+).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17]3)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N:24]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36]([CH:41]=O)=[CH:35]3)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:1]1([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[C:17]3=[CH:41][C:36]2[NH:37][C:38]3[C:34]([CH:35]=2)=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:40][CH:39]=3)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCCc4ccccc43)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
5-(3,4-Dihydro-2H-quinoline-1-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7](I)[CH:8]=[CH:9][CH:10]=1)#[N:2].[F:12][C:13]1[CH:14]=[C:15]([O:28][CH2:29][C:30]#[CH:31])[CH:16]=[C:17]([C:19]2([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]2[O:24][CH3:25])[CH:18]=1.N1CCCCC1>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.C1(C)C=CC=CC=1>[C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:31]#[C:30][CH2:29][O:28][C:15]2[CH:16]=[C:17]([C:19]3([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]3[O:24][CH3:25])[CH:18]=[C:13]([F:12])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#CCOc1cccc(I)c1
Reactant: C#CCOc1cc(F)cc(C2(OC)CCCC2OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC1CCCC1(OC)c1cc(F)cc(OCC#Cc2cccc(OCC#N)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
A mixture of 3-cyanomethoxyphenyl iodide (0.355 g), tetrakis(triphenylphosphine)palladium (0.079 g) and toluene (7 ml) was stirred at ambient temperature for 15 minutes. To this mixture there were added in turn (1RS,2SR)-1-[5-fluoro-3-(2-propynyloxy)phenyl]-1,2-dimethoxycyclopentane (0.252 g), cuprous iodide (0.013 g) and piperidine (0.274 ml) and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between toluene and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using methylene chloride as eluent. There was thus obtained (1RS,2SR)-1-[3-(3-(3-cyanomethoxyphenyl)prop-2-ynyloxy)-5-fluorophenyl-1,2-dimethoxycyclopentane (0.194 g, 35%), as an oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][C:13]=2[CH3:15])[CH:8]=[C:9]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(C)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCCC(=O)O)c(O)c2cc(Cc3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 26.2 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-8-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.097 mmol), β-alanine (3.44 g, 38.6 mmol) and NaOMe solution (58 mL, 29 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was further purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 12 mg of the title compound. MS: (+) m/z 472.18 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:41]([CH3:44])[CH2:42][CH3:43])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19]([C:21]1[CH:22]=[CH:23][C:24]2[C:33]3[CH:32]=[C:31]4[CH2:34][CH2:35][CH:36](Br)[C:37](=[O:38])[C:30]4=[CH:29][C:28]=3[O:27][CH2:26][C:25]=2[CH:40]=1)=[O:20])=[O:16])=[O:8])=[O:4].[C:45]([O:49][C:50]([N:52]1[C@@H:56]([CH3:57])[CH2:55][CH2:54][C@H:53]1[C:58]([OH:60])=[O:59])=[O:51])([CH3:48])([CH3:47])[CH3:46].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[CH3:57][C@@H:56]1[N:52]([C:50]([O:49][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:51])[C@H:53]([C:58]([O:60][CH:36]2[CH2:35][CH2:34][C:31]3=[CH:32][C:33]4[C:24]5[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][O:17][C:15]([C@@H:10]6[CH2:11][CH2:12][C@H:13]([CH3:14])[N:9]6[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C@@H:41]([CH3:44])[CH2:42][CH3:43])=[O:16])=[CH:40][C:25]=5[CH2:26][O:27][C:28]=4[CH:29]=[C:30]3[C:37]2=[O:38])=[O:59])[CH2:54][CH2:55]1
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(OC(=O)[C@@H]1CC[C@H](C)N1C(=O)OC(C)(C)C)C3=O
Temperature: 50 °C
Yield: 43 %

Procedure:
To a solution of (2S,5S)-2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl 1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carboxylate (5.95 g, 8.88 mmol) in THF (60 mL) was added (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (3.05 g, 13.3 mmol) and Cs2CO3 (2.31 g, 7.09 mmol). The resulting solution was heated to 50° C. for 18 h. The solution was cooled to room temperature and diluted with EtOAc and washed with aqueous HCl (0.5 M). The aqueous layer was backextracted with EtOAc (2×), and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 25-100% EtOAc (5% MeOH)/Hexanes) to provide (2S,5S)-1-tert-butyl 2-(3-(2-((2S,5S)-1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 5-methylpyrrolidine-1,2-dicarboxylate (3.116, 43% over 2 steps) as a orange foam. LCMS-ESI+: calc'd for C44H55N3O12: 817.38 (M+). Found: 817.65 (M+).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2]O.[C:5]1([CH3:15])[CH:10]=[CH:9][C:8](S(O)(=O)=O)=[CH:7][CH:6]=1>C1C=CC=CC=1>[CH3:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:5][CH2:15][CH2:2][CH2:1][OH:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCO

Procedure:
The synthesis of starting materials (1)-(3) is known in the art. To prepare the next intermediate, (4), 9 g (44 mmol) of (3), 20 ml of ethylene glycol, 100 ml of benzene and 3 mg of p-toluene sulfonic acid were refluxed overnight with a Dean-Stark. After evaporation of the solvent and separation on a silica gel column, 9.2 g of the cetal (4) were obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[N:44]1[CH:49]=[CH:48][N:47]=[CH:46][C:45]=1[C:50](Cl)=[O:51]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:50]([C:45]4[CH:46]=[N:47][CH:48]=[CH:49][N:44]=4)=[O:51])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cnccn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)c2cnccn2)C3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.085 g, 0.00021 mol) in dry N,N-Dimethylformamide (1.00 mL, 0.0129 mol) was added N,N-Diisopropylethylamine (0.1120 mL, 0.0006430 mol) cooled at 0° C., added Pyrazine-2-carbonyl chloride (0.0508 g, 0.000356 mol) stirred at 0° C. for 30 minutes. The reaction mixture was filtered and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.95 (dd, J=8.4, 1.3, 1H), 8.81 (dd, J=7.1, 2.5, 1H), 8.75 (d, J=3.9, 1H), 8.68 (d, J=15.6, 1H), 8.17 (dd, J=43.7, 8.7, 2H), 7.48 (dd, J=25.1, 8.8, 2H), 6.18 (dt, J=11.1, 5.6, 1H), 4.85 (d, J=18.5, 1H), 4.72 (d, J=7.4, 1H), 4.11 (d, J=5.5, 1H), 3.88 (d, J=9.3, 1H), 3.78-3.54 (m, 6H), 3.43 (t, J=12.3, 1H), 3.11 (dq, J=14.5, 7.2, 2H), 2.76 (s, 2H), 1.26 (d, J=6.6, 3H), 1.06 (q, J=7.3, 3H). LC/MS-m/z+503.2 (M+H)+.
Reaction SMILES: Cl.[OH:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[C:4](=[NH:8])[O:5]CC.C(N(CC)CC)C.[C:24](Cl)(Cl)=[O:25]>O1CCCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:3]1[O:2][C:24](=[O:25])[NH:5][C:4]1=[O:8]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=N)C(O)c1ccccc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1C1OC(=O)NC1=O
Reaction time: 1 h
Yield: 42 %

Procedure:
Ethyl 1-hydroxy-1-(2-methoxyphenyl)methanecarboximidate hydrochloride (18 g., 0.073 mole) was suspended in 500 ml. of tetrahydrofuran, cooled to 0°-5° C., and triethylamine (23.6 g., 0.234 mole) was added. The stirred reaction mixture was perfused with phosgene for 30 minutes. Stirring at 0°-5° C. was continued for 1 hour. The reaction mixture was slowly poured over 1 l. of crushed ice and product extracted into three portions of chloroform. The combined chloroform extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to solids. The residue was recrystallized from toluene to yield 5-(2-methoxyphenyl)oxazolidine-2,4-dione (6.4 g., 42%; m.p. 175°-177° C.; m/e 207). A second drop (3.7 g., 24%, m.p. 175°-177° C.) was obtained from the toluene mother liquor.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:9]2=[N:10]S[N:12]=[C:8]2[C:7]([Br:13])=[CH:6][CH:5]=1>CCO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Br:13])=[C:8]([NH2:12])[C:9]=1[NH2:10]
Reactant: Brc1ccc(Br)c2nsnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1c(Br)ccc(Br)c1N
Temperature: 30 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
NaBH4 (26 g, 680 mmol, 10 equiv) was added portionwise (2 h) to a vigorously stirred suspension of 4,7-dibromo-benzo[1,2,5]thiadiazole (Step 179.7) (20 g, 68.0 mmol) in EtOH (400 mL), under a nitrogen atmosphere and keeping the internal temperature below 15° C. The reaction mixture was allowed to warm to 30° C., stirred for 1 h, cooled to 5° C., quenched by addition of H2O (50 mL), and concentrated. The residue was diluted with Et2O/H2O. The resulting suspension was filtered and the filtrate extracted with Et2O. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in hexane to provide 12 g of the title compound as a white solid: ESI-MS: 263/265/267 [M−H]−; tR=4.20 min (System 1).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:11]C(=O)OC(C)(C)C)([CH2:8][S:9][CH3:10])[CH2:4][O:3]1.[ClH:20]>CO>[ClH:20].[NH2:11][C:5]([CH2:8][S:9][CH3:10])([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CSCC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: Cl
Solvent: CO
Product: CSCC(N)(CO)CO
Yield: 100 %

Procedure:
A solution of tert-butyl 2,2-dimethyl-5-(methylthiomethyl)-1,3-dioxan-5-ylcarbamate (2.64 g, 9.06 mmol) in methanol (10 mL) was added to a solution of concentrated hydrochloric acid (8 mL) in methanol (100 mL) and evaporated to give a yellow oil, which was purified by flash column chromatography (CH2Cl2:methanol:7 M methanolic ammonia, 5:2:1). The residue was reconverted to the hydrochloride salt by treatment with a solution of concentrated hydrochloric acid (1 mL) in methanol (5 mL) to give the 2-amino-2-(methylthiomethyl)propane-1,3-diol, hydrochloride salt (1.37 g, 100%). 1H NMR (D2O) δ 3.74 (s, 4H), 2.88 (s, 2H), 2.19 (s, 3H). 13C NMR (DMSO) δ 64.4 (2C), 57.9, 48.9, 17.5. +ESMS Found 152.0744 (M−Cl−) C5H14NO2S requires 152.0745.