Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)([CH:10]([CH3:12])[CH3:11])[C:6]([O:8][CH3:9])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31]>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:5]([C:6]([O:8][CH3:9])=[O:7])([CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CNCCc1cccc(C(=O)OC)c1
Reactant: COC(=O)C(CCCCl)(c1ccc(OC)c(OC)c1)C(C)C
Product: COC(=O)c1cccc(CCN(C)CCCC(C(=O)OC)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1e with 2d produced 3aj. MS found M+H=486. The oxalate salt of 3aj was recrystallized from ethyl acetate; mp 87-90° C.
Reaction SMILES: [ClH:1].[CH:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=O)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)([CH3:4])[CH3:3].S(Cl)([Cl:30])=O>>[ClH:30].[CH:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([Cl:1])=[O:27])=[CH:21][C:20]=3[Cl:30])[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)([CH3:4])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(C)N1CCN(C(=O)C2CCN(c3ccc(C(=O)O)cc3)CC2)CC1
Agent: Cl
Product: CC(C)N1CCN(C(=O)C2CCN(c3ccc(C(=O)Cl)cc3Cl)CC2)CC1

Procedure:
1-Isopropyl4-[1-(4-carboxy-phenyl)-piperidin-4-carbonyl]-piperazine hydrochloride (D9) (0.25 g) was dissolved in thionyl chloride (10 ml) and heated at reflux for 1.5 h. The reaction mixture was then evaporated to a minimum (co-evaporated with DCM, 3×10 ml) to give the subtitled compound as a yellow oil (0.25 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C@@H:12]2[CH2:16][CH2:15][N:14](C([O-])=O)[N:13]2[C:20](=[O:39])[C@@H:21]([CH2:27][N:28]([CH:37]=[O:38])[O:29]CC2C=CC=CC=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:11])=[N+:6]([O-:8])[CH:7]=1>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C@@H:12]2[CH2:16][CH2:15][NH:14][N:13]2[C:20](=[O:39])[C@@H:21]([CH2:27][N:28]([CH:37]=[O:38])[OH:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:11])=[N+:6]([O-:8])[CH:7]=1
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccc(F)c[n+]2[O-])CCN1C(=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCC[C@H](CN(O)C=O)C(=O)N1NCC[C@H]1C(=O)Nc1ccc(F)c[n+]1[O-]
Reaction time: 0.62 h
Yield: 73.5 %

Procedure:
To a 50 mL round-bottomed flask was added (3S)-3-{[(5-fluoro-1-oxido-2-pyridinyl)amino]carbonyl}-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-pyrazolidinecarboxylate (103 mg, 0.162 mmol) in methanol (3 ml), followed by Pearlman's catalyst (10 mg). The mixture was stirred under a balloon of H2 for 37 min, and the catalyst was filtered off. The filtrate was concentrated and the residue was purified by RP-HPLC to provide (3S)—N-(5-fluoro-1-oxido-2-pyridinyl)-2-((2R)-2-{[formyl(hydroxy)amino]methyl}heptanoyl)-3-pyrazolidinecarboxamide (49 mg, 73%). LCMS: (M+H)+: 412.0. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.76-0.98 (m, 3H) 1.26-1.46 (m, 6H) 1.48-1.57 (m, 1H) 1.63-1.77 (m, 1H) 2.30-2.44 (m, 1H) 2.46-2.59 (m, 1H) 2.91 (td, J=10.67, 6.44 Hz, 1H) 3.20-3.29 (m, 1H) 3.52 (dd, J=13.77, 4.42 Hz, 1H) 3.77-3.96 (m, 2H) 4.81-4.88 (m, 1H) 7.47 (ddd, J=9.66, 7.14, 2.65 Hz, 1H) 7.90 (s, 1H) 8.40-8.61 (m, 2H)
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]3[N:19]=[CH:20][N:21]([CH3:22])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:23]([F:26])([F:25])[F:24].C(Br)(Br)(Br)[Br:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:28][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]3[N:19]=[CH:20][N:21]([CH3:22])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:23]([F:26])([F:25])[F:24]
Reactant: BrC(Br)(Br)Br
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(CCCO)c(C(F)(F)F)c3)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cnc2c(C#N)nc(-c3ccc(CCCBr)c(C(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
6-[4-(3-Hydroxypropyl)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.3 g) was gently heated in THF (36 ml) until all dissolved and then cooled to 0° C. in an ice bath. Carbon tetrabromide (2.4 g) was added followed by triphenylphosphine (1.9 g). The mixture was stirred at 0° C. for 15 minutes and then at room temperature for 20 minutes until the cloudy suspension became a clear solution. The reaction mixture was diluted with DCM (100 ml) and washed with water (100 ml×2). Organic layer was dried over sodium sulphate and solvent was evaporated under reduced pressure. The residue was then columned (100 g SiO2 column, 1:1 EtOAc/Heptane to EtOAc gradient) to afford 6-(4-(3-bromopropyl)-3-(trifluoromethyl)-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.2 g) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:15][S:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[N:23][CH:24]=1)(=[O:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:20]=2)[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
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: [Na+]
Solvent: C1COCCO1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 100 °C
Yield: 70.7 %

Procedure:
Into a microwave vial was added 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.040 g, 0.14 mmol), [5-(methylsulfonyl)pyridin-3-yl]boronic acid (0.035 g, 0.17 mmol), 1.0 M sodium carbonate (0.35 mL, 0.35 mmol), 1,4-dioxane (0.87 mL) and tetrakis(triphenylphosphine)palladium(0) (0.010 g, 0.0086 mmol). The mixture was bubbled with N2 for 5 min, then heated at 100° C. overnight. The cooled reaction mixture was purified on silica gel to give the desired product (0.035 g, 71%). LCMS calculated for C16H17ClNO4S (M+H)+: m/z=354.1. found: 354.0.
Reaction SMILES: [CH3:1][CH:2]([C:6](O)=O)[C:3]([OH:5])=[O:4].[CH3:9][NH:10][CH3:11].C=O>O>[CH3:9][N:10]([CH3:11])[CH2:6][CH:2]([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CC(C(=O)O)C(=O)O
Reactant: CNC
Agent: C=O
Solvent: O
Product: CC(CN(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 1.0 ml of water was dissolved 1.5 g of methylmalonic acid, after which 1.26 g of a 50% aqueous dimethylamine solution and 0.96 ml of a 37% aqueous formaldehyde solution were added with stirring at 0° C., and the resulting mixture was stirred at 0° to 5° C. for 3 hours and then at 80° C. for 30 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([CH:8]=[CH:9][CH2:10][CH2:11][O:12]CC2C=CC=CC=2)[CH2:5][CH2:4][O:3]1>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:5][CH2:4][O:3]1
Reactant: CC1(C)CC(C=CCCOCc2ccccc2)CCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CC(CCCCO)CCO1
Reaction time: 16 h
Yield: 94.7 %

Procedure:
A solution of 2,2-dimethyl-4-{4-[(phenylmethyl)oxy]-1-buten-1-yl}tetrahydro-2H-pyran (7.46 g, 27.2 mmol) I ethyl acetate (70 ml) was hydrogenated over 10% palladium on activated carbon (1.447 g, 1.359 mmol) at atmospheric pressure and room temperature. After 16 hours, the mixture was filtered under vacuum through Celite, washed through with EtOAc (2×50 ml) and the filtrate was evaporated to dryness to give a yellowish mobile oil (4.8 g). The residue was purified by chromatography on silica (70 g) using a cyclohexane:ethyl acetate 0->50% gradient over 40 mins using a Flashmaster II. The desired fractions (analysed with a permanganate dip) were combined and concentrated under vacuum to give the title compound as a yellow oil (1.675 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[Se:19][C:18]([CH:20]=O)=[CH:17][CH:16]=3)=[C:11]([F:22])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:23]C(C)([O-])C.[K+].O.Cl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[Se:19][C:18]([CH:20]=[CH2:23])=[CH:17][CH:16]=3)=[C:11]([F:22])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccc(-c3ccc(C=O)[se]3)c(F)c2)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(-c2ccc(-c3ccc(CC)cc3)cc2F)[se]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 g (13.9 mmol) of methyltriphenylphosphonium bromide are initially introduced together with 4.20 g (11.8 mmol) of 5-(4′-ethyl-3-fluorobiphenyl-4-yl)selenophene-2-carbaldehyde in 180 ml of THF, and a solution of 1.50 g (13.4 mmol) of potassium tert-butoxide in 20 ml of THF is added with ice-cooling. The mixture is stirred at RT for 3 h. Water and 2 N hydrochloric acid are added, and the batch is extracted with MTBE. The organic phase is washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). 2-(4′-Ethyl-3-fluorobiphenyl-4-yl)-5-vinylselenophene is obtained as a beige solid.
Reaction SMILES: OO.[CH:3]([C:6]1[NH:11][C:10](=S)[NH:9][C:8](=[O:13])[C:7]=1[CH3:14])([CH3:5])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[CH:3]([C:6]1[N:11]=[CH:10][N:9]=[C:8]([OH:13])[C:7]=1[CH3:14])([CH3:5])[CH3:4]
Reactant: Cc1c(C(C)C)[nH]c(=S)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: O
Product: Cc1c(O)ncnc1C(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
To a solution of 30% hydrogen peroxide (12 mL) and water (23 mL) was slowly added 6-isopropyl-5-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1.0 g, 5.4 mmol). The reaction mixture was stirred at 70° C. for 3 h. After cooling to room temperature, saturated sodium carbonate was slowly added until the pH reached 10. To this mixture was slowly added a 1 M solution of sodium thiosulfate until residual peroxide was quenched, whereupon the aqueous solution was concentrated to dryness. The residue was suspended in chloroform (100 mL), filtered to remove inorganic salts and the filtrate concentrated to provide 6-isopropyl-5-methylpyrimidin-4-ol (0.25 g, 30% yield) as a white solid that was used without further purification. MS (EI) for C8H12N2O: 153 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C([Sn](CCCC)(CCCC)[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)CCC.C(OCC)C.[F-].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[CH2:16][O:17][CH2:18][C:19]1[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1Cl
Temperature: 70 °C

Procedure:
2-Chlorobenzoyl chloride (1.27 ml), tri-n-butyl-((3,5-bis(trifluoromethyl)phenyl)methyloxymethyl)tin (part (a), 6.2 g) and benzylchlorobis(triphenylphosphine)palladium (II) (80 mg) were dissolved in chloroform (10 ml) and the solution heated to 70° C. for 36 hours. On cooling diethyl ether and saturated aqueous potassium fluoride were added and this solution filtered through a pad of Hyflo. The organic layer was washed with water, dried (MgSO4) and reduced in vacuo giving a residue which was purified by chromatography on silica gel to give 2'-chloro-2-((3,5-bis(trifluoromethyl)phenyl) methyloxy)acetophenone, 1H NMR (360MHz, CDCl3) δ 7.79 (3H, bs, bis(CF3) aryl CH2,4,6), 7.54-7.26 (4H, m, aryl), 4.75 (2H, s), 4.76 (2H, s).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21]>>[F:1][C:2]([F:12])([F:13])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:9][CH:10]=1
Reactant: Oc1ccc(OCC(F)(F)F)cc1
Reactant: CCOC(=O)NCCCl
Product: CCOC(=O)NCCOc1ccc(OCC(F)(F)F)cc1

Procedure:
Following the procedure of Example 1, 4-(2,2,2-trifluoroethoxy)phenol (0.42 g, 2.2 mmol) and ethyl N-(2-chloroethyl)carbamate (0.40 g, 2.6 mmol) are reacted together to give ethyl N-{2-[4-(2,2,2-trifluoroethoxy)phenoxy]ethyl}carbamate (compound 28, Table A).
Reaction SMILES: C[O:2][C:3](=[O:77])[C:4](=[CH2:76])[NH:5][C:6](=[O:75])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:74])[C@H:13]([CH2:68][C:69]1[N:73]=[CH:72][NH:71][CH:70]=1)[NH:14][C:15](=[O:67])[C@H:16]([C@H:63]([CH2:65][CH3:66])[CH3:64])[NH:17][C:18](=[O:62])[C@H:19]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)[NH:20][C:21](=[O:53])[C@H:22]([CH:50]([CH3:52])[CH3:51])[NH:23][C:24](=[O:49])[C@H:25]([CH2:42][CH2:43][CH2:44][NH:45][C:46](=[NH:48])[NH2:47])[N:26]([C:30](=[O:41])[CH2:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:33])[N+:27]([O-:29])=[O:28].[OH-].[Li+].Cl>O1CCOCC1>[C:37]([O:36][C:34]([N:32]([CH2:31][C:30]([N:26]([N+:27]([O-:29])=[O:28])[C@H:25]([C:24]([NH:23][C@H:22]([C:21]([NH:20][C@H:19]([C:18]([NH:17][C@H:16]([C:15]([NH:14][C@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([NH:5][C:4]([C:3]([OH:77])=[O:2])=[CH2:76])=[O:75])=[O:74])[CH2:68][C:69]1[N:73]=[CH:72][NH:71][CH:70]=1)=[O:67])[C@H:63]([CH2:65][CH3:66])[CH3:64])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([OH:61])=[CH:57][CH:56]=1)=[O:53])[CH:50]([CH3:51])[CH3:52])=[O:49])[CH2:42][CH2:43][CH2:44][NH:45][C:46](=[NH:47])[NH2:48])=[O:41])[CH3:33])=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: C=C(NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)CN(C)C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C)[C@@H](C)CC)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)CN(C)C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C)[C@@H](C)CC)C(=O)O
Reaction time: 3 h

Procedure:
2.09 g of t-butoxycarbonylsarcosylnitroarginylvalyltyrosylisoleucylhistidylprolyldehydroalanine methyl ester is dissolved in 30 ml of dioxane. To this solution is added 60 ml of 1 N lithium hydroxide. The reaction mixture is stirred for three hours, then neutralized with 1 N hydrochloric acid to pH 7. The solvent is removed by vacuum and the residue is dissolved in N,N-dimethylformamide. Ths solution is filtered and the solvent removed by vacuum. The residue is dissolved in dioxane and added to 300 ml of cold rapidly stirring ethyl ether. The precipate is filtered and dried in vacuo to afford t-butoxycarbonylsarcosylnitroarginylvalyltyrosylisoleucylhistidylprolyldehydroalanine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:46][C@@H:47]2[CH2:51][O:50][C:49]([CH3:53])([CH3:52])[O:48]2)(=O)=O)=CC=1.CCOC(C)=O>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH2:46][C@@H:47]4[CH2:51][O:50][C:49]([CH3:53])([CH3:52])[O:48]4)=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: C[C@H](c1c(O)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](c1c(OC[C@@H]2COC(C)(C)O2)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Temperature: 60 °C

Procedure:
To a suspension of tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (84.5 mg, 0.180 mmol) and potassium carbonate (104.5 mg, 0.7561 mmol) in DMF (3 mL), ((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (103.6 mg, 0.3618 mmol) in DMF (2 mL) was added and the reaction mixture was heated to 60° C. for a total of 23 h. EtOAc was added to dilute the reaction mixture and a standard aqueous workup was performed. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled silica gel loading cartridge [RediSepRf 5 gram] and purified using the Teledyne/ISCO system [RediSepRf 12 g Gold Silica], eluting with a 5-20% EtOAc:heptane solvent system. Fractions containing product were combined and concentrated in vacuo. The material obtained was dissolved in MeOH, passed through a syringe filter, and purified a second time by MDP, under acidic conditions (formic acid). Fractions containing product were pooled together and concentrated in vacuo, affording the title material as a clear and colorless film. 1H NMR (400 MHz, CDCl3): δ=8.43 (d, J=2.3 Hz, 1H), 7.53 (s, 1H), 7.53 (s, 1H), 7.02 (dd, J=9.1, 8.3 Hz, 1H), 6.70 (dd, J=9.1, 4.0 Hz, 1H), 4.92 (q, J=7.0 Hz, 1H), 4.31 (quint, J=5.7 Hz, 1H), 3.97 (dd, J=8.3, 6.6 Hz, 1H), 3.91 (dd, J=9.0, 5.9 Hz, 1H), 3.65 (br s, 1H), 3.46 (br s, 1H), 1.76 (d, J=7.1 Hz, 3H), 1.69 (s, 9H), 1.36 (d, J=5.3 Hz, 6H). MS (ES+): m/z 605.30/606.98/608.99 (23/61/9) [MH++Na]. HPLC: tR 4.15 min (ZQ3, nonpolar—5 min).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>COCCOCCOC>[NH:10]([C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: CSc1nccc(O)n1
Solvent: COCCOCCOC
Product: Oc1ccnc(Nc2ccccc2)n1
Temperature: 160 °C
Yield: 69.2 %

Procedure:
2-Methylthio-4-hydroxypyrimidine (1.42 g, 10 mmol) was dissolved in 2-methoxyethylether (10 ml). To this solution was added aniline (910 μl, 10 mmol) and the reaction mixture heated at 160° C. for 18 hours. The resulting precipitate was filtered off and washed with diethyl ether (10 ml), water (10 ml), diethyl ether (2×10 ml) and dried under vacuum to give the title product as a colourless solid (1.296 g, 69%). NMR (300 MHz): 5.79, (d, 1H), 6.99 (t, 1H), 7.24 (m, 2H), 7.57 (m, 2H), 7.73 (m, 1H), 8.80 (br, 1H); m/z: (ES+) 188.1 (MH+).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:20]3[CH:21]=[C:14]([F:13])[C:15]([C:16]#[N:17])=[C:18]([F:23])[CH:19]=3)[C@H:5]2[CH:9]([CH3:10])[CH3:11])[CH2:3][CH2:2]1
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC(C)[C@@H]1N(c2cc(F)c(C#N)c(F)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (215 mg), 2,4,6-trifluorobenzonitrile (157 mg) and lithium carbonate (163 mg), the title compound was obtained as a colorless solid (yield: 115 mg, yield: 38%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@@H:12]([CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[O:11][C:10]2=[O:26])[CH:5]=[CH:6][C:7]=1[I:8].O.NN>C(O)C>[NH2:15][CH2:14][C@@H:12]1[O:11][C:10](=[O:26])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:13]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A solution of phthalimide 106 (23.3 g, 50.0 mmol) in ethanol (EtOH, 150 mL) was treated with hydrazine monohydrate (12.52 g, 12.1 mL, 250 mmol, 5.0 equiv) at 25° C., and the resulting reaction mixture was warmed to reflux for 2 h. A white precipitate formed as the reaction mixture refluxed. When TLC and HPLC showed that the reaction was complete, the reaction mixture was cooled to room temperature before being quenched with H2O (100 mL). The aqueous solution was then extracted with CH2Cl2 (3×200 mL), and the combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5S)-5-aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one 107 (16.0 g, 95.2% yield) as a white powder. This product was directly used in the subsequent reactions without further purification. C10H10FIN2O2, LCMS (EI) m/e 337 (M++H).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[NH2:22][C:23]1[C:31]2[O:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>>[CH3:32][C:29]1([CH3:33])[CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:22][C:20]3[O:8][CH2:9][C:10]4[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=4[N:19]=3)[C:31]=2[O:30]1
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Product: CC1(C)Cc2cccc(NC3=Nc4ccc([N+](=O)[O-])cc4CO3)c2O1
Yield: 67 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (3.75 g, 11 mmol) and 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4) (1.86 g, 11 mmol) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (2.5 g, 65%), MS (ISP) m/e=340.3 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH:14]1([NH:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:20]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O-:21])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: ONC1CCCCC1
Reactant: CCOc1cc(C=O)ccc1OC
Product: CCOc1cc(C=[N+]([O-])C2CCCCC2)ccc1OC

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3-ethoxy-4-methoxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was isolated in 57% yield as a solid, m.p. 113.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27]Br)[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[CH3:30][O:31][P:32]([O:35]C)[O:33][CH3:34]>>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:32]([O:33][CH3:34])([O:31][CH3:30])=[O:35])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: COC(=O)C(CC=CCBr)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: COP(OC)OC
Product: COC(=O)C(CC=CCP(=O)(OC)OC)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
Under a N2 atmosphere, a solution of 2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester (490 mg, 1.05 mmol) in trimethylphosphite (2.5 mL, 21.1 mmol) was heated at 120° C. for 1 hour. The reaction was allowed to cool to room temperature. The reaction mixture was worked up by removal of the solvent in vacuo followed by chromatography using EtOAc-hexanes to provide 460 mg (88%) of the product as an oil. 1H NMR (300 MHz, CDCl3) δ 1.77 (s, 3H), 2.081-2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H, J=22 Hz), 2.54 (d, 1H, J=22 Hz), 2.55-2.63 (m, 1H), 3.36 (d, 2H, J=7 Hz), 3.57 (s, 3H), 3.72 (d, 6H, J=11 Hz), 3.76 (s, 3H), 5.20 (s, 2H), 5.20-5.26 (m, 1H), 5.36-5.56 (m, 2H), 7.69 (s, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 30.1 ppm; MS (m/z) 497.2 [M+H]+, 519.2 [M+Na]+.