Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH:23]=2)[N:9]=1.[H-].[Na+].I[CH3:51]>CN(C=O)C.C(OCC)(=O)C.O>[F:47][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:51])[C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH:23]=2)[N:9]=1
Reactant: CI
Reactant: O=C(Nc1cccc(Cn2nc(CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(Cc3ccccc3)c2=O)c1)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(Cl)c(Cl)c1)c1cccc(Cn2nc(CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(Cc3ccccc3)c2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound of Example 12 (0.187 g, 0.27 mmol) was dissolved in DMF (10 ml) and sodium hydride (0.016 g, 0.40 mmol) was added followed by iodomethane (0.025 ml, 0.40 mmol). The solution was stirred at 25° C. for 16 hours and diluted with ethyl acetate (30 ml) and water (20 ml). The organic layer was collected and washed with water (3×50 ml), dried (MgSO4) and filtered and the solvent evaporated. The residue was chromatographed on silica eluting with 30% ethyl acetate/hexanes to yield the title compound as a colourless oil. (84%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[CH3:9][O:10][C:11]1([C:17]2[CH:18]=[C:19]([CH2:23]Br)[CH:20]=[CH:21][CH:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CN(C=O)C>[CH3:9][O:10][C:11]1([C:17]2[CH:18]=[C:19]([CH2:23][O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: COC1(c2cccc(CBr)c2)CCOCC1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COCc1cccc(C2(OC)CCOCC2)c1
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 49.7 %

Procedure:
A solution of methyl glycolate (0.35 g, 3.9 mmol) in 5 mL of anhydrous DMF was added to a suspension of sodium hydride (0.11 g, 4.6 mmol) in 5 mL of anhydrous DMF at 5° C, and the reaction mixture was stirred for 40 minutes at 5° C. A solution of 3-[(4-methoxy)tetrahydropyran-4-yl]-α-bromotoluene (1 g, 3.9 mmol) in 10 mL of anhydrous DMF was added to the cold methyl glycolate solution while maintaining the temperature at 5° C. The mixture was stirred for 2 h at 5° C, then for 18 h at room temperature. The mixture was quenched with water (100 mL) and the aqueous solution was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash column chromatography on silica gel, eluting with 25% ethyl acetate in hexane, to give 0.57 g (50%) of methyl 3-[(4-methoxy)-tetrahydropyran-4-yl]phenylmethoxyacetate as a clear oil: HRMS calcd for C16H22O5 295.1545. Found 295.1502.
Reaction SMILES: [Na][S:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([S:10][Na])[S:5][N:4]=1.Br[C:13]1[S:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=1>CO>[N+:18]([C:15]1[S:14][C:13]([S:2][C:3]2[C:7]([C:8]#[N:9])=[C:6]([S:10][C:13]3[S:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=3)[S:5][N:4]=2)=[N:17][CH:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: N#Cc1c(S[Na])nsc1S[Na]
Solvent: CO
Product: N#Cc1c(Sc2ncc([N+](=O)[O-])s2)nsc1Sc1ncc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 4.36 (0.02 mol.) of 3,5-di(sodiomercapto)-4-isothiazole carbonitrile in methanol was added 8.4 g (0.04 mol.) of 2-bromo-5-nitrothiazole. A yellow-brown solid begins to precipitate almost immediately. The reaction mixture is stirred for an additional 2 hours at room temperature (~22° C.). The precipitate is collected by suction filtration, washed with water and methanol and dried in vacuo to yield 6.77 g (79% yield from the isothiazole) of a tan solid, m.p. 197°-199.5° C.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH2:27][CH2:28][C:29]([NH:31][NH2:32])=[O:30])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14].Cl>C(OCC)(OCC)OCC.C(OCC)(=O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([CH2:27][CH2:28][C:29]2[O:30][CH:1]=[N:32][N:31]=2)[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]=1[OH:22])([CH3:12])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: CC(C)(C)c1cc(CCc2nnco2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 774.4 %

Procedure:
A catalytic amount of p-toluenesulfonic acid (25 mg) is added to a stirring solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid hydrazide (0.50 g, 1.71 mmol) in triethyl orthoformate (10 mL). After 30 minutes, 10 mL of 1N hydrochloric acid is added, and stirring is continued for 30 minutes. The reaction mixture is diluted with ethyl acetate and washed twice with a saturated solution of sodium bicarbonate, twice with water, and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a crude product which is chromatographed on a column of silica with ethyl acetate/hexane (1/9 then 1/4) to afford 0.34 g (67%) of 2,6-bis(1,1-dimethylethyl)-4-[2-(1,3,4-oxadiazol-2-yl)ethyl]phenol, mp 100.0°-101.0° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15].Br[CH2:19][CH2:20][CH2:21]Br.[Cl-].[NH4+]>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[C:13]1([C:14]([O:16][CH3:17])=[O:15])[CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)Cc1c(F)cccc1[N+](=O)[O-]
Reactant: BrCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C1(c2c(F)cccc2[N+](=O)[O-])CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of sodium hydride (9.49 g) in DMF (75 mL) was added dropwise a solution of methyl (2-fluoro-6-nitrophenyl)acetate (23 g) and 1,3-dibromopropane (13.1 mL) in DMF (15 mL) at 0° C. The reaction mixture was stirred at room temperature for 4 hr, cooled to 0° C. Saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (11.3 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[Br:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27](=O)[CH2:28]Br>>[Br:23][C:24]1[CH:25]=[C:26]([C:27]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:28]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1cccc(Br)c1
Product: O=C(O)c1cc(-c2nc(-c3cccc(Br)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 34 %

Procedure:
4-[4-(3-Bromo-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (106 mg, 34%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3-bromophenacyl bromide (available from Aldrich Chemical Company, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.43 (s, 1H), 8.08-8.29 (m, 4H), 7.41-7.82 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Yield: 74.4 %

Procedure:
4-nitro-2-phenylbenzoyl methionine methyl ester (0.35 g, 0.90 mmol) was taken up in ethyl acetate (9.0 ml). To this mixture was added SnCl2.2H2O (1.02 g, 4.50 mmol) and the reaction was heated under nitrogen at reflux for 1 h. The mixture was poured onto ice, the solution was made basic using NaHCO3 and the product was extracted into ethyl acetate several times (7-8). The ethyl acetate fractions were combined washed with brine and dried over Na2SO4 and the solvent was removed in vacuo to give 0.24 g (73.4%) of yellow solid. 1H NMR (CDCl3) 1.58-1.70 (1H, m), 1.80-1.92 (1H, m), 1.98 (3H, s), 2.06 (2H, t, J=7.7 Hz), 3.62 (3H, s), 4.00 (2H, br s), 4.56-4.63 (1H, m), 5.84 (1H, d, J=7.7 Hz), 6.50 (1H, s), 6.61 (1H, d, J=8.4 Hz), 7.29-7.42 (5H, m), 7.58 (1H, d, J=8.3 Hz); 13C NMR (CDCl3) 15.02, 29.25, 31.25, 51.57, 52.15, 113.27, 115.88, 123.52, 127.56, 128.37, 128.44, 130.92, 140.66, 141.44, 148.53, 168.58, 171.91.
Reaction SMILES: [OH-].[K+].[N+:3]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O-:5])=[O:4].[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=CC=C[CH:13]=1.C(OCC=C)(=O)C.C([O-])(=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)(C)C.CO>[CH2:17]([C:6]1([N+:3]([O-:5])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH:12]=[CH2:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])C1CCCCC1
Agent: [Pd+2]
Agent: C=CCOC(C)=O
Agent: CC(=O)[O-]
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: C=CCC1([N+](=O)[O-])CCCCC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A 3 neck 2 L round bottom flask equipped with dropping funnel, temperature controller, nitrogen outlet, stir bar and condenser is charged with 71 g (1.27 mols) of potassium hydroxide (KOH), 300 mL of methanol and 300 mL of isopropanol. The addition takes place at room temperature, however, while the base is dissolving in the solvent there is approximately 30° C. increase in temperature. The base solution is allowed to stir under nitrogen for 20 minutes. During this time, the temperature of the flask goes down to 44.7° C. To the above base solution, 156 g of nitrocyclohexane (“NCyHex”) (1.16 mols) is added slowly with vigorous stirring. The mixture stirred for 10 minutes, and palladium acetate (0.56 mmol)/triphenyl phosphine (1.7 mmol) added as catalyst. The resulting yellow solution stirred under nitrogen for another 5 minutes and 139.5 mL (1.06 mols) of allyl acetate added drop-wise to the mixture via the dropping funnel. During the addition of the acetate, the reaction mixture turns brown but transparent. During the addition, the temperature rises. At this point, heat is switched on and the mixture stirred for 8 h at 55° C. followed by overnight stiffing at room temperature. The next day the mixture is heated again to 55° C. followed by room temperature stirring overnight. After the reaction is complete, the contents of the flask are poured into a separatory funnel containing 600 mL of water. The organic layer is extracted with pentane (3×200 mL) and dried under MgSO4. Excess solvent is removed under a rotary evaporator and 167 g (93.5%) of deep brown solution of the desired 1-allyl-1-nitrocyclohexane (11) obtained at 90.7% purity. GC/MS analysis shows [MH]+ m/z 123.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:51][NH:52][CH3:53]>ClCCl>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)[C:9]([N:52]([CH3:53])[CH3:51])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Yield: 91 %

Procedure:
A solution of compound 50.3 (50 mg, 0.1 mmol) in dichloromethane (2 mL) was treated with 1-hydroxybenzotriazole (15 mg, 0.1 mmol) and EDC (21 mg, 0.11 mmol) sequentially. The resulting mixture was stirred for 1 h. before dimethylamine (9 mg, 0.2 mmol) was added dropwise. The reaction was quenched 30 min. later with water (5 mL). The reaction mixture was extracted with dichloromethane (2 mL×3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure to yield amide 50.4 (48 mg). The product was used in the next step without further purification. MS ESI (pos.) m/e: 527 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([O:24]C)=[O:23])=[O:19])=[C:5]2[OH:26].O.[OH-].[Li+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[C:5]2[OH:26]
Reactant: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Reaction time: 0.5 h

Procedure:
Methyl N-((6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (0.684 g, 1.79 mmol, 1.0 eq.) was suspended in water (10.0 mL) and treated with lithium hydroxide monohydrate (0.227 g, 5.40 mmol). After 30 minutes at ambient temperature, the resulting homogeneous mixture was quenched with 1N HCl solution to pH=2. The white solid that precipitated upon acidification was collected by vacuum filtration and washed with 1:1 H2O/acetone (2×2.0 mL). The product was dried under vacuum at 80° C. for 24 hours to give the title compound in quantitative yield. MS m/e=366.0 (M+H)+. Calculated for C17H16ClNO6 365.07.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Solvent: Clc1ccccc1
Product: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1

Procedure:
Methyl 3-acetyl-4-hydroxybenzoate was reacted in chlorobenzene with 1.1 eq. of N-bromosuccinimide and a trace of AlBN to form methyl 3-acetyl-5-bromo-4-hydroxybenzoate. Colorless crystals, mp 106°-108° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[CH3:19])(C(C)(C)C)(C)C.Cl.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:37][C@H:36]3[N:32]([CH2:33][CH2:34][CH2:35]3)[C:31]([CH3:39])([CH3:38])[CH2:30]2)[C:25]([F:40])=[CH:24][N:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[CH3:38][C:31]1([CH3:39])[CH2:30][C@H:29]([NH:28][C:26]2[C:25]([F:40])=[CH:24][N:23]=[C:22]([NH:16][C:15]3[CH:17]=[CH:18][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([CH3:19])[CH:14]=3)[N:27]=2)[CH2:37][C@H:36]2[N:32]1[CH2:33][CH2:34][CH2:35]2
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Reactant: Cc1cc(N)ccc1OCCO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(Nc2ncc(F)c(N[C@@H]3C[C@@H]4CCCN4C(C)(C)C3)n2)ccc1OCCO
Yield: 59.9 %

Procedure:
The general displacement procedure described herein was used with 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-methylaniline (563 mg, 2.0 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (478 mg, 1.4 mmol) and pTsOH.H2O (544 mg, 2.9 mmol) in IPA (10 mL) at reflux to give the product (360 mg, 59% yield) as a solid, after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 9:1) as eluent.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].[CH3:6][C:7]([CH3:14])([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9]>C1(C)C=CC=CC=1>[C:8]([NH:10][C:11]([N:4]1[CH2:5][CH:3]1[C:1]#[N:2])=[O:12])(=[O:9])[C:7]([CH3:14])([CH3:13])[CH3:6]
Reactant: N#CC1CN1
Reactant: CC(C)(C)C(=O)N=C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)NC(=O)N1CC1C#N

Procedure:
A solution of 1.61 g. 2-cyanoaziridine in 30 ml. toluene is added dropwise at 20° to 30° C. to a solution of 3 g. trimethyl-acetyl isocyanate in 40 ml. anhydrous toluene and the reaction mixture then stirred for 1 hour at ambient temperature, whereafter the milky solution obtained is evaporated in a vacuum. The evaporation residue is rubbed with a glass rod until crystallization commences and the crystals obtained are triturated with diethyl ether. There is thus obtained 1.82 g. 1-(N-pivaloyl-carbamoyl)-2-cyanoaziridine which, after drying at 60° C. in a vacuum, melts at 136°-138° C.
Reaction SMILES: COC1C=C(O)C=CC=1.C(=O)([O-])[O-].[K+].[K+].C(OC(C1CCC(=O)C(Br)C1)=O)C.C([O:31][C:32]([CH:34]1[CH2:39][CH2:38][C:37](=O)[CH:36]([O:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=2)[CH2:35]1)=[O:33])C.C(OC(C1CC2OC3C=C(OC)C=CC=3C=2CC1)=O)C.[OH-].[Na+]>C(O)C.O.CN(C)C=O>[CH3:49][O:48][C:44]1[CH:45]=[CH:46][C:47]2[C:37]3[CH2:38][CH2:39][CH:34]([C:32]([OH:31])=[O:33])[CH2:35][C:36]=3[O:41][C:42]=2[CH:43]=1
Reactant: CCOC(=O)C1CCC(=O)C(Oc2cccc(OC)c2)C1
Agent: CCOC(=O)C1CCC(=O)C(Br)C1
Agent: CCOC(=O)C1CCc2c(oc3cc(OC)ccc23)C1
Agent: COc1cccc(O)c1
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc2c3c(oc2c1)CC(C(=O)O)CC3
Temperature: 0 °C

Procedure:
A suspension of 6.2 g. of freshly distilled 3-methoxyphenol and 6.9 g. of potassium carbonate in 20 ml. of dimethylformamide was heated at 100° for 15 minutes. To the stirred suspension was added dropwise 12.5 g. of 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 5 ml. of dimethylformamide, and the resulting mixture was stirred at 100° for 30 minutes. After cooling, 150 ml. of water was added, and the reaction mixture was extracted with three 150 ml. portions of ether. The ether layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate, and treated with charcoal. Evaporation of the solvent gave 8.5 g. of 3-(m-methoxyphenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester as a yellow oil. A mixture of this material and 85 g. of polyphosphoric acid was stirred for 15 minutes at room temperature, and added to 150 ml. of ice water. Thereafter, the mixture was extracted with three 150 ml. portions of ether. The ether extracts were washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Evaporation of the solvent gave 7 g. of 7-methoxy-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester as a dark oil, which was dissolved in 100 ml. of ethanol and 50 ml. of 2N sodium hydroxide. The resulting solution was heated at reflux temperature for 1 hour. The ethanol was removed under reduced pressure. After the addition of 150 ml. of water, the reaction mixture was extracted with ether. The aqueous layer was treated with charcoal, cooled in an ice water bath, and neutralized with 50 ml. of 2N hydrochloric acid. The solids which formed were removed by filtration and were crystallized from acetone-water to give 3.8 g. of crystals, m.p. 175°-180°. Recrystallization from acetonitrile-water gave 7-methoxy-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid as white crystals, m.p. 181°-183°.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:37])[N:21]([CH3:36])[C@@H:22]([CH2:29][N:30]([CH3:35])[S:31]([CH3:34])(=[O:33])=[O:32])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:6][NH:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH3:36])[C@@H:22]([CH2:29][N:30]([CH3:35])[S:31]([CH3:34])(=[O:32])=[O:33])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[O:37]
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 106.5 %

Procedure:
A solution of of N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-((N-methyl-N-(methylsufonyl)amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester (1.94 g, 3.37 mmol) in dichloromethane (7 ml) was cooled to 0° C. Trifluoroacetic acid (7 ml) was added. The reaction mixture was stirred for 45 min at 0° C. A saturated aqueous solution of sodium hydrogen carbonate (30 ml) was added. Solid sodium hydrogen carbonate was added until pH 7. Water (100 ml) was added, until a clear solution was obtained. The phases were separated. The aqueous solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, to give 1.70 g of (2R)-2-Methylamino-N-methyl-N-((1R)-1-((N-methyl-N-(methylsulfonyl)amino)methyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:19][C:20]([S@@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21].[BH4-].[Na+].CO>C1COCC1.[Cl-].[Na+].O.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[C:20]([S@@:23]([NH:25][C@H:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:24])([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CCOC(=O)CCCC(=O)c1cc(F)cc(F)c1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CCC[C@H](N[S@@](=O)C(C)(C)C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-(3,5-difluorophenyl)-5-oxovalerate (5.00 g, 19.5 mmol) and (S)-2-methylpropane-2-sulfinamide (2.88 g, 23.8 mmol) in THF (123 mL) was added titanium tetraethoxide (8.18 mL, 39.0 mmol). The reaction vessel was quickly sealed and placed into a 60° C. bath for 16 h. After cooling to ambient temperature a septum and nitrogen inlet were attached prior to cooling to 0° C. Sodium borohydride (1.48 g, 39.0 mmol) was then added, and a complete reaction was observed after 1 h. Methyl alcohol was then slowly added until gas evolution had stopped. The reaction mixture was then diluted with brine (60 mL) while experiencing rapid stirring. The resultant slurry was filtered through celite, washing with EtOAc as needed. The combined organics were then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of EtOAc:Hexanes—10:90 to 50:50, to give the title compound. MS: m/z=362 (M+1).