Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:11](=O)[CH2:10][C:9](=[O:13])[N:8]([CH3:14])[C:7]1=[O:15])#[C-:2].P(Cl)(Cl)([Cl:22])=O.P(Cl)(Cl)(Cl)(Cl)Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:22][C:11]1[N:6]([CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=2[N+:1]#[C-:2])[C:7](=[O:15])[N:8]([CH3:14])[C:9](=[O:13])[CH:10]=1
Reactant: [C-]#[N+]c1ccccc1CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: CC#N
Product: [C-]#[N+]c1ccccc1Cn1c(Cl)cc(=O)n(C)c1=O
Yield: 70.5 %

Procedure:
In an alternate embodiment, a solution of 1-(2-isocyanobenzyl)-3-methylpyrimidine-2,4,6(1H,3H,5H)-trione (18 mmol), phosphorus oxychloride (85 ml), benzyltriethylammonium chloride (16.5 g, 72 mmol) and phosphorus pentachloride (3.8 g, 18 mol) in acetonitrile (80 ml) was refluxed for 4-5 h with stirring. After evaporation under reduced pressure, the resulting oily residue was mixed with methylene chloride (or chloroform) and the mixture was poured into water and ice (50 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. Crude product was crystallized from THF-hexanes to give desired compound in 70.5% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH3:10])[CH:5]=[CH:6][C:7]=1[NH2:8].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1.O>C1COCC1.C(Cl)Cl>[CH3:17][C:14]([S:12]([NH:11][CH:9]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:23](=[O:24])[NH:1][C:2]=2[CH:3]=1)[CH3:10])=[O:13])([CH3:16])[CH3:15]
Reactant: CC(NS(=O)C(C)(C)C)c1ccc(N)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(NS(=O)C(C)(C)C)c1ccc2[nH]c(=O)[nH]c2c1
Yield: 65 %

Procedure:
A mixture of N-[1-(3,4-diaminophenyl)ethyl]-2-methylpropane-2-sulfinamide and CDI (569 mg, 3.51 mmol) in THF-DCM (10 ml-10 ml) was refluxed for 6 hours. After cooling to the room temperture, water (10 mL) was added to the mixture. The mixture was extracted with EtOAc (150 ml) and organic layer was washed with brine (30 ml), dried over sodium sulfate and concentrated. The residue was recrystallized from EtOAc to afford 430 mg (65%) of the title compound as a pale brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11 (9H, s), 1.38 (3H, d, J=7.3 Hz), 4.37-4.28 (1H, m), 5.53 (1H, d, J=6.6 Hz), 6.84 (1H, d, J=7.3 Hz), 6.93 (1H, d, J=8.1 Hz), 6.99 (1H, s), 10.54 (1H, br.s), 10.60 (1H, br.s). MS (ESI) m/z 282 (M+H)+, 280 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Br:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)[CH3:5].[C:30]([O:34][C:35](=O)[O:36]C(C)(C)C)([CH3:33])([CH3:32])[CH3:31].CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.CN(C1C=CN=CC=1)C>[C:30]([O:34][C:35]([N:9]1[C:8]2[CH2:7][CH:6]([C:4]([S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:3]([O:2][CH3:1])=[O:29])[CH3:5])[CH2:18][CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([Br:19])[CH:14]=2)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Br)cc23)C1)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Br)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To 1.2 g (2.52 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester (from example 99) in 40 mL of THF were added 31 mg (0.25 mmol, 0.1 eq) of DMAP and 660 mg (3.02 mmol, 1.2 eq) of carbonic acid di-tert-butyl ester at 0° C. The reaction mixture was stirred at RT for 2 hours. EtOAc and a solution of aqueous NaHCO3 were added, the phases were separated, and the organic one was extracted with 1M KHSO4. The organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography afforded 1.3 g (90%) of (RS,SR)-2-(-1-benzenesulfonyl-1-methoxycarbonyl-ethyl)-6-bromo-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as white solid, MS: 575 (M,1Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)(=[O:11])=[O:10].[CH2:21]1[NH:26][CH2:25][CH2:24][N:23]2[CH2:27][CH2:28][CH2:29][C@H:22]12>CN(C)C(=O)C.CC1CCCO1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:26]2[CH2:25][CH2:24][N:23]3[CH2:27][CH2:28][CH2:29][C@@H:22]3[CH2:21]2)=[O:17])[CH:13]=1)(=[O:10])=[O:11]
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Reactant: C1C[C@@H]2CNCCN2C1
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(S(=O)(=O)Nc2ccccc2F)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg, 2.71 mmol) and 2-(3H-[1,2,3]triazolo[4,5-h]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1133 mg, 2.98 mmol) in N,N-dimethylacetamide (6.5 mL) and 2-methyltetrahydrofuran (19.5 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (479 mg, 3.79 mmol). The reaction was stirred at room temperature for 3 hours, diluted with 2-methyltetrahydrofuran (5 mL), and washed with saturated bicarbonate (2×25 mL). The combined aqueous layers were adjusted to pH 7 with buffer and re-extracted with 2-methyltetrahydrofuran (3×15 mL). The combined organic layers were concentrated under reduced pressure. The residue was taken up in ethanol (25 mL) and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.Cl[S:14]([C:17]1[CH:39]=[CH:38][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[O:24])=[C:19]([O:40][CH2:41][C:42]([O:44][CH2:45][CH2:46][S:47]([C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=2)(=[O:49])=[O:48])=[O:43])[CH:18]=1)(=[O:16])=[O:15]>N1C=CC=CC=1.C1(C)C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:14]([C:17]2[CH:39]=[CH:38][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)(=[O:29])=[O:30])=[O:24])=[C:19]([O:40][CH2:41][C:42]([O:44][CH2:45][CH2:46][S:47]([C:50]3[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=3)(=[O:49])=[O:48])=[O:43])[CH:18]=2)(=[O:15])=[O:16])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccc(S(=O)(=O)Cl)cc2OCC(=O)OCCS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2ccc(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)c(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)c2)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 58.3 %

Procedure:
4-Methoxy-2-nitroaniline (2.3 g, 0.014 mol) and 2-(4-tolylsulfonyl)ethyl 4-chlorosulfonyl-2-(2-[4-tolylsulfonyl]ethoxycarbonylmethoxy)phenoxyacetate (Intermediate A16, 9.6 g, 0.014 mol) were dissolved in 40 mL of pyridine and stirred under positive nitrogen pressure. After ca. 16 hr, the mixture was diluted with 50 mL of toluene and 20 mL of dichloromethane and was concentrated at aspirator pressure. The residue was purified on a flash silica gel column (dichloromethane→5:1 dichloromethane:ethyl acetate) to yield 6.7 g (58%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:15][C:14]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=4)[O:16]3)[CH2:13]2)=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:45][O:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][O:48]1>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:15][C:14]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:45][O:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][O:48]5)=[O:29])[CH:21]=4)[O:16]3)[CH2:13]2)=[CH:3]1
Reactant: NOC1CCCCO1
Reactant: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)O)ccc4O3)C2)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)NOC5CCCCO5)ccc4O3)C2)c2ccccc21
Yield: 45.5 %

Procedure:
A suspension of (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (180 mg, 0.447 mmol) in DCM (5 ml) was treated with TEA (0.09 ml, 0.67 mmol) and then with EDC (128 mg, 0.67 mmol), HOBt (90 mg, 0.67 mmol) and NH2OTHP (67 mg, 0.57 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (102 mg) as a white solid.
Reaction SMILES: O1CC[CH2:3][CH2:2]1.[H-].[Na+].[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([O-:12])=[O:11].Cl[C:18]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:34][CH2:33][C:28]3([O:32][CH2:31][CH2:30][O:29]3)[CH2:27][CH2:26]2)[N:21]=[C:20]([C:35]([F:38])([F:37])[F:36])[N:19]=1>C(=O)(O)[O-]>[O:32]1[C:28]2([CH2:33][CH2:34][CH:25]([O:24][C:22]3[N:21]=[C:20]([C:35]([F:38])([F:37])[F:36])[N:19]=[C:18]([CH:9]([C:10]([O:12][CH2:2][CH3:3])=[O:11])[C:8]([O:14][CH2:15][CH3:16])=[O:13])[CH:23]=3)[CH2:26][CH2:27]2)[O:29][CH2:30][CH2:31]1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: FC(F)(F)c1nc(Cl)cc(OC2CCC3(CC2)OCCO3)n1
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: 64 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a mixture of tetrahydrofuran (40 mL) and NaH in mineral oil (1.1 g, 28 mmol) at 0° C. was added ethyl malonate (4.2 mL, 28 mmol), dropwise. 4-chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine (described in Example 1, Step 1) (3.75 g, 11.1 mmol), was then added. The reaction mixture was stirred at 64° C. After 3 hours, HPLC & LCMS analysis showed 70% reaction completion. Heated for another 6 hours, and then cooled to 20° C. Only a trace of decarboxylation product formed. The reaction was diluted with aqueous bicarbonate, and extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na2SO4, and evaporated in vacuo to give 8.5 g oil (includes excess ethyl malonate and mineral oil). The crude product was purified by chromatography on a 120 g silica gel column, using solvent A=hexane; solvent B=EtOAc; flow 60 mL/min; A, 3 min; Gradient to 40% B in 40 min; detector set at 254 nm; collected 47 mL fractions; retention time, 28 min. The combined fractions were evaporated to give 4.6 g, colorless oil, 90% yield. 1H NMR (300 MHz, CDCl3): δ7.05 (s, 1H); 5.30 (m, 1H, OCH); 4.85 (s, 1H, CH); 4.25 (m, 2H, OCH2); 3.95 (s, 4H, OCH2); 1.6-2.1 (m, 8H); 1.28 (t, 3H, CH3).
Reaction SMILES: [CH2:1]([C:3]1[N:16]=[C:6]2[NH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[H-].[Na+].Br[CH2:20][C:21]1[CH:41]=[CH:40][C:24]([O:25][CH:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:23]([CH2:42][CH2:43][CH3:44])[CH:22]=1.CCOC(C)=O>CN(C=O)C>[C:27]([CH:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:25][C:24]1[CH:40]=[CH:41][C:21]([CH2:20][N:16]2[C:6]3=[N:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:22][C:23]=1[CH2:42][CH2:43][CH3:44])([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28]
Reactant: CCc1nc2[nH]c(C(=O)OC)cc(C)c-2n1
Reactant: CCCc1cc(CBr)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)OC)nc32)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a 25 mL round bottom flask were placed 41.8 mg (0.19 mmol) of methyl 2-ethyl-7-methylimidazo[4,5-b]pyridine-5-carboxylate (the product of Step G of this Example) and a 60% oil dispersion of NaH (5 mg, 0.21 mmol). The flask was evacuated and filled with nitrogen. Dry DMF (2 mL) was added to the mixture dropwise at 0° C. The solution was stirred at rt for 5 minutes. To the solution was added 80 mg (0.19 mmol) of tert-butyl 2-(4-bromomethyl-2-propyl- phenoxy)-2-phenylacetate (Step O) in dry DMF (2 mL) at rt. After the solution was stirred at rt for 15 hours, it was poured into EtOAc (10 mL) and washed with H2O and brine, and dried over anhydrous MgSO4. Concentration followed by purification by flash chromatography (hexane: EtOAc=2:1) afforded 63.6 mg of the title compound as a colorless glass.
Reaction SMILES: [NH2:1][C@H:2]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[CH:11]=[CH:12][C:4]=2[CH2:3]1.[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42](O)=[O:43])[CH:39]=1)[CH2:34]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42]([NH:1][C@H:2]3[C:15](=[O:16])[N:14]([CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:13][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[CH:11]=[CH:12][C:4]=4[CH2:3]3)=[O:43])[CH:39]=1)[CH2:34]2
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: N[C@@H]1Cc2ccc3[nH]ncc3c2CN(CCN2CCCC2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(CCN2CCCC2)C1=O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7-(R)-amino-9-(2-pyrrolidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazacyclohepta[e]inden-8-one (72 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (78 mg, 0.28 mmol) [Bell et al. WO 2006/031606], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.C(SC(=O)[CH2:19][CH2:20][C@H:21]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])C1C=CC=CC=1.Cl.[NH2:42][C@@H:43]([CH2:49][SH:50])[C:44]([O:46][CH2:47][CH3:48])=[O:45].C(CCP(CCC(O)=O)CCC(O)=O)(O)=[O:52]>CN(C=O)C.O>[C:36]([O:35][C:33]([NH:32][C@@H:21]([CH2:20][C:19]([NH:42][C@@H:43]([CH2:49][SH:50])[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:52])[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:34])([CH3:37])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)SCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CS)NC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
DIPEA (0.098 ml, 0.563 mmol) was added to a solution of (S)-benzyl 5-(benzylthio)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate (Compound 5b-2) (208.2 mg, 0.469 mmol) and (R)-ethyl 2-amino-3-mercaptopropanoate hydrochloride (104.5 mg, 0.563 mmol) in DMF (1.2 ml) and water (0.3 ml), and the mixture was stirred at 50° C. for three hours. A 0.4 M aqueous tris(2-carboxyethyl)phosphine (TCEP) solution (3.27 ml) and DMF (3.27 ml) were then added to the reaction solution, after which the mixture was stirred at room temperature for one hour. The reaction mixture was then purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→20/80) to afford (S)-benzyl 2-((tert-butoxycarbonyl)amino)-4-(((R)-1-ethoxy-3-mercapto-1-oxopropan-2-yl)amino)-4-oxobutanoate (Compound 5c-2) (192.4 mg, 88%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][CH2:9][CH2:10][N:11](CCN)CCN.O.[N+]([O-])([O-])=O.[Ga+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:8][CH2:9][CH2:10][NH2:11]
Reactant: NCCN(CCN)CCN
Reactant: O=Cc1ccc[nH]1
Agent: O=[N+]([O-])[O-]
Agent: [Ga+3]
Solvent: O
Product: NCCN=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The ligand [(((pyrrole-2-yl)methylidene)amino)ethyl]amine was prepared by adding a methanolic solution of pyrrole-2-carboxaldehyde (1.430 g, 15 mmol, 100 ml) to a methanolic solution of tris(2-aminoethyl)amine (0.720 g, 5 mmol, 10 ml). The resulting yellow solution was stirred at room temperature for 30 min. A methanolic solution of gallium(III) nitrate hydrate (1.280 g, 5 mmol, 150 ml) was added to the ligand solution and stirred at room temperature for 30 min. The solution was filtered and left to stand at ambient temperature until crystallization occurred. The crude material was then sublimed at 235° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:23]([SiH2:27][O:28][C:29]([CH3:41])([CH3:40])[C:30]1[CH:31]=[C:32]([CH2:37][CH2:38][NH2:39])[CH:33]=[CH:34][C:35]=1[Cl:36])([CH3:26])([CH3:25])[CH3:24].[F:42][C:43]([F:49])([F:48])[CH2:44][C:45](O)=[O:46].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([SiH2:27][O:28][C:29]([CH3:41])([CH3:40])[C:30]1[CH:31]=[C:32]([CH2:37][CH2:38][NH:39][C:45](=[O:46])[CH2:44][C:43]([F:49])([F:48])[F:42])[CH:33]=[CH:34][C:35]=1[Cl:36])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCN)ccc1Cl
Reactant: O=C(O)CC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCNC(=O)CC(F)(F)F)ccc1Cl
Reaction time: 1 h
Yield: 28.2 %

Procedure:
TBTU (2.09 g, 6.50 mmol) was added to a sol. of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethylamine (1.30 g, 4.33 mmol), 3,3,3-trifluoropropionic acid (0.574 mL, 6.50 mmol) and DIPEA (2.97 mL, 17.3 mmol) in CH2Cl2 (43 mL). The mixture was stirred for 1 h, and CH2Cl2 was added. The mixture was washed with aq. sat. NH4Cl, aq. 10% Na2CO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 60:40) yielded the title compound (500 mg, 28%). LC-MS: tR=1.12 min; ES+: 410.14.
Reaction SMILES: ClB.CSC.[CH3:6][SiH:7]([CH2:9][CH2:10][Si:11]([CH3:21])([CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH3:8].[OH:22]O>C1COCC1>[CH3:6][SiH:7]([CH2:9][CH2:10][Si:11]([CH3:21])([CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:22])[CH3:8]
Reactant: OO
Reactant: C=CCCCCCC[Si](C)(C)CC[SiH](C)C
Agent: BCl
Solvent: CSC
Solvent: C1CCOC1
Product: C[SiH](C)CC[Si](C)(C)CCCCCCCCO
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Monochloroborane-methyl sulfide (1.10 ml, 1.16 g, 10.5 mmol) was added dropwise to a stirred, cooled (0° C.) solution of compound 9 (2.56 g, 10.0 mmol) in THF (30 ml). The reaction mixture was stirred at 0° C. for 24 h, and a solution of hydrogen peroxide (10 ml, 30% in water) added dropwise and the reaction mixture stirred at 0° C. for 4 h, washed with water and the organic layer extracted into hexane/ethyl acetate (3×30 ml, 1:1). The combined extracts were washed with brine, dried (MgS04) and the solvent removed in vacuo to yield colorless oil. The crude product was purified by column chromatography [silica gel eluted with hexane/ethyl acetate (4:1)] to yield a colorless oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].C([CH:7](Br)[C:8](=O)[C:9]([O-:11])=[O:10])C.[CH2:14](O)[CH3:15]>>[NH2:1][C:2]1[O:3][CH:7]=[C:8]([C:9]([O:11][CH2:14][CH3:15])=[O:10])[N:4]=1
Reactant: CCC(Br)C(=O)C(=O)[O-]
Reactant: CCO
Reactant: NC(N)=O
Product: CCOC(=O)c1coc(N)n1

Procedure:
To a 250 ml 3-neck round bottom flask was added (20 g, 0.3332 moles) urea, (150 ml) ethanol and (42.42 g, 0.2175 moles, 0.65 eq) ethylbromopyruvate. The mixture was then heated under agitation to reflux for 16 hours. The reaction solution changed from yellow to red in color. The reaction solution was then evaporated to dryness and the crude product was taken up in (50 ml) water and (150 ml) ethyl acetate. The pH was adjusted from 1 to 10 using 2N sodium hydroxide, changing the biphasic mixture a dark red. The mixture was separated and the aqueous phase was extracted twice with ethyl acetate. The organic layers were then combined and washed with water and brine. The resulting yellow solution was concentrated to ˜50 ml, causing an off-white solid to precipitate out. The solid was filtered off and washed with ethanol and diethyl ether. The mother liquor was then evaporated to dryness and the resulting oily solid was taken up in (150 ml) ethyl acetate and concentrated to ˜50 ml. An off-white solid precipitated out. The mixture was cooled in an ice bath, and the solid was filtered off and washed with ethanol and diethyl ether to give ethyl 2-amino-1,3-oxazole-4-carboxylate (14.79 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]([N:12]2[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][C@H:13]2[CH3:27])=[O:11])=[C:6]([CH2:30][OH:31])[CH:5]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O1CCCC1>[C:37]([O:36][C:34](=[O:35])[CH2:33][O:31][CH2:30][C:6]1[CH:5]=[C:4]([Cl:3])[CH:29]=[CH:28][C:7]=1[O:8][CH2:9][C:10]([N:12]1[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:14][C@H:13]1[CH3:27])=[O:11])([CH3:40])([CH3:39])[CH3:38]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CO
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1COCC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To a 0° C. solution of sodium hydride (0.025 g, 60% dispersion, 1.0 mmol) in tetrahydrofuran (2 mL) was added a solution of 2-(4-chloro-2-hydroxymethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.17 g, 0.40 mmol) and tert-butyl bromoacetate (0.23 g, 3.0 mmol) in tetrahydrofuran (2 mL). The reaction mixture was warmed to ambient temperature overnight, quenched with water and diluted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified via chromatography on silica gel to give the title compound (0.14 g).