Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([OH:24])=O)[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:47]([O:49][C:50](=[O:53])[CH2:51][NH2:52])[CH3:48]>CN(C)C=O.ClCCl>[CH2:47]([O:49][C:50](=[O:53])[CH2:51][NH:52][C:22]([C:15]1[N:16]2[C:17]([CH2:18][O:19][CH2:20][CH2:21]2)=[C:13]([C:11](=[O:12])[NH:10][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH3:9])[CH:14]=1)=[O:24])[CH3:48]
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)O)n2c1COCC2)c1ccccc1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cc(C(=O)N[C@H](CC)c2ccccc2)c2n1CCOC2
Temperature: 40 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11a) (50 mg, 0.168 mmol) in dimethylformamide (1.7 ml) was added 1-hydroxybenzotriazole (23 mg, 0.168 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg, 0.168 mmol). The mixture was stirred for 1 h at 40° C., then amino-acetic acid ethyl ester (17 mg, 0.168 mmol) was added and the mixture was stirred at 25° C. overnight. Excess dichloromethane was added and the mixture was washed consecutively with water, aqueous sodium hydrogencarbonate and brine. The organic layer was evaporated to dryness. The residue was dissolved in a small amount of acetonitrile, excess water was added and the solution was freeze-dried to give 52 mg (82%) of {[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-amino}-acetic acid ethyl ester. LC/MS (method 4): Rt=1.19 min; m/z=414.2 (M+H+). 1H-NMR: δ (ppm)=8.46 (1H, t), 8.21 (1H, d), 7.35-7.36 (3H, m), 7.30 (2H, t), 7.21 (1H, t), 4.91 (2H, dd), 4.82 (1H, q), 4.19 (2H, t), 4.11 (2H, q), 3.90-3.92 (4H, m), 1.71-1.83 (2H, m), 1.21 (3H, t), 0.88 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:34](Cl)=[O:35].O>C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:34]([N:24]1[CH2:25][CH2:26][N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:23]1=[O:22])=[O:35]
Reactant: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: ClCCl
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)c(F)c3)ccn2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A mixture of 2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.150 g, 0.528 mmol) and TEA (3.2 mL, 22.93 mmol) in DCM (5 mL) was cooled to 0° C., treated with a solution of Example B2 (0.164 g, 0.705 mmol) in DCM (1.5 mL), warmed to RT and stirred for 1 h. The mixture was treated with water, stirred for 10 min, the layers separated and the organic layer dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with Et2O, sonicated and the resulting solid collected via filtration to afford N-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (167 mg, 66%). 1H NMR (400 MHz, DMSO-d6): δ 10.74 (d, J=2.5 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.19 (t, J=9.1 Hz, 1 H), 7.95 (d, J=0.7 Hz, 1 H), 7.28 (dd, J=11.7, 2.7 Hz, 1 H), 7.22 (d, J=2.4 Hz, 1 H), 7.03 (dd, J=9.1, 2.5 Hz, 1 H), 6.67 (dd, J=5.7, 2.4 Hz, 1 H), 3.93-3.77 (m, 8 H), 3.46 (t, J=8.2 Hz, 2 H), 3.38 (dd, J=12.5, 10.6 Hz, 2 H), 1.71 (qd, J=12.2, 4.5 Hz, 2 H), 1.60-1.57 (m, 2H); MS (ESI) m/z: 481.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1C(O)=O.[CH:19]1([CH2:25][N:26]2[C:30](=[O:31])[CH:29]=[CH:28][C:27]2=[O:32])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(OCC)(=O)C.CCCCCC>[CH:19]1([CH2:25][N:26]2[C:27](=[O:32])[CH:28]3[CH:7]([C:6]4[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:11]4[CH:12]([CH:29]3[C:30]2=[O:31])[CH2:16][CH2:17][CH2:18]4)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C1C=CC(=O)N1CC1CCCCC1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2C3C(=O)N(CC4CCCCC4)C(=O)C3C3CCCN32)cc1

Procedure:
7.B)g) (3aRS,4SR,8aRS,8bSR)-4-(2-Cyclohexylmethyl-1,3-dioxo-decahydro-pyrrolo[3,4-a]pyrrolizin-4-yl)-benzonitrile was prepared analogously to Example 4.B)g) from 4-cyano-benzaldehyde, L-proline and N-cyclohexylmethylmaleimide. Colourless crystals. M.p.: 119°-122° C. (ethyl acetate/hexane). ISP-MS: 378.4 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C1C2C(COC([NH:63][C@:64]([C:68](O)=[O:69])([CH3:67])[CH2:65][CH3:66])=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C>ClCCl>[NH2:63][C@:64]([C:68]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:69])([CH3:67])[CH2:65][CH3:66]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC[C@@](C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@](C)(N)CC)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
A solution of #114 (447 mg, 0.707 mmol, 1.0 eq.) in 2 mL of dichloromethane was added to a solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-isovaline (240 mg, 0.707 mmol, 1.0 eq.) in 4 mL of dichloromethane. Hunig's base (0.373 mL, 2.12 mmol, 3.0 eq.) was added followed by HATU (332 mg, 0.425 mmol, 1.2 eq.). The reaction was allowed to stir at room temperature for 12 hours. The reaction was concentrated in vacuo and then taken up in ethyl acetate before being washed two times with 1M HCl and once with brine. The organic layer was dried over sodium sulfate and decanted. The organic solvent was removed in a genevac. THF (4 mL) was added followed by diethylamine (2 mL, 19 mmol, 26.9 eq.). The reaction was allowed to stir for ˜12 hours. Reaction was concentrated using a genevac followed by silica chromatography (Gradient: 0%-30% methanol in ethyl acetate) producing #148 (182 mg, 35%) as a solid. LC-MS (Protocol Q1): m/z 732.3 [M+H+] retention time=0.71 minutes. 1H NMR (400 MHz, DMSO-d6), δ 8.56 (d), 8.46-8.52 (m), 8.30 (d), 8.02-8.15 (m), 7.98 (d), 7.80 (d), 7.40-7.53 (m), 7.15-7.30 (m), 4.70-4.80 (m), 4.44-4.69 (m), 3.96-4.05 (m), 3.70-3.79 (m), 3.62-3.69 (m), 3.41-3.59 (m), 2.99-3.35 (m), 2.31-2.95 (m), 2.67-2.71 (m), 2.55-2.59 (m), 2.32-2.48 (m), 2.20-2.31 (m), 1.97-2.19 (m), 1.61-1.88 (m), 1.37-1.56 (m), 1.20-1.34 (m), 1.14-1.19 (m), 1.02-1.11 (m), 0.97-1.01 (m), 0.86-0.96 (m), 0.71-0.83 (m).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][CH2:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:23]([O:25]CC)=[O:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])C.[OH-].[Na+]>C(O)C.O>[C:4]([C:5]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:34])[CH2:6][CH2:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:16])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]([OH:25])=[O:24])([OH:35])=[O:3]
Reactant: CCOC(=O)C(C)(CCCCSCCCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCCCSCCCCC(C)(C(=O)O)c1ccccc1)(C(=O)O)c1ccccc1
Yield: 68.3 %

Procedure:
A solution of 6-(5-ethoxycarbonyl-5-phenylhexylsulfanyl)-2-methyl-2-phenylhexanoic acid ethyl ester (6.00 g, 12.0 mmol) and sodium hydroxide (3.1 g, 74.0 mmol) in ethanol (40 mL) and deionized water (4 mL) was heated to reflux for 2 h. The ethanol was evaporated in vacuo and the residue was dissolved in water (20 mL) and extracted with diethyl ether (20 mL). The organic phase was discarded. The aqueous layer was acidified with 2 N hydrochloric acid (15 ml) to pH 2-3 and extracted with diethyl ether (4′ 50 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated in vacuo. The residue (4.53 g) was purified by column chromatography on silica gel (hexanes/ethyl acetate=10/1) to give 6-(5-carboxy-5-phenyl-hexylsulfanyl)-2-methyl-2-phenyl-hexanoic acid (3.63 g, 68%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): d (ppm): 7.42-7.20 (m, 10H), 2.45 (t, J=7.3 Hz, 4H), 2.15-1.80 (m, 4H), 1.65-1.45 (m, 4H), 1.56 (s, 6H), 1.40-1.15 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): d (ppm): 182.43, 142.89, 128.41, 126.91, 126.05, 50.00, 38.53, 31.80, 30.00, 24.03, 22.40. HRMS (LSIMS, nba): Calcd. for C26H35O4S1 (MH+): 443.2256, found: 443.2231.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[Cl:31][CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[Cl:31][CH2:32][C:33]([N:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:15]2[C:16](=[O:19])[C:17]3[S:18][C:10]([C:7]4[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=4)=[CH:11][C:12]=3[N:13]=[CH:14]2)=[CH:23][CH:24]=1)[CH3:30])=[O:34]
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C(=O)CCl
Temperature: 60 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of the compound (200 mg) obtained in Example 4, chloroacetyl chloride (51 mg), triethylamine (146 mg) and tetrahydrofuran (2 ml) was stirred at 60° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [developing solvent:ethyl acetate-methanol (20:1, volume ratio)] and crystallized from hexane to give the title compound (130 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.C(N(CC)CC)C.ClC(Cl)(O[C:28](=O)[O:29][C:30](Cl)(Cl)Cl)Cl.C[O:37][C:38]1[N:43]=[C:42]([NH2:44])[CH:41]=[N:40][CH:39]=1>C(Cl)Cl.O>[CH3:30][O:29][C:28]1[N:44]=[C:42]([NH:43][C:38]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)=[O:37])[CH:41]=[N:40][CH:39]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cncc(N)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cncc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
A mixture of 350 mg (1.60 mmol) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine and 1.35 ml (9.59 mmol) of triethylamine in 10 ml of DCM is added, under nitrogen, to a solution of 474.07 mg (1.60 mmol) of triphosgene in 30 ml of DCM. The mixture is stirred for 30 minutes at room temperature, followed by addition of 1 g (7.99 mmol) of 6-methoxypyrazin-2-amine. The resulting mixture is stirred for 2 hours at room temperature. Water is added and the product is extracted with DCM. The solution is dried over MgSO4 and then filtered. The filtrate is evaporated under reduced pressure and the residue is then chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0 v/v) up to (96/4 v/v). The solvent is evaporated off under reduced pressure. The residue is taken up in ethyl acetate and washed three times with 1N hydrochloric acid solution and then with saturated NaCl solution. The resulting solution is dried over MgSO4. 167 mg of 1-(6-methoxypyrazin-2-yl)-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]urea are obtained.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:31]=[C:32]([C:36](=[O:38])[CH3:37])[CH:33]=[CH:34][CH:35]=1>>[C:36]([C:32]1[CH:31]=[C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:38])[CH3:37]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)c1cccc(Br)c1
Product: COc1ccc(-c2cccc(C(C)=O)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (140 mg, 0.36 mmol) is coupled to 3′-bromoacetophenone (85 mg, 0.43 mmol) using Method B to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34]>O1CCCC1>[CH2:33]([O:32][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1)=[O:35])[CH3:34]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc(N)cc3)cs2)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc(-c2csc(Cn3cc(C(=O)OCC)cn3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
In an ice-bath, to a solution (4 mL) of the crude compound (0.84 mmol) obtained in Example 36b in tetrahydrofuran were added triethylamine (0.15 ml, 1.1 mmol) and ethyl chlorocarbonate (79 ml, 1.0 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (hexane-ethyl acetate) to give the title compound (180 mg, 54% in 2 steps) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][CH:10]=1)=[O:5])[CH3:2].[Cl:17]N1C(=O)CCC1=O>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][C:10]=1[Cl:17])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1coc(-c2ccccc2)n1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccccc2)oc1Cl
Yield: 37.7 %

Procedure:
Mixture of 2-phenyl-oxazole-4-carboxylic acid ethyl ester (217 mg, 1 mmol), 1-chloro-pyrrolidine-2,5-dione (400 mg, 3 mmol) and two drops of sulfuric acid in chloroform (10 mL) was heated at 90 degrees for overnight. After the reaction was complete, solvent was evaporated. To the residue, water was added, and then the mixture was extracted with ethyl acetate twice. The organic layers were collected, combined, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 5-40% ethyl acetate in hexane for 30 min) gave 5-chloro-2-phenyl-oxazole-4-carboxylic acid ethyl ester (95 mg, 37%) as a white solid. LCMS calcd for C12H10ClNO3 (m/e) 251, obsd 252 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C@@H:6]2[CH2:30][CH2:29][C@@:28]3([CH3:31])[C@@H:8]([CH2:9][CH2:10][C@@H:11]4[C@@H:27]3[CH2:26][CH2:25][C@@:24]3([CH3:32])[C@H:12]4[CH2:13][CH2:14][C@@H:15]3[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]2)[CH2:3]1.C(N(CC)CC)C.[CH2:40]([S:56](Cl)(=[O:58])=[O:57])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C1C=CC=CC=1>[CH2:40]([S:56]([O:1][CH:2]1[CH2:3][N:4]([C@@H:6]2[CH2:30][CH2:29][C@@:28]3([CH3:31])[C@@H:8]([CH2:9][CH2:10][C@@H:11]4[C@@H:27]3[CH2:26][CH2:25][C@@:24]3([CH3:32])[C@H:12]4[CH2:13][CH2:14][C@@H:15]3[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]2)[CH2:5]1)(=[O:58])=[O:57])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N5CC(O)C5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)OC1CN([C@@H]2CC[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]43)C2)C1
Temperature: 25 °C
Reaction time: 480 h

Procedure:
To a stirred suspension of 1.5 g 3α-(3-hydroxy-1-azetidinyl)-5α-cholestane (prepared as described in Example 1 and purified by column chromatography, m.p. 191.5°-195.5° C.) and 0.34 g triethylamine in 33 ml dry benzene, add a solution of 0.78 g 98% hexadecanesulfonyl chloride in 7 ml dry benzene. Stir the resultant cloudy solution at room temperature for 20 days. Concentrate the reaction mixture in vacuo to about one-third the original volume and filter the resultant precipitate. Remove the solvent in vacuo from the filtrate. Dissolve the resultant residue in 80 ml ethyl ether and filter through a column of 45-50 g silica gel eluting with additional ethyl ether as needed to afford the title compound, m.p. 64.5°-68.0° C.
Reaction SMILES: [C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](O)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][C:8]=2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH2:34]([O:36][C:37](=[O:48])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1)[NH2:39])[CH3:35].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH2:34]([O:36][C:37](=[O:48])[C@@H:38]([NH:39][C:27]([C:24]1[N:16]2[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:30]=[CH:31][C:7]([C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=4)=[C:8]([CH3:32])[CH:9]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17]2)=[CH:26][CH:25]=1)=[O:28])[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=1)[CH3:35]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3=CCCCC3)c(C)c1)C2
Temperature: 25 °C
Reaction time: 36 h
Yield: 59.5 %

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 5, Step E (0.240 g, 0.563 mmol), L-tyrosine ethyl ester hydrochloride (0.157 g, 0.676 mmol), 1-hydroxy benzotriazole (0.084 g, 0.619 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.119 g, 0.619 mmol) were combined in amine-free N,N-dimethylformamide (2.25 mL), followed by the addition of N,N-diisopropylethylamine (0.294 mL, 1.69 mmol). The reaction was stirred at room temperature for 36 hours, then diluted with ethyl acetate and washed with water, 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexane, followed by precipitation from diethyl ether with petroleum ether, to afford 0.207 g of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9](=[O:16])[N:10]([CH2:11][C:12](OC)=[O:13])[C:6]=2[C:5]([N+:22]([O-])=O)=[C:4](Cl)[N:3]=1>CO.[Pd]>[O:16]=[C:9]1[N:10]2[C:6]3[C:5]([NH:22][C:12](=[O:13])[CH2:11]2)=[CH:4][N:3]=[CH:2][C:7]=3[N:8]1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)OC)c2c([N+](=O)[O-])c(Cl)nc(Cl)c21
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cn1c(=O)n2c3c(cncc31)NC(=O)C2
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of dimethyl 2,2′-(4,6-dichloro-7-nitro-2-oxo-1H-imidazo[4,5-c]pyridine-1,3-diyl)diacetate (40 mg, 0.10 mmol) from Step E and 10% Pd/C (12 mg) in MeOH (2 mL) was stirred under an atmosphere of hydrogen (ca 1 atm) for 6 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude material was heated at 80° C. for 2 h in toluene (2 mL) and AcOH (2 mL) then concentrated to give the title compound. MS: m/z=263 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([S:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N+:13]=1[O-:19])C.C1C=C(Cl)C=C(C(OO)=[O:28])C=1.C(O)C.[OH2:34]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][S:11]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N+:13]=1[O-:19])(=[O:28])=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C)c(C(C)Sc2cc(C)cc[n+]2[O-])c1
Reactant: O
Solvent: CCO
Product: Cc1ccc(C)c(CS(=O)(=O)c2cc(C)cc[n+]2[O-])c1

Procedure:
The sulfide compound (0.006 mole) is oxidized with MCPBA (0.014 mol) and is isolated in the manner described in Example 1. Yield 62% of theory. Melting point 156°-158° C. from ethanol/water (80/20 v/v) I.R. N→O 1275 cm-1, SO2 1135, 1310 cm-1.
Reaction SMILES: [C:1]1(/[CH:7]=[C:8]2/[C:9](=[O:13])[O:10][CH2:11][CH2:12]/2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:19].CC(N=NC(C#N)(C)C)(C#N)C>>[C:1]1([CH:7]2[C:8]3([CH2:12][CH2:11][O:10][C:9]3=[O:13])[O:19]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OCC/C1=C\c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=C1OCCC12OC2c1ccccc1
Yield: 60 %

Procedure:
To a solution of 3-[1-phenyl-meth-(E)-ylidene]-dihydro-furan-2-one (21a) (4.0 g, 22.9 mmol) and 3-chloroperoxybenzoic acid (6.18 g, 27.6 mmol) in 1,2-dichloroetheane (70 mL) was added catalytic amount of AIBN (50 mg) at 80° C. and refluxed in the dark for 6 h. The resulting solution was cooled and filtered, the solvent was removed under reduced pressure, and the residue dissolved in dichloromethane. The organic phase was washed consecutively with saturated aqueous solutions of NaHCO3 (20 mL), KI (20 mL), Na2S2O3 (20 mL), and NaHCO3 (20 mL) then dried over anhydrous MgSO4 and evaporated under reduced pressure. Product was purified by silica gel flash chromatography using ethyl acetate:petroleum ether (1:4) gave 2.62 g in 60% yield of the title compound.