Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N=[CH:17][N:16](C(N2C=NC=C2)=O)[CH:15]=1.Cl.CNC.CCN(CC)CC>C1COCC1>[CH3:15][N:16]([CH3:17])[C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a stirred solution of 2-(3-nitrophenyl)acetic acid (0.2 g, 1.104 mmol) in THF (6 ml) was added CDI (0.269 g, 1.656 mmol). resulting mixture was heated at 50° C. for 1 hr, cooled to room temperature and then dimethyl amine hydrochloride (0.108 g, 1.325 mmol) and Et3N (0.15 ml, 1.104 mmol) were added sequentially. Resulting reaction mixture was stirred for 24 h at ambient temperature. Solvents were evaporated under vacuum. The residue was purified by flash chromatography to obtain N,N-dimethyl-2-(3-nitrophenyl)acetamide (0.192, 84% yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][C:21]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)=[CH:27][CH:26]=1)([OH:24])[CH2:22][OH:23]>CC#N>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:32]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:21]([OH:24])([CH2:20][OH:19])[CH2:22][OH:23])=[CH:30][CH:29]=2)=[O:33])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1ccc(C(O)(CO)CO)cc1)Oc1ccccc1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(C(O)(CO)CO)cc2)n(-c2cccc(Cl)c2)n1
Reaction time: 16 h
Yield: 66.7 %

Procedure:
To a stirred MeCN (9 mL) solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (102 mg, 0.387 mmol, 1.0 eq), TEA (0.214 mL, 1.55 mmol, 4.0 eq) followed by phenyl 4-(1,2,3-trihydroxypropan-2-yl)phenylcarbamate (119 mg, 0.395 mmol, 1.02 eq) was added at RT and the mixture was stirred for 16 h at reflux, then it was concentrated under vacuum and the residue purified by CC using EtOAc as eluent to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,2,3-trihydroxypropan-2-yl)phenyl)urea (122 mg; 67%).
Reaction SMILES: COC(=O)[C@H:4]([NH:12][CH2:13][CH2:14][NH:15][C:16]([O:18]C(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:5]([C@H:4]1[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:14][NH:15][C:16]1=[O:18])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NCCNC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCCN(Cc2ccccc2)[C@@H]1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
(3R)-3-Benzylpiperazin-2-one (4.1 g; 21.6 mmol, prepared as described in Example 1) was dissolved in methanol (40 ml). Benzaldehyde (2.3 g; 21.6 mmol) was added followed by 4 Å molsieves (2 g) and the mixture was stirred under an atmosphere of nitrogen for 1/2 h. Acetic acid (1.2 ml) was added and sodium cyanoborohydride (2.0 g; 32.4 mmol) was added portion wise during 20 minutes. The reaction mixture was stirred overnight and the filtered. From the filtrate the solvent was evaporated and the residue was dissolved into ethyl acetate (15 ml) and purified on silica gel using ethyl acetate as eluent. This afforded 2.6 g of (3R)-3,4-dibenzylpiperazin-2-one.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][C@H:16](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][N:14]2[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])(=O)=O)=CC=1.[NH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>C1(C)C=CC=CC=1>[CH3:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([N:14]2[CH2:15][C@H:16]3[CH2:17][C@@H:13]2[CH2:12][N:39]3[CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)(=[O:30])=[O:31])=[CH:37][CH:36]=1
Reactant: NCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H]2CN3Cc2cccnc2)cc1
Yield: 45.9 %

Procedure:
((2R,4S)-1-[(4-Methylphenyl)sulfonyl]-4-{[(4-methylphenyl)sulfonyl]oxy}pyrrolidinyl)methyl 4-methylbenzenesulfonate (1.5 g, 2.6 mmol), prepared as described in (J. Med. Chem. (1990) 33, 1344) and 3-(aminomethyl)pyridine (1.0 g, 9.3 mmol) in 20 mL of toluene were heated under reflux for 16 hours. The mixture was cooled, filtered, and the filter cake was washed with 20 mL of toluene. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (silica gel; hexanes:EtOAc, 9:1 to 1:1) to provide the title compound (410 mg, 46%). 1H NMR (DMSO-d6, 300 MHz) δ 0.86 (d, J=8.5 Hz, 1H), 1.62 (d, J=9.7 Hz, 1H), 2.42 (s, 3H), 2.44 (m, 1H), 2.66 (dd, J=2.4, 9.5 Hz, 1H), 2.99 (dd, J=2.0, 9.5 Hz, 1H), 3.39-3.48 (m, 2H), 3.62-3.41 (d, J=9.5 Hz, 1H), 4.23 (br s, 1H), 4.35 (t, J=5.1 Hz, 1H), 7.31 (m, 1H), 7.43-7.46 (m, 2H), 7.62 (m, 1H), 7.71-7.74 (m, 2H), 8.31-8.43 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([OH:16])[C:14]#[CH:15].[O-]Cl.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH:15]=[C:14]([CH2:13][OH:16])[O:10][N:9]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C#CCO
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2cc(CO)on2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-nitro-benzaldehyde oxime (2.40 g, 14.4 mmol) was dissolved in methylene chloride (70 ml, 0.2 M), and then propargyl alcohol (2.51 ml, 43.2 mmol) was added to the solution. To the resulting solution was slowly added dropwise 10% NaOCl (17.8 ml, 28.8 mmol) using a dropping funnel. After the addition of NaOCl was completed, the mixture was stirred for about 5 hours while increasing the temperature slowly to room temperature. The completion of the reaction was confirmed by liquid chromatography, and then the mixture was distilled under reduced pressure to remove methylene chloride. Water (200 ml) was added to the residue and the resulting solid was filtered off. The filtered compound was washed with excess of water and finally washed with diethyl ether. The thus-obtained solid compound was recrystallized from ethyl acetate/hexane (1:2) to obtain [3-(4-nitro-phenyl)-isoxazol-5-yl]-methanol in a white sold phase.
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][C:12]([C:18]([O:21][C:22]([C:28](F)=[O:29])([C:24]([F:27])([F:26])[F:25])[F:23])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[OH:31][CH2:32][CH2:33][CH2:34][O:35][CH:36]([CH2:38][OH:39])[CH3:37]>C([O-])(O)=O.[Na+]>[C:1]([C:5]([C:8]([O:11][C:12]([C:18]([O:21][C:22]([C:28]([O:39][CH2:38][CH:36]([O:35][CH2:34][CH2:33][CH2:32][O:31][C:28]([C:22]([O:21][C:18]([C:12]([O:11][C:8]([C:5]([C:1]([F:2])([F:3])[F:4])([F:6])[F:7])([F:9])[F:10])([C:14]([F:15])([F:17])[F:16])[F:13])([F:20])[F:19])([C:24]([F:27])([F:26])[F:25])[F:23])=[O:29])[CH3:37])=[O:29])([C:24]([F:25])([F:26])[F:27])[F:23])([F:19])[F:20])([C:14]([F:17])([F:16])[F:15])[F:13])([F:9])[F:10])([F:6])[F:7])([F:4])([F:2])[F:3]
Reactant: CC(CO)OCCCO
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(COC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)OCCCOC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
CF3(CF2)2OCF(CF3)CF2OCF(CF3)COF (120.69 g) was loaded into an autoclave and stirred under a nitrogen stream, and HO(CH2)3OCH(CH3)CH2OH (15.1 g) prepared in Example 2-3 was fed over 2 hours, while the temperature in the autoclave was maintained at 30° C. or below. Then, the reaction solution was stirred at room temperature under a nitrogen stream overnight and poured onto saturated aqueous NaHCO3 (500 mL) with ice.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]12[O:12][CH2:11][C:8]([CH3:13])([CH2:9][O:10]1)[CH2:7][O:6]2.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+].[Na+].[I-:39]>C(#N)C>[I-:39].[CH3:13][C:8]12[CH2:11][O:12][C:5]([CH2:4][CH2:3][CH2:2][P+:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([O:10][CH2:9]1)[O:6][CH2:7]2
Reactant: CC12COC(CCCCl)(OC1)OC2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC12COC(CCC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)(OC1)OC2
Yield: 59.7 %

Procedure:
A mixture of Intermediate 22 (5 g), triphenylphosphine (33.6 g), NaHCO3 (7 g) and NaI (19.3 g) in acetonitrile (175 ml) was heated under reflux for 17 h. After cooling the inorganic solids were filtered off and washed with dichloromethane. The combined filtrates were evaporated and the residue was triturated firstly with ER (discarded) and then with CH2Cl2. The CH2Cl2 extracts were evaporated in vacuo and the residue, which solidified on trituration with ER, was crystallised from EA-acetonitrile to give the title compound (8.1 g) m.p. 189°-191°.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([O:25][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: OC1CCCCC1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OC1CCCCC1

Procedure:
The title compound, white solid, m.p. 117-119° C. and MS: m/e=337.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and cyclohexanol.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([O:16][C:17](=[O:25])[C:18]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[CH2:9]2.[Cl-].[NH4+]>CCOCC.C1COCC1>[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([O:16][C:17](=[O:25])[C:18]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[OH:19])[CH2:9]2
Reactant: Cl[Mg]C1CCCC1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccco1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclopentylmagnesium chloride, 0.0472 mol (23.6 ml of a solution 2M in ether) was added to a solution of 9.4 g (0.0377 mol) of 2-fur-2-yl-2-oxoacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester dissolved in 125 ml of THF, at −70° C. under a N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 16 h, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, washed with water, and dried over MgSO4. After removal of the solvent, the oil obtained (7.5 g) was purified by chromatography on silica gel eluting with chloroform/methanol/ammonia 95:5:0.5. Appropriate fractions were combined and evaporated to obtain the two diastereomers: I-14a, I-14b
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[OH:25].O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2,4-dichlorophenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 ml), extracted with EtOAc (2×50 mL), washed with H2O (2×50 ml) and brine (50 ml), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(2,4-dichloro-phenoxy)-1-nitrobenzene. The crude product was used for further transformation .
Reaction SMILES: [NH2:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][CH:3]=1.CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1>C(O)(=O)C>[CH3:15][CH:10]1[N:9]2[C:14]3[C:5](=[CH:4][CH:3]=[C:2]([N:1]4[CH:22]=[CH:26][CH:25]=[CH:24]4)[C:13]=3[CH2:12][CH2:11]1)[C:6](=[O:19])[C:7]([C:16]([OH:18])=[O:17])=[CH:8]2
Reactant: COC1CCC(OC)O1
Reactant: CC1CCc2c(N)ccc3c(=O)c(C(=O)O)cn1c23
Solvent: CC(=O)O
Product: CC1CCc2c(-n3cccc3)ccc3c(=O)c(C(=O)O)cn1c23

Procedure:
To a suspension of 3.0 g of 8-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in 30 ml of glacial acetic acid was added 3.0 g of 2,5-dimethoxytetrahydrofuran and the mixture was heated on a steam bath for 1.5 hours. Cooling produced a solid which was separated by filtration to provide 6,7-dihydro-5-methyl-1-oxo-8-(1-pyrryl)-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 303°-305° C. Analysis: Calculated for C18H16N2O3 : %C, 70.1; %H, 5.2; %N, 9.1; Found: %C, 69.5; %H, 5.1; %N, 9.2. The structural assignment was confirmed by infrared spectral analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[N:7]([CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH:34][C:35]([NH2:37])=[S:36])[CH:32]=2)[NH:27][C:26]=1[C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:48][C:49](=O)[CH3:50]>>[C:1]([O:5][C:6](=[O:46])[N:7]([CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH:34][C:35]3[S:36][CH:48]=[C:49]([CH3:50])[N:37]=3)[CH:32]=2)[NH:27][C:26]=1[C:38]1[CH:39]=[C:40]([CH3:45])[CH:41]=[C:42]([CH3:44])[CH:43]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:14][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)CCl
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(NC(N)=S)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OC(C)(C)C)c1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(Nc4nc(C)cs4)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of {2-[2-(3,5-dimethylphenyl)-5-thioureido-1H-indol-3-yl]ethyl}-[4-(4-methanesulfonylaminophenyl)butyl]carbamic acid tert-butyl ester (15 mg in 0.80 mL ethanol) was added 0.010 mL chloroacetone and the resulting suspension heated to reflux on an oil bath. After 5 hours, the mixture was cooled to room temperature and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (methylene chloride:methanol, 96:4) gave the title compound (15 mg).
Reaction SMILES: O.[C:2]([C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][C@@H:11]([NH:26][C:27](=[O:38])[NH:28][C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([OH:34])=[O:33])[C:10]1=[O:39])=[O:7])([CH3:5])([CH3:4])[CH3:3].[Cl-].[Ca+2:41].[Cl-].O>C(O)C.N>[C:2]([C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][C@@H:11]([NH:26][C:27](=[O:38])[NH:28][C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([O-:34])=[O:33])[C:10]1=[O:39])=[O:7])([CH3:5])([CH3:3])[CH3:4].[Ca+2:41].[C:2]([C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][C@@H:11]([NH:26][C:27](=[O:38])[NH:28][C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([O-:34])=[O:33])[C:10]1=[O:39])=[O:7])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc(C(=O)O)c2)CN(C2CCCCC2)c2ccccc21
Agent: N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc(C(=O)[O-])c2)CN(C2CCCCC2)c2ccccc21
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
In 220 ml of ethanol was suspended 22.0 g of (R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoic acid monohydrate. Under ice cooling, the resulting suspension was dissolved in 26.4 ml of concentrated aqueous ammonia. To the reaction mixture was added 22 ml of an aqueous solution of 3.05 g of calcium chloride, followed by stirring for 30 minutes. Water was added. The precipitate was collected by filtration and washed with a mixed solvent of water and ethanol (2:1), whereby 21.0 g of the title compound as powder was obtained.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][CH:10]([CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([O:13][CH3:14])=[O:12].C>O1CCOCC1>[N:9]([CH:10]([CH2:15][CH:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:11]([O:13][CH3:14])=[O:12])=[C:2]=[O:1]
Reactant: COC(=O)C(N)CC=Cc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)C(CC=Cc1ccccc1)N=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of methyl 2-amino-5-phenyl-4-pentenoate, prepared as described by D. Ferroud, J. P. Genet, and R. Kiolle in Tetrahedron Letters, 1986, 27, 23-26, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give methyl 2-isocyanato-5-phenyl-4-pentenoate.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C@H:9]([N:26]1[CH2:30][C:29]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])=[CH:28][C:27]1=[O:39])[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH2:18][C@@H:19]2[CH2:23][O:22]C(C)(C)[O:20]2)[N:14]=1)=[O:11])(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[O:31][C:29]1[CH2:30][N:26]([C@@H:9]([CH2:8][CH2:7][OH:6])[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH2:18][C@@H:19]([OH:20])[CH2:23][OH:22])[N:14]=2)=[O:11])[C:27](=[O:39])[CH:28]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](CCO)N1CC(Oc2ccccc2Cl)=CC1=O
Yield: 45.4 %

Procedure:
In a round bottom flask was placed (S)-4-(t-butyl-dimethyl-silanyloxy)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-butyramide (128 mg, 0.21 mmol), methanol (5 mL) and p-toluenesulfonic acid monohydrate (10 mg) and stirred at 25° C. for 16 h. The mixture was then concentrated and treated with ethyl acetate and methanol to solubilize the material and concentrated in vacuo with silica gel (1 g). Purification by Biotage flash chromatography (AnaLogix, 25 g column, 100% ethyl acetate to 20% methanol/ethyl acetate) afforded material that was not pure. A second purification by Biotage flash chromatography (AnaLogix, 25 g column, 100% ethyl acetate to 20% methanol/ethyl acetate) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-4-hydroxy-butyramide (43 mg, 45%) as a white foam: HR-ES-MS m/z calculated for C20H23N4O6Cl [M+H]+ 451.1379, observed 451.1379; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-2.06 (m, 2H), 3.23-3.31 (m, 2H), 3.37-3.50 (m, 2H), 3.72-3.81 (m, 1H), 3.86 (dd, J=13.9, 7.9 Hz, 1H), 4.09 (dd, J=13.5, 3.9 Hz, 1H), 4.29 (d, J=18.3 Hz, 1H), 4.50-4.60 (m, 2H), 4.71 (t, J=5.6 Hz, 1H), 4.80 (s, 1H), 4.84 (dd, J=8.4, 5.4 Hz, 1H), 4.94 (d, J=5.3 Hz, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.34-7.41 (m, 1H), 7.43-7.57 (m, 2H), 7.66 (dd, J=8.0, 1.2 Hz, 1H), 10.59 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[O:18][CH3:19])=[CH:4][C:3]=1[Cl:20].[Cl-].[NH4+]>O1CCCC1.O.[Fe]>[Cl:20][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[O:18][CH3:19]
Reactant: COc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A mixture of 1,2-dichloro-4-(2-methoxy-4-nitrophenoxy)benzene (60 g, 190.40 mmol, 1.00 equiv), Fe (53 g, 946.43 mmol, 4.97 equiv) and ammonium chloride (10 g, 188.68 mmol, 0.99 equiv) in tetrahydrofuran/water (1/2) (600 mL) was stirred overnight at 60° C. under an inert atmosphere of nitrogen. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. The resulting solution was extracted with dichloromethane and the organic layers combined. The resulting mixture was washed with 3×500 mL of brine. The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum to give 40 g (74%) of 4-(3,4-dichlorophenoxy)-3-methoxyaniline as a light gray solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.Br[CH:14]([CH2:19][CH3:20])[C:15]([O:17][CH3:18])=[O:16].Cl>C1COCC1.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9]([C:8]([CH:14]([CH2:19][CH3:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: CCC(Br)C(=O)OC
Reactant: COc1ccc2c(c1)CCC2=O
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(C(=O)OC)C1=CCc2cc(OC)ccc21
Temperature: 60 °C
Yield: 104.4 %

Procedure:
An oven dried 5-L four-necked round-bottomed flask was fitted with a thermometer, a condenser, an addition funnel, and a mechanical stirrer. Under an argon atmosphere, a suspension of 5-methoxy-1-indanone (80.0 g, 494 mmol), Zn powder (Lancaster, 56.2 g, 865 mmol) in THF (2 L, anhydrous) was stirred at 60° C. (internal temperature), while a solution of methyl bromobutyrate (134.1 g, 741 mmol) in THF (400 mL, anhydrous) was added slowly using an addition funnel. After completion of the addition, the reaction mixture was stirred at 60° C. (internal temperature) for 1 h. The reaction was followed by TLC analysis of aliquots following 1 N aqueous HCl workup. After the reaction was completed, it was cooled in an ice-water bath followed by slow addition HCl (3 L, 1 N aqueous solution). The internal temperature was kept below 20° C. The mixture was then extracted with EtOAc (1 L). The organic layer was washed with water until pH 6.0-7.0, then with brine, dried over Na2SO4, and then filtered. The product (127 g, >99%), a yellow oil, was obtained after solvent removal and drying under vacuum. 1H NMR (300 MHz), (DMSO-d6) δ 7.28 (d, 1H), 7.05 (d, 1H), 6.82 (dd, 1H), 6.22 (s, 1H), 3.72 (s, 3H), 3.60 (m, 1H), 3.58 (s, 3H), 3.28 (s, 2H), 1.95 (m, 1H), 1.80 (m, 1H), 0.88 (t, 3H).