Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N+:17]([O-])=O)=[CH:11][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:5]=1)([O-])=O.Cl>C(O)(=O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([NH2:17])=[CH:11][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:5]=1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2-c2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)C(=O)c1cc(N)ccc1-2
Temperature: 25 °C

Procedure:
2,7-Dinitro-9-fluorenone (162 g, 0.6 mol, from Aldrich) was added cautiously to a solution of hydrated stannous chloride (1100 g, 4.9 mol, from Aldrich) in a mixture of concentrated hydrochloric acid (900 ml) and acetic acid (1600 ml). The suspension was stirred and refluxed for 1 hour. The mixture was cooled to room temperature, and a solid appeared. The solid was harvested by filtration. The solid was washed first with concentrated hydrochloric acid, and then with water until the filtrate color was violet. The residue was dissolved in boiling water. The solution was filtered and then made alkaline with sodium hydroxide to from a precipitate. The precipitate was washed with water, dried, and recrystallized from dioxane. The yield of 2,7-diamino-9-fluorenone was 108 g (85.7%). The melting point was found to be 284–286° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[C:10]([CH3:14])([CH2:12][OH:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>ClCCl.CN(C)C1C=CN=CC=1>[C:25]([O:13][CH2:12][C:10]([CH3:11])([CH3:14])[C@@H:9]([C:15]([OH:17])=[O:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)OCc1ccccc1)C(C)(C)CO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of the product of Example 174D (0.175 g, 0.519 mmol) in dichloromethane (5.0 mL) were added 4-(dimethylamino)pyridine (0.070 g, 0.573 mmol) and acetic anhydride (0.054 mL, 0.571 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction was extracted with ethyl acetate and the organic layer was washed with 10% citric acid, dilute NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in a mixture of ethyl acetate (4.0 mL) and methanol (1.0 mL) and 20% Pd(OH)2 on carbon (0.10 g) was added, and the reaction was stirred under an atmosphere of hydrogen (balloon pressure) for 1 hour. The mixture was filtered through celite and the solvent was evaporated to give the title compound (0.15 g), which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)=[O:31]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1ccc(CCO)cc1)OC(C)C
Product: CC(C)OC(Cc1ccc(CCOC(=O)Nc2ccc(Cl)cc2Cl)cc1)C(=O)O

Procedure:
Using ethyl 3-[4-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][NH:26][CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])[C:5]1=[O:34])[CH:2]=[CH2:3].[C:36](N1C=CN=C1)(N1C=CN=C1)=[O:37]>O1CCOCC1>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:27][C:28]([CH3:29])([CH3:30])[O:31][C:36]2=[O:37])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNCC(C)(C)O)C1=O
Solvent: C1COCCO1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CC(C)(C)OC2=O)C1=O

Procedure:
To a solution of 42 mg (0.081 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydroxy-2-methylpropylamino)butan-2-yl)-3-methylpiperidin-2-one (Example 100, Step A) in dioxane (2705 μL) was added carbonyldiimidazole (132 mg, 0.812 mmol). The reaction was heated to 100° for 6 h. Purification of the residue by reversed phase HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.) (eluent: 60 to 85% MeCN/water (0.1% TFA), gradient elution) provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.BrC1C=C2C3(CCNC3)CN(C(NC3SC(Cl)=CN=3)=O)C2=CC=1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:14][CH2:13][N:12]([C:50](=[O:51])[CH2:49][O:48][CH3:47])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: O=C(Nc1ncc(Cl)s1)N1C[C@]2(CCNC2)c2cc(Cl)ccc21
Agent: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Product: COCC(=O)N1CC[C@@]2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 3, with the exceptions that the (R)-5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide obtained as an intermediate of Example 52 was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that methoxyacetyl chloride was used instead of acetyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:10].Cl[CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21].C(N)CN>>[Si:8]([CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH:1][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21])([O:13][CH3:14])([O:9][CH3:10])[O:11][CH3:12]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CO[Si](CCCNCCN)(OC)OC
Solvent: NCCN
Product: CO[Si](CCCNCCNCCC[Si](OC)(OC)OC)(OC)OC
Temperature: 140 °C
Yield: 972.3 %

Procedure:
A 2 liter, 3-necked reaction flask equipped with a magnetic stirrer, electric heating mantle, dropping funnel and water condenser, containing 22.0 grams of NH2CH2CH2NH(CH2)3Si(OCH3)3 was heated to 140° C. whereupon the addition thereto of 198.0 grams of 3-chloropropyltrimethoxy silane (Cl(CH2)3Si(OCH3)3) was commenced. Cl(CH2)3Si(OCH3)3 was introduced dropwise to the reaction flask over a period of 1 hour while maintaining a temperature of 145° C. to 150° C. by the occasional application of a water bath. The resultant mixture was cooled to 75° C., and 90 grams of anhydrous ethylenediamine was added to the cooled mixture. Thereafter, the mixture was allowed to separate into layers with the upper product containing layer being separated therefrom and stripped by vacuum distillation of low boiling volatiles to yield 370 grams of (CH3O)3SiC3H6NHC2H4NHC3H6Si(OCH3)3. Amine titration and 13C NMR and 29Si NMR analysis verified the assigned structure of the resultant product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Product: O=[N+]([O-])c1ccc(-n2ccc3ccccc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-4-nitrobenzene: ESMS m/e: 238.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[SiH](C)C1C=CC=CC=1.FC(F)(F)C(O)=O.[Cl:33]CCl>>[ClH:33].[CH2:10]([NH:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCCl
Reactant: C(=NOCc1ccccc1)c1ccccc1
Agent: C[SiH](C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1ccc(CNOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of crude N-benzyloxybenzylideneamine from Example 22(a) (3.0 g, 14.2 mmol) in dichloromethane (30 mL) at 0° C. was added dimethylphenylsilane (3.09 mL, 20.3 mmol) followed by trifluoroacetic acid (3.92 mL, 50.6 mmol). The solution was allowed to warm to room temperature and was stirred for 16 hours. The solution was concentrated by rotary evaporation. To the crude oil was added dichloromethane (20 mL) and a hydrogen chloride saturated solution of dichloromethane (20 mL). The insoluble material (300 mg) was filtered and the solution was concentrated by rotary evaporation. To the crude oil was added a hydrogen chloride saturated solution of ether (20 mL). Additional ether (100 mL) was added and the insoluble material was filtered. The solid obtained was combined with the initial solid filtered above to give the title compound (1.57 g, 45%).
Reaction SMILES: C[O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>CO>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:24])=[O:2])=[CH:21][CH:20]=1
Reactant: CCCCCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reaction time: 2.5 h
Yield: 31 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4-tridecadienoic acid methyl ester (11 g) was saponified in a refluxing mixture of methanol (40 mL) and 2N NaOH (40 mL). After 2.5 hours the reaction was worked up in the usual way and the crude acid was crystallized from hexane to give 3.27 g of (E,E)-5-(4-methoxyphenyl)-2,4-tridecadienoic acid, mp 109°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[C:14](#[N:18])[CH2:15][C:16]#[N:17].C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+].C(O)(=O)C>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[C:15]([C:14]#[N:18])[C:16]#[N:17])=[CH:5][CH:4]=1
Reactant: N#CCC#N
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(=C(C#N)C#N)CCC2
Yield: 73.3 %

Procedure:
To a solution of 7-methoxy-3,4-dihydronaphthalen-1(2H)-one 46.1 (10.0 g, 56.7 mmol, Aldrich) and malononitrile (4.07 mL, 64.7 mmol) in toluene (40.0 mL, 378 mmol) was added ammonium acetate (0.938 mL, 13.1 mmol) and acetic acid (3.90 mL, 68.1 mmol). The mixture was refluxed vigorously for 17 hours and water was removed using a Dean Stark trap under the reflux condenser. The resulting mixture was concentrated and purified by silica gel column chromatography to give 48.1 (9.32 g, 73.2% yield). MS ESI (pos.) M/E: 225 (M+H).
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.[CH:11]([NH:13][C:14]([CH3:19])([CH3:18])[CH2:15][CH2:16]O)=[O:12]>>[CH:1]([O:3][CH2:16][CH2:15][C:14]([NH:13][CH:11]=[O:12])([CH3:19])[CH3:18])=[O:2]
Reactant: O=CO
Reactant: CC(C)(CCO)NC=O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(CCOC=O)NC=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Formic acid (6.90 g, 0.15 mol) was added to acetic anhydride (15.30 g, 0.15 mol) and warmed to 45°-50° C. for one hour on a water bath. The resulting solution was cooled to below 0° C. in an ice/acetone bath. 3-Formamido-3-methyl-1-butanol (13.10 g, 0.10 mol) was added and the solution allowed to slowly warm to room temperature with stirring (16 hours). The solution was distilled under vacuum (1 Torr, 105°-110° C.) to yield 12.43 g (78%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]1[C:18]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([C:40]3[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=3)[C:19]=2[N:20]=[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[N:22]=1>C(Cl)Cl.O>[CH2:1]([NH:8][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([N:35]2[C:19]3[N:20]=[C:21]([N:23]4[CH2:24][CH2:25][N:26]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH2:27][CH2:28]4)[N:22]=[C:17]([CH3:16])[C:18]=3[CH:38]=[CH:37][C:36]2=[O:39])=[CH:41][CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N2CCN(c3ccccc3)CC2)nc2c1ccc(=O)n2-c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nc(N2CCN(c3ccccc3)CC2)nc2c1ccc(=O)n2-c1ccc(C(=O)NCc2ccccc2)cc1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a solution of benzylamine (0.0536 g; 0.50mmol) and a drop of triethylamine in 5 mL of methylene chloride, compound L (0.043 g; 0.094 mmol) in 3 mL of methylene chloride was added at room temperature. The reaction mixture was stirred for 2 h and then diluted with 10 mL of methylene chloride and 10 mL of water. The organic phase was dried over CaCl2, concentrated and the crude reaction mixture purified by silica gel column chromatography (eluant: CH2Cl2/CH3OH=190/10) to yield compound 15 (0.039 g; 78%).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22](Br)([CH3:24])[CH3:23]>>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][C:22]([O:18][N:13]2[C:14]([CH3:17])([CH3:16])[CH2:15][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][C:12]2([CH3:20])[CH3:19])([CH3:24])[CH3:23])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC(C)(Br)Br
Product: CC(C)(ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C

Procedure:
The title compound is prepared from 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 2,2-dibromopropane according to the procedure of Example 30A.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:40])[C:6]([NH:29][C@@H:30]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][S:32]([OH:35])(=[O:34])=[O:33])=[N:7][C:8]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1)#[N:2].Cl>CC#N>[C:1]([C:3]1[CH:4]=[C:5]([F:40])[C:6]([NH:29][C@@H:30]([C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][S:32]([OH:35])(=[O:33])=[O:34])=[N:7][C:8]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](CS(=O)(=O)O)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)[C@@H](CS(=O)(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)c(C#N)cc1F
Temperature: 100 °C

Procedure:
To a solution of (S)-2-((5-cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)amino)-3,3-dimethylbutane-1-sulfonic acid, 101a, (0.12 g, 0.21 mmol) in CH3CN (5 mL) was added HCl (2 mL of 4M solution in dioxane). The reaction mixture was heated at 100° C. for 18 hours in a pressure vial and then cooled to room temperature. The solvent was removed under reduced pressure and the product was purified by preparative HPLC chromatography (10-80% CH3CN/water, 0.5% TFA, 15 min) to give 42 mg of the desired product as an off-white solid: 1H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd, J=9.2, 2.6 Hz, 1H), 8.22 (d, J=5.7 Hz, 1H), 8.13 (s, 1H), 5.16 (m, 1H), 3.46-3.33 (m, 3H), 1.10 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 449.22 (M+H).
Reaction SMILES: [C:1](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][NH2:20].O>C1C=CC=CC=1>[C:1](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)/C=C/c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)/C=C/c1ccc(CC(C)NCC(O)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-(E)-(2-carbomethoxyethenyl)phenylpropan-2-one (2.18 g) and 2-hydroxy-2-phenylethanamine (1.37 g) was refluxed in benzene under a Dean and Stark apparatus until the theoretical amount of water had been collected. The solvent was evaporated, methanol added, and sodium borohydride (1.0 g) added portionwise at room temperature. The solution was left to stir for 0.5 h, and solvent removed. Water was added, the mixture extracted with ether and the combined ether layers dried (MgSO4). Removal of the solvent gave the title compound, isolated as a 1:1 mixture of diastereoisomers, as the hemi-fumarate hemihydrate mp 99°-100.5° (ethyl acetate). τ (DMSO) 8.95 (3H, d, J=6 Hz), 6.4-7.5 (5H, m), 6.31 (3H, s), 5.2-4.9 (1H, m), 3.45 (1H, d, J=16 Hz+2H, s), 2.15-2.9 (10H, m), 1.6 (4H, s, disappears with D2O).
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:12].[OH-]>>[NH2:12]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:9]\[C:10]#[N:11]
Reactant: N#CCC(=O)c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Product: N#C/C=C(\N)c1ccccc1
Reaction time: 20 h
Yield: 18.8 %

Procedure:
A mixture of benzoylacetonitrile (510 mg, 3.51 mmol) and conc. NH4OH (4 mL, 56.0 mmol) in a sealed tube was stirred at 80 C for 20 h. After cooling, solids precipitated out, which were collected by filtration, dried on vacuum to give (Z)-3-amino-3-phenylacrylonitrile (95 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([CH2:20][C@H:21]([NH:25]S(C1C(C)=C(C)C(C)=C(C)C=1C)(=O)=O)[C:22]([OH:24])=[O:23])[NH:14][C:13]2=[O:40].C(OC(=O)[C@H](CC(=O)N)N[C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])(C)(C)C.N[C:65]1[CH:66]=C(B(O)O)C=C[CH:70]=1.NC1NCCN=1>>[NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][C:7]1[CH:8]=[C:9]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]([CH2:20][C@H:21]([NH:25][C:49]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[O:50])[C:22]([OH:24])=[O:23])[NH:14][C:13]3=[O:40])[CH:70]=[CH:65][CH:66]=1
Reactant: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Cc1c(C)c(C)c(S(=O)(=O)N[C@@H](Cc2nc3ccc(/C=C/CNC4=NCCN4)cc3c(=O)[nH]2)C(=O)O)c(C)c1C
Agent: NC1=NCCN1
Product: O=C(N[C@@H](Cc1nc2ccc(-c3cccc(NC4=NCCN4)c3)cc2c(=O)[nH]1)C(=O)O)OCc1ccccc1

Procedure:
Compound 9 was prepared as described for Compound 1, but instead of Compound AA2, N-carbobenzyloxyasparagine tert-butyl ester (8.2 g) was reacted with Compound AA3 and produced Compound AC1. Scheme AC shows the Suzuki cross coupling of Compound AC1 with 3-aminophenylboronic acid to produce Compound AC2. As shown in the illustration for Scheme AA, intermediate Compound AC2 (0.19 g) was converted to the corresponding 2-aminoimidazoline by coupling with Compound AA5 followed by hydrolysis to yield Compound 9. Compound 9 was isolated as a white solid (TFA salt): 1H NMR (DMSO, d6) δ 3.0 (m, 1 H), 3.2 (m, 1 H), 3.4 (m, 2 H), 3.6 (s, 4H), 4.7 (m, 1 H), 5.0 (s, 2 H), 7.0 (m, 1 H), 7.3 (m, 5 H), 7.5 (m, 2 H), 7.7 (d, J=8 Hz, 1 H), 7.8 (d, J=8 Hz, 1 H), 8.1 (d, J=8 Hz, 1 H), 8.3 (s, 1 H); MS m/e 527 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]>[Fe].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: NC(=O)c1cc(Cl)ccc1N
Temperature: 90 °C

Procedure:
To 5-chloro-2-nitrobenzamide (2.0 g) (prepared according to the procedure described in Example 1, Part A) was added 50 mL of glacial acetic acid. This solution was heated to 90° C. and iron powder (2.8 g) was added in small portions over 15 minutes. When addition was complete the reaction mixture was stirred at 90°-100° C. After 2 hours the reaction was cooled to room temperature and was evaporated to dryness. The resulting residue was partitioned between ethyl acetate and aqueous sodium carbonate. This brown slurry was filtered and the ethyl acetate layer was recovered and washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield 1.7 g (100%) of a buff powder: 1H NMR (DMSO-d6, 300 MHz) δ7.83 (bs, 1H), 7.59 (d, 1H), 7.17 (bs, 1H), 7.14 (dd, 1H), 6.70 (m, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6]C(O)=O.C([N:12]([CH2:15]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:24])C=CC=CC=1>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:12]=[C:15]=[O:24]
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1cccs1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C=NCc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To 2-thiopheneacetic acid (2.84 g, 20 mmol) in dry toluene (22.5 mL) was added dry triethylamine (2.93 mL, 4.2 mmol) and diphenyl phosphorylazide (4.31 mL, 4 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then heated at reflux for a further 3 hours. After cooling, the mixture was concentrated under reduced pressure and purified by distillation using an oil pump to give thiophen-2-ylmethyl isocyanate (0.35 g, 12%) as a colourless oil.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([S:13](Cl)(=[O:15])=[O:14])[CH:9]=[CH:10][C:11]=1[Cl:12].O>N1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([S:13]([NH:4][O:2][CH3:3])(=[O:14])=[O:15])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: CON
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CONS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 18 h
Yield: 94.6 %

Procedure:
To a suspension of methoxylamine hydrochloride (0.93 g (11.1 mmol)) in pyridine (5.0 ml), 3,4-dichlorobenzenesulfonyl chloride (2.73 g (11.1 mmol)) was added with stirring under cooling with ice and the resulting mixture was stirred for one hour under cooling with ice, and at room temperature for 18 hours. Water (50.0 ml) was then added to the reaction mixture to bring about separation of crystals. The crystals were filtered and washed with water to give 2.69 g (95%) of 3,4-dichloro-N-methoxybenzenesulfonamide as pale yellow crystals.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[OH:19][C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21]1>C(Cl)Cl>[C:1]([N:23]1[CH2:24][C@H:20]([OH:19])[CH2:21][C@H:22]1[C:25]([OH:27])=[O:26])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
The FMOC-trans-4-hydroxy-L-proline 57 was prepared as follows: 1.1 equivalents of FMOC-chloride is added to 1.0 equivalents of trans-4-hydroxy-L-proline (Aldrich company) and allowed to stir for 12 hour at 25° C. in 0.10M methylene chloride. The resulting mixture is quenched with water, washed with sodium bicarbonate and dried over magnesium sulfate (standard workup conditions). The crude compound can then be purified by flash chromatography. Mass Spectral analysis: m/e calc'd for C53H58O11N2Cs (M+Cs+): 1031.3095, found 1031.3143