Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23]CCI.[NH4+].[Cl-]>CCCCC.C(OCC)C.COCCOC>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([I:23])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ICCI
Reactant: COc1cc2cccc(NC(=O)OC(C)(C)C)c2cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Solvent: COCCOC
Product: COc1cc2c(I)ccc(NC(=O)OC(C)(C)C)c2cc1OC
Temperature: -20 °C
Reaction time: 5 h

Procedure:
t-Buthyllithium (2.7 mL of a 1.7 M solution in pentane, 4.61 mmol) was added to a solution of 1-(N-tert-Butoxycarbonylamino)-6,7-dimethoxynaphthalene (0.50 g, 1.65 mmol) in dry diethyl ether (5.0 mL) and dry DME (2.5 mL) at −40° C. under nitrogen. The resulting mixture was stirred at −20° C. for 5 h and then cooled to −78° C. A solution of 1,2-diiodoethane (1.30 g, 4.61 mmol) in dry DME was added and the resulting solution was allowed to warm to ambient temperature over several hours. Aq. NH4Cl was added, and the mixture was extracted twice with DCM. The combined organic extracts were washed with water, dried, filtered and evaporated to leave a dark glass. The compound was purified by column chromatography to give the pure product 1-(N-tert-Butoxycarbonylamino)-6,7-dimethoxy-4-iodonaphthalene. 1H NMR (200 MHz) (DMSO-d6) δ 1.51 (s, 9H), 3.82 (s, 3H), 3.97 (s, 3H), 7.42 (t, J=8.5 Hz, 1H), 7.48 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 9.28 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6].Cl.O1CCOCC1>CO>[ClH:1].[Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Cl)c2F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1cccc(Cl)c1F)N1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 35.1 g of tert-butyl 4-(3-chloro-2-fluorobenzoyl)piperazine-1-carboxylate and 50 ml of methanol was added a hydrochloric acid-1,4-dioxane solution (4 M, 100 ml) followed by stirring at room temperature for 2.5 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in diethyl ether, filtered and collected to give the title compound.
Reaction SMILES: CC([O-])=O.[K+].[C:6]([CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])#[N:7].[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]#[N:18].O>C(O)(C)C>[NH2:18][C:17]([C:16]([Cl:20])([Cl:19])[Cl:15])=[C:8]([C:6]#[N:7])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: C=CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: C=CCOC(=O)C(C#N)=C(N)C(Cl)(Cl)Cl
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To a solution of KOAc (589.4 g, 6.006 mol) in isopropanol (3 L) was added allyl cyanoacetate (429.4 g, 403.2 mL, 3.432 mol) and the reaction mixture was cooled to 5° C. Trichloroacetonitrile (495.5 g, 3.432 mol) was added in 50 mL portions, maintaining temperature below 15° C. The reaction mixture was then allowed to warm to 20° C. and stirred for 3 h. Water (˜4 L) was added to dissolve the inorganic materials and precipitate out the desired product. The mixture was stirred for 20 minutes and the solid was isolated by filtration under vacuum. This solid was filtered, washed with water (2×0.5 L) and dried in a vacuum oven overnight at 40° C. to afford allyl 3-amino-4,4,4-trichloro-2-cyanobut-2-enoate 2 as an off-white powder (787 g, 85%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[CH:13][CH:12]=[N:11]1>C(O)(=O)C>[I:1][C:13]1[CH:12]=[N:11][N:10]([CH3:9])[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:16]=1
Reactant: Cn1nccc1-c1ccc(C(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Cn1ncc(I)c1-c1ccc(C(F)(F)F)cn1
Temperature: 70 °C

Procedure:
N-Iodosuccinimide (95%, 427 mg, 1.80 mmol) was added to a mixture of 2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridine (C13) (390 mg, 1.72 mmol) and acetic acid (4 mL), and the reaction mixture was heated at 70° C. for 1 hour. The mixture was concentrated in vacuo and subjected to silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to afford the product as a white solid. Yield: 524 mg, 1.48 mmol, 86%. APCI m/z 353.8 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.89 (s, 3H), 7.66 (s, 1H), 8.00 (br d, J=8 Hz, 1H), 8.17 (br dd, J=8, 2 Hz, 1H), 8.83 (br d, J=2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]([CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[C:27]1[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:30]1[CH:31]=[CH:32][C:27]([N:26]([C:21]2[N:20]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:28][CH:29]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: O=S(=O)(Oc1ccc(N(c2ncccn2)C2CCOCC2)cc1)C(F)(F)F
Product: COC(=O)C(C/C=C/c1ccc(N(c2ncccn2)C2CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 59.2 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (164.0 mg) was reacted with trifluoromethanesulfonic acid 4-[pyrimidin-2-yl-(tetrahydropyran-4-yl)amino]phenyl ester (220.0 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyrimidin-2-yl-(tetrahydro-pyran-4-yl)-amino)phenyl]pent-4-enoic acid methyl ester (178.5 mg). Column chromatography (silica gel, eluent: chloroform/cyclohexane=1/2→chloroform) and thin layer chromatography (silica gel, developing solvent: cyclohexane/ethyl acetate=1/1) were used for purification.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:32])[N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[O:31]=[C:25]1[CH:24]([N:17]2[C:16](=[O:32])[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][NH:12][C:8]([NH:7][C:3]3[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=3)=[O:9])[C:18]2=[O:23])[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
m-Tolyl isocyanate (0.4 g, 3.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.8 g, 2.3 mmol) and triethylamine (0.3 g, 3.2 mmol) in THF (40 mL) at 5° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with ether (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-m-tolyl-urea (0.7 g, 76%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.23 (s, 3H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 4.71 (d, J=6.0 Hz, 2H), 5.13-5.20 (dd, J=5.4 and 12.6 Hz, 1H), 6.70-6.77 (m, 2H), 7.05-7.17 (m, 2H), 7.25 (s, 1H), 7.75-7.88 (m, 3H), 8.70 (s, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 21.19, 21.99, 30.93, 38.71, 48.86, 114.90, 118.25, 121.85, 121.95, 127.18, 128.46, 131.60, 133.66, 134.71, 137.73, 140.18, 140.30, 155.22, 167.01, 167.59, 169.82, 172.76; Anal. calcd. for C22H20N4O5+0.5H2O: C, 61.53; H, 4.93; N, 13.05. Found: C, 61.87; H, 4.72; N, 12.92.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=2[C:10]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:21].[OH2:25]>>[C:1]1([S:7][C:8]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=2[C:10]([OH:21])=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Sc1ccccc1
Reactant: O
Reactant: O=S(=O)(O)O
Product: O=C(O)c1ccc(C(F)(F)F)cc1Sc1ccccc1

Procedure:
A mixture of 2-phenylsulphenyl-4-trifluoromethylbenzonitrile (9 g), concentrated sulphuric acid (27 ml) and water was heated at reflux for 10 hours. The mixture was then cooled, poured into water and extracted with dichloromethane. The organic extract was extracted with aqueous sodium hydroxide. The resulting aqueous solution was acidified with aqueous hydrochloric acid to pH 1. The suspension was extracted with dichloromethane, dried over anhydrous sodium sulphate, filtered and after evaporation of the dichloromethane, 2-phenylsulphenyl-4-trifluoromethylbenzoic acid was obtained as a white solid (7.5 g), m.p. 161° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.2 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (150 mg, 0.33 mmol), N,N-dimethylglycine (40 mg, 0.39 mmol), EDCl (69 mg, 0.36 mmol), HOBt (48 mg, 0.36 mmol), and N,N-diisopropylethylamine (227 μL, 1.30 mmol) in DMF (2 mL) was stirred at rt for 6 h. An additional 0.5 eq. of N,N-dimethylglycine was added and the mixture continued to stir at rt for 16 hr. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 40% acetonitrile in water to provide 39 mg (24%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1 H), 7.92 (s, 1 H), 7.81 (d, 1 H), 7.66 (s, 1 H), 7.28-7.39 (m, 5 H), 7.15 (dd, 1 H), 6.60 (s, 1 H), 5.67 (s, 2 H), 4.32 (dd, 1 H) 3.33-3.46 (m, 1 H), 3.01-3.20 (m, 4 H), 2.66-2.78 (m, 1 H), 2.19 (s, 6 H), 2.05 (d, 2 H), 1.44-1.75 (m, 2 H); ES-MS m/z 509.23 [M+H]+, HPLC RT (min) 2.12.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].CN(C=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]>C(OCC)C>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][S:27]([C:30]([F:33])([F:31])[F:32])(=[O:29])=[O:28])[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH3:9]
Reactant: COC(=O)c1cc(O)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
With cooling with ice, potassium carbonate (152 mg, 1.10 mmol) and iodoethane (0.088 mL, 1.10 mmol) were added to a DMF solution (2.0 mL) of methyl 3-hydroxy-5-trifluoromethane-sulfonyloxybenzoate (300 mg, 1.00 mmol), and stirred at room temperature for 14 hours. The reaction mixture was diluted with diethyl ether (30 mL), then washed with water and aqueous saturated sodium chloride solution, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][SH:17])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:19][C:20]1[CH2:25][CH2:24][CH:23]([C:26]([CH3:28])=[CH2:27])[CH2:22][CH:21]=1>CCOCC>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][S:17][C:26]([CH:23]1[CH2:24][CH2:25][C:20]([CH3:19])=[CH:21][CH2:22]1)([CH3:28])[CH3:27])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: C=C(C)C1CC=C(C)CC1
Reactant: COC(=O)[C@H](CS)NC(=O)OCc1ccccc1
Solvent: CCOCC
Product: COC(=O)[C@H](CSC(C)(C)C1CC=C(C)CC1)NC(=O)OCc1ccccc1

Procedure:
The ether is prepared from N-CBZ-L-cysteine methyl ester and α-limonene in a manner similar to that described in Example 1B. The product can be characterized by NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13](N)=[C:12]([Cl:17])[CH:11]=1.O.C(#[N:21])C>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:3]([C:2]([CH3:8])([CH3:7])[CH3:1])[C:4]([NH2:21])=[O:5])=[C:12]([Cl:17])[CH:11]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: CC#N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Product: CC(C)(C)C(C(N)=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
3,3-Dimethylbutanoyl chloride (717 mg, 0.74 mL, 5.32 mmol) was added to a solution of 4-Bromo-2-chloro-phenylamine (1.0 g, 4.84 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.04 g, 72% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:21](=[O:30])[CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:21](=[O:30])[CH:20]=1
Reactant: NCc1ccn(-c2ccsc2)c(=O)c1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccn(-c2ccsc2)c(=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (97 mg, 0.30 mmol), 4-aminomethyl-1-thiophen-3-yl-1H-pyridin-2-one (61 mg, 0.30 mmol), and triethylamine (77 μL, 0.59 mmol) in N,N-dimethylformamide (2 mL) is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure, and the residue is triturated with acetonitrile to provide (4Z)-6-iodo-4-[({[2-oxo-1-(3-thienyl)-1,2-dihydropyridin-4-yl]methyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione as a mauve powder (65 mg, 43%).
Reaction SMILES: [CH3:1][C:2]1([C:11]#[C:12][Si](C)(C)C)[CH2:10][C:6]2[CH:7]=[N:8][O:9][C:5]=2[CH:4]=[CH:3]1.C[O-].[Na+]>CCOCC.CO.C(Cl)Cl.CCOCC>[C:11]([C:2]1([CH3:1])[CH2:10][CH:6]([C:7]#[N:8])[C:5](=[O:9])[CH:4]=[CH:3]1)#[CH:12]
Reactant: CC1(C#C[Si](C)(C)C)C=Cc2oncc2C1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: C#CC1(C)C=CC(=O)C(C#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 9 (75 mg, 0.32 mmol) in dry ether (7.4 mL) was added a solution of sodium methoxide (565 mg) in dry methanol (6 mL). The mixture was stirred at room temperature for 1 h. The mixture was diluted with methylene chloride/ether (1:2, 40 mL). The mixture was washed with 5% aqueous HCl solution (10 mL ×2). The acidic washings were extracted with methylene chloride/ether (1:2, 10 mL ×1). The original organic solution and the extract were combined. The combined solution was washed with water (15 mL ×2) and brine (15 mL ×1), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give MCE-4 as a crystalline solid (51 mg, quantitative yield). This material was used without further purification for the next step.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1CCCCC1.CC1C=CC(S(O)(=O)=O)=CC=1.[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=O)=[CH:31][CH:30]=1.Cl.[NH2:39][NH2:40]>C(Cl)Cl.C1C=CC=CC=1>[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]2[C:6]3[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8][C:7]=3[NH:40][N:39]=2)=[CH:31][CH:30]=1
Reactant: NN
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(=O)N1CCc2[nH]nc(-c3ccc(Br)cc3)c2C1
Temperature: 125 °C
Reaction time: 17 h
Yield: 50.9 %

Procedure:
A flask equipped with a Dean-Stark trap was charged with N-acetyl-4-piperidone (100.1 g, 709 mmol), piperidine (68 mL, 779 mmol), pTsOH (3.7 g) and benzene (500 mL). The mixture was heated to 125° C. After 17 h the mixture was allowed to cool and divided into two portions. A solution of p-bromobenzoyl chloride (70.0 g, 319 mmol) in CH2Cl2 (400 mL) was added dropwise to a 0° C. solution of the enamine (ca. 355 mmol) in CH2Cl2 (320 mL) over 15 h. The mixture was then allowed to warm to 23° C. and stirred for an additional 5 h. The solution was treated with 1 N HCl (500 mL) and stirred vigorously for 1.5 h. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×300 mL). The combined extracts were washed with sat. aqueous NaHCO3 (300 mL), H2O (300 mL), brine (300 mL), dried over Na2SO4 and concentrated. The residue was dissolved in MeOH (300 mL) and treated with NH2NH2 (50.0 mL, 1.59 mol). The mixture was stirred for 17 h before the precipitate formed was collected by filtration and air dried to give 52 g (50%) of the title compound which was suitable for use without further purification. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): m/z calculated for C14H1579BrN3O [M+H]+, 320.04, found 320. 1H NMR (CD3OD/CDCl3, 400 MHz, a mixture of amide rotamers): 7.53 and 7.35 (A and B of AA′BB′, J=8.5 Hz, 2H), 7.51 and 7.39 (A and B of AA′BB′, J=8.6 Hz, 2H), 4.72 (s, 2H), 4.58 (s, 2H), 3.85 (t, J=5.9 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 2.81, (t, J=5.8 Hz, 2H), 2.74, (t, J=5.8 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:17][CH:16]3[NH:18][CH:12]([CH2:13][O:14][CH2:15]3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[BH3-][C:22]#N.[Na+]>CC#N.CC(O)=O>[CH3:22][N:18]1[CH:12]2[CH2:13][O:14][CH2:15][CH:16]1[CH2:17][N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH2:11]2
Reactant: [BH3-]C#N
Reactant: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1C2COCC1CN(S(=O)(=O)c1ccccc1)C2
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of 112f (2.0g, 7.5 mmol) in MeCN (60 ml) was added HCHO (1.4 ml, 16 mmol) and 5 drops of AcOH at room temperature. Then NaCNBH3 (1 g, 16 mmol) added and the mixture was stirred for 2h. It was poured onto water and extracted with EA (100*3). The organic layer was dried over Na2SO4, filtered off, evaporated, and purified through a silica gel column eluting with PE:EA=5:1 to 1:1 to give 112g as a colorless oil (1.5g, 72%) MS: [M+H]+: 283
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])OC1C=CC=CC=1.O.[C:20](OCC)(=O)[CH3:21].Cl.C[N:28]([CH3:31])C=O>C1(N)CC1>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:28][CH:31]1[CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(Nc1ccc(O)cc1Cl)Oc1ccccc1
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Agent: Cl
Agent: NC1CC1
Solvent: O
Product: O=C(Nc1ccc(O)cc1Cl)NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
After dissolving phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL), cyclopropylamine (22.7 mL) was added while cooling on ice, and the mixture was stirring at room temperature overnight. Water (400 mL), ethyl acetate (300 mL) and 6N-HCl (55 mL) were then added, the mixture was stirred, and the organic layer was separated. The organic layer was washed twice with a 10% aqueous solution of sodium chloride (200 mL), and dried over magnesium sulfate. Prism crystals obtained by concentrating the solvent were filtered and washed with heptane to give 22.8 g of the titled compound (77% yield from 4-amino-3-chlorophenol).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]1[C:19]([OH:21])=[O:20])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:23]>C1COCC1.C(=O)(O)[O-].[Na+]>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([O:18][CH3:23])[CH2:15][C@H:14]1[C:19]([OH:21])=[O:20])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (543 mg, 22.6 mmol, 2.00 equiv) was carefully added to a solution of (2S,4R)-1-[(benzyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid (3-1, 3.00 g, 11.3 mmol, 1 equiv) in THF (100 mL) at 0° C., and resulting mixture was stirred for 20 minutes. Iodomethane (2.11 mL, 33.9 mmol, 3.00 equiv) was added, and the mixture was warmed to 23° C. and stirred for 20 h. The reaction mixture was then diluted with saturated sodium bicarbonate solution washed with ethyl acetate (2×100 mL). The aqueous layer was then acidified with 1 N HCl solution to pH 3 and extracted with ethyl acetate (100 ml). This organic layer was then dried over sodium sulfate and concentrated to provide (2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxy-2-pyrrolidinecarboxylic acid (3-2) as a light yellow oil. 1H NMR (400 MHz, CDCl3) major rotamer: δ7.40-7.25 (br m, 5H), 5.20 (s, 2H), 4.52 (t, 1H, J=7.4 Hz), 4.00 (m, 1H), 3.67 (dd, 1H, J=11.4, 2.8 Hz), 3.57 (dd, 1H, J=11.4, 4.6 Hz), 3.32 (s, 3H), 2.34 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]=1[OH:20].CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2].[C:42]([O:47][CH2:48][CH2:49][N:50]=[C:51]=[O:52])(=[O:46])[C:43]([CH3:45])=[CH2:44].COC1C=CC(O)=CC=1>C1COCC1.C(OCC)C>[C:42]([O:47][CH2:48][CH2:49][NH:50][C:51]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]=1[OH:20])=[O:52])(=[O:46])[C:43]([CH3:45])=[CH2:44]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: COc1ccc(N=Nc2cc(C)cc(CO)c2O)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: COc1ccc(O)cc1
Agent: [Sn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C(=O)OCCNC(=O)OCc1cc(C)cc(N=Nc2ccc(OC)cc2)c1O
Temperature: 60 °C
Reaction time: 20 h

Procedure:
In a 500 ml 3-neck round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 5.01 g (18.4 mmol) 2-(hydroxymethyl)-6-((4-methoxyphenyl)diazenyl)-4-methylphenol from Example 2 in 300 ml anhydrous THF. Stannous octoate (50 mg, Pfaltz & Bauer) was added followed by 2-isocyanatoethyl methacrylate (3.14 g, 20.2 mmol). MEHQ (100 mg) was added. The reaction mixture was stirred for 20 hr at 60° C. and then poured into 200 ml diethyl ether, and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and rotovapped to give the desired product which was recrystallized in ethanol to give 6.0 g (76%) of an orange solid. 1H NMR (CDCl3) delta: 13.22 (s, 1H, Ar—OH), 7.85 (m, 2H, Ar—H), 7.69 (s, 1H, Ar—H), 7.23 (s, 1H, Ar—HI), 7.03 (m, 2H, Ar—H), 6.09 (s, 1H, vinyl-H), 5.57 (s, 1H, vinyl-H), 5.24 (s, 2H, Ar—CH2), 5.02 (s, 1H, CONH), 4.24 (m, 2H, CH2OCO), 3.90 (s, 3H, Ar—OCH3), 3.53 (m, 2H, OCNHCH2), 2.38 (s, 3H, Ar—CH3), 1.92 (s, 3H, CH3—C═C).