Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:33]=[CH:32][C:20]2[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:33]=[CH:32][C:20]3[N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(N)ccc21
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3C(=O)OC(C)(C)C)nc1Cl
Yield: 54.2 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (100 mg, 0.59 mmol), thionyl chloride (5 mL), pyridine (10 mL) and tert-butyl 7-amino-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate obtained in Example (95b) (0.3 g, 1.20 mmol), to obtain 0.13 g of the title compound as a pale yellow solid (56%).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>CN(C)C=O>[CH3:8][C:1]1[CH:6]=[CH:5][C:4]([S:7][C:10]2[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Cc1ccc(S)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2cc(C(=O)O)co2)cc1

Procedure:
Using reagent quantities identical to that of Example 9, p-toluenethiol and cuprous oxide were combined in 45 ml. of dimethylformamide heated at 135° C. for about 1.5 hours, cooled somewhat, 5-bromofuran-3-carboxylic acid in 40 ml. of dimethylformamide added, and the mixture refluxed for 24 hours. Crude product (185 mg.) was recovered according to the procedure of Example 10. Recrystallization from methanol/water afforded purified 5-(4-methylphenylthio)furan-3-carboxylic acid (135 mg., m.p. 116°-119° C.).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C(=O)(OC(Cl)C)[O:8][C@:9]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[NH:26][C:27]([C@@]12C(C)(C)[C@@](C)(CC1)C(=O)O2)=[O:28])([C:14]#[C:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([F:13])([F:12])[F:11].C(OC)(C)(C)C.O>CN(C)C=O>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]2[NH:26][C:27](=[O:28])[O:8][C@:9]([C:14]#[C:15][CH:16]3[CH2:18][CH2:17]3)([C:10]([F:13])([F:12])[F:11])[C:19]=2[CH:24]=1
Reactant: CC(Cl)OC(=O)O[C@@](C#CC1CC1)(c1cc(Cl)ccc1NC(=O)[C@@]12CC[C@@](C)(C(=O)O1)C2(C)C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
K2CO3 (13.3 g, 95.8 mmol) powder was added to a solution of (S)-2-(5-chloro-2-((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamido) phenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-yl 1-chloroethyl carbonate (7, R1 is 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptyl, R3 is 1-chloroethyl, 36.8 g, 63.9 mmol) in N,N-dimethylformamide (150 mL). The reaction mixture was stirred at room temperature overnight. Methyl t-butyl ether (300 mL) and water (300 mL) were added to the mixture, and the resulting layers were separated. The organic layer was washed with brine and evaporated to 60 mL then petroleum ether (200 mL) was added. The resulting mixture was filtered and rinsed with petroleum ether to give (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (Efavirenz, 1) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=O)=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>C(OCC)(=O)C.C(Cl)Cl.[Pd]>[CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:17]=[S:18])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CN(C)c1ccc(N=O)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C)c1ccc(N=C=S)cc1

Procedure:
A solution of 14.7 g (66 mmol) of ethyl N-methyl-N-(4-nitrosophenyl)glycinate in 200 mL of ethyl acetate was reduced (10% Pd/C, 50 psi H2) until uptake was complete, dried 1 hr (Na2SO4), filtered, concentrated, and dissolved in a solution of 12.5 g (70 mmol) of thiocarbonyldimidazole in 100 mL CH2Cl2 /300 ml toluene. When tlc showed only product (2 hr,Rf 0.6, CH2Cl2), the solution was washed with 2×100 mL of water, passed throug a silica plug to remove color, and recrystallized from hexane (300 mL) to give 13.6g (54 mmol, 82%) mp 90-91°. Anal. C12H14N2O2S (250): Calcd.: C,57.58; H,5.64; N,11.19; S,12.81. Found: C,57.63; H,5.59; N,11.17; S,12.49. MS(FD) m/z250. 1H NMR(CDCl3)δ: 7.10,d,2H,ArH; 6.58,d,2H,ArH; 4.18,q,2H,CH2 --O; 4.05,s,2H,CH2 --N; 3.07,s,3H,CH3 --N; 1.25,s,3H,CH3 --C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:13]=[C:12]([O:14]C(=O)C)[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH:6]C(=O)C>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:13]=[C:12]([OH:14])[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH2:6]
Reactant: COc1cc(CNC(C)=O)c(Cl)cc1OC(C)=O
Agent: Cl
Solvent: CCO
Product: COc1cc(CN)c(Cl)cc1O

Procedure:
37% hydrochloric acid (2.5 ml) was added to a solution of 2-chloro-4-acetyloxy-5-methoxy-N-acetyl-benzylamine 2b (0.45 g, 1.66 mmol) in abs. ethanol (15 ml) and the mixture was refluxed for 12 hours. The reaction was cooled and the solvent was evaporated under reduced pressure. The residue was recrystallized from dry acetone to afford the title compound as white crystals in quantitative yield.
Reaction SMILES: [CH2:1]([NH:11][C:12]([NH:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[H-].[Na+].Br[CH2:26][CH2:27][CH2:28]Br.Cl>CN(C=O)C>[CH2:1]([N:11]1[CH2:28][CH2:27][CH2:26][N:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=CCCCCCCCCNC(=O)NOCc1ccccc1
Reactant: BrCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCN1CCCN(OCc2ccccc2)C1=O
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 9-decenyl isocyanate, prepared as in Example 18 above from 10.8 ml of 10-undecenoyl chloride in 1,2-dichloroethane (150 ml) at room temperature was added benzyloxyamine (7.2 g). After 20 minutes, the mixture was evaporated, hexane (50 ml) was added, and the mixture cooled to 0° C. The resulting solids were collected by filtration, to provide N-(9-decenyl)-N'-benzyloxyurea as a white solid (7.14 g, mp 53°-55° C.). To a stirred slurry of this urea (3.50 g, 11.65 mmol) in DMF (35 ml) at room temperature under nitrogen was added sodium hydride (490 mg of a 60% dispersion in oil). After one hour, 1,3-dibromopropane (1.45 ml) was added, and the reaction was stirred for two hours. The mixture was poured into 1% aqueous HCl (200 ml), and extracted twice with ether. The combined extracts were washed with water, dried (MgSO4), filtered and evaporated. Purification by chromatography on silica gave 3-decyl-1-benzyloxy-3,4,5,6-tetrahydro-lH-pyrimidin-2-one as a colorless oil (1.92 g, 48% yield). Hydrogenolysis as in Example 2 above provided the title compound as a light magenta solid, after recrystallization from carbon tetrachloride, mp 45°-46° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH2:21]([NH:24][CH:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][C:29]([O:37][CH3:38])=[C:30]([O:35][CH3:36])[CH:31]=2)[CH2:26]1)[CH:22]=[CH2:23]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:24]([CH2:21][CH:22]=[CH2:23])[CH:25]3[CH2:34][CH2:33][C:32]4[C:27](=[CH:28][C:29]([O:37][CH3:38])=[C:30]([O:35][CH3:36])[CH:31]=4)[CH2:26]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: C=CCNC1CCc2cc(OC)c(OC)cc2C1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: C=CCN(CCCN1CCc2cc(OC)c(OC)cc2CC1=O)C1CCc2cc(OC)c(OC)cc2C1

Procedure:
The title compound is prepared from 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane and 2-allylamino-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene analogously to Example 1. Mp: 226°-228° C.
Reaction SMILES: [CH2:1]([C@H:8]([C@H:12]([OH:16])[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:19](OC)([CH3:21])[CH3:20]>CC(C)=O.[Cu](Cl)Cl>[CH3:20][C:19]1([CH3:21])[O:16][C@H:12]([C@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([OH:11])=[O:10])[C:13](=[O:15])[O:14]1
Reactant: O=C(O)[C@@H](O)[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: CC1(C)OC(=O)[C@@H]([C@H](Cc2ccccc2)C(=O)O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
To a solution of (2R,3S)-2-benzyl-3-hydroxysuccinic acid (2.08 g; 9.28 mmol; 1.00 eq.) in acetone (50.0 mL) was added 2,2-dimethoxypropane (2.3 mL; 18.55 mmol; 2.0 eq.) and copper(II) chloride (124.73 mg; 0.93 mmol; 0.10 eq.). The resulting reaction mixture was stirred for 4 h at RT. The reaction mixture was evaporated and the residue taken up in CHCl3. Activated charcoal is added and the resulting mixture stirred for one hour. Filtration on a pad of celite gave the title product (single diastereoisomer) as a greenish oil (1.81 g, 74%) used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:33](OCC)=[O:34])[C:28](OCC)=[O:29])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:28]([OH:29])[C:27]([C:24]3[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=3)=[C:33]([OH:34])[N:16]=2)=[N:6]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: CCOC(=O)C(C(=O)OCC)c1ccncc1
Solvent: Cc1ccccc1
Product: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(O)c1-c1ccncc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
3.27 g (12.1 mmol)1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximid-amide from example III were suspended in 40 ml toluene, reacted with 2.88 g (12.1 mmol) diethyl 2-(4-pyridinyl)malonate (commercially available by Mercachem) and stirred overnight at 140° C. For purification the deposited solid is sucked off and dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N+:3]=1[O-].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH2:11][O:16][C:13](=[O:15])[CH3:14])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)[n+]1[O-]
Product: CC(=O)OCc1ccc([N+](=O)[O-])c(Cl)n1
Temperature: 60 °C

Procedure:
2-Chloro-3-nitro-6-picoline-N-oxide (1.6 g, 8.5 mmol) was dissolved in acetic anhydride (5 mL) and the solution was heated in a 60° C. oil bath for 3 hours. The solvents were removed under vacuum and the dark residue was partitioned between methylene chloride (30 mL) and saturated aqueous potassium carbonate (100 mL). The aqueous layer was re-extracted with more methylene chloride (2×40 mL) and the combined methylene chloride layers were dried with magnesium sulfate, filtered and evaporated under vacuum. The crude solid was dissolved in methylene chloride (5 mL) and was loaded onto a silica gel column (E. Merck 60, 230-400 mesh, 2.5×24 cm). The column was eluted with methylene chloride collecting 8 mL fractions. Fractions 11-26 were combined and evaporated to give the title compound (0.42 g) as a white solid.
Reaction SMILES: [C:1]([O-:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[NH4+]>O>[C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C([O-])CCCCC(=O)O
Agent: [NH4+]
Solvent: O
Product: O=C(O)CCCCC(=O)O
Temperature: 200 °C
Yield: 82.3 %

Procedure:
A 300 mL Parr autoclave was charged with 80 g of synthetic monoammonium adipate and 124 g of water. The autoclave was sealed and the contents stirred and heated to about 200° C. (autogenic pressure was about 203 psig). Once the contents reached temperature, water was then fed to the autoclave at a rate of about 2 g/min and vapor was removed from the autoclave at a rate of about 2 g/min with a back pressure regulator. Vapor exiting the autoclave was condensed and collected in a receiver. The autoclave was run under those conditions until a total of 1210 g of water had been fed and a total of 1185 g of distillate collected. The contents of the autoclave (209 g) were partially cooled and discharged from the reactor. The slurry was allowed to stand with stirring at room temperature over night in an Erlenmeyer flask. The slurry was then filtered and the solids rinsed with 25 g of water. The moist solids were dried in a vacuum oven at 75° C. for 1 hr yielding 59 g of adipic acid product. Analysis via an ammonium ion electrode revealed 0.015 mmole ammonium ion/g of solid. The melting point of the recovered solid was 151° C. to 154° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][O:28][CH2:29][C:30](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:30]([CH2:29][O:28][CH3:27])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: COCC(=O)O
Product: COCc1nc([C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)no1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and methoxyacetic acid, the title compound was obtained in 91% purity by HPLC.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14]([NH2:16]=O)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[ClH:28]>C(OCC)(=O)C.[Pd]>[ClH:28].[C:18]1([C:11]2([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C([NH2+][O-])C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(=O)C1(c2ccccc2)CCNCC1
Temperature: 5 °C

Procedure:
Combine 1-benzyl-4-phenylpiperidine-4-carboxylic acid amide N-oxide (529 g, 1700 mmol), 10% palladium-on-carbon (25 g), and acetic acid (5 L) in an autoclave. Flush the autoclave with nitrogen and then charge with 255 psi of hydrogen. Stir while recharging the autoclave with hydrogen as required to maintain the pressure above 100 psi. When hydrogen consumption ceases, flush the autoclave with nitrogen remove the catalyst by filtration. Evaporate the filtrate invacuo to give a residue. Dissolve the residue in ethyl acetate (5 L), acidify by the addition of 12M aqueous hydrochloric acid solution (150 mL), and heat to reflux for 15 minutes. Cool the mixture to 5° C. to give solid. Collect the solid by filtration, rinse with ethyl acetate, and air dry to give the title compound.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2>>[CH2:1]([NH:3][C:4]([N:12]1[C:13]2[C:9](=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)[CH2:10][C:11]1=[O:16])=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: CCNC(=O)N1C(=O)Cc2cc(Cl)ccc21
Temperature: 138 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Ethyl isocyanate (71.37 ml, 2.5 eq) was added to a solution of 5-chlorooxindole (60.45 g, 1.0 eq) in 500 ml xylenes. The reaction mixture was heated under reflux for 2 hours (138° C.) and then cooled to room temperature and evaporated to dryness. Isopropyl ether (500 ml) was added to the reaction vessel and the mixture was heated to 60° C. and stirred about 2 hours before cooling overnight in an ice bath to promote crystallization of the product. The white crystalline product was collected by filtration, washed once with isopropyl ether and then dried under vacuum to afford 5-Chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethylamide in 90% yield (78.0 g), mp 121-122° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.O[CH2:26][CH2:27][CH2:28][O:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:40]=[C:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38](=[O:39])[N:30]1[O:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1OCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCCCON2C(=O)c3ccccc3C2=O)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
To a solution of 100 mg (0.30 mmol) of methyl (2S)-3-(4-hydroxyphenyl)-2-[(phenylmethoxy)carbonylamino]propanoate, as prepared in the preceding step, 67 mg (0.30 mmol) of 2-(3-hydroxypropoxy)isoindoline-1,3-dione, as prepared in step 2, and 88 mg (0.34 mmol) of triphenylphosphine in 10 mL THF at water/ice mixture temperature was added 66 mL (0.34 mmol) of DIAD dropwise. The solution was stirred at the same temperature for additional 20 min. Then the solution was allowed to warm to room temperature and stirred overnight. The solvent was removed under reduced pressure. The mixture was chromatographed on a silica gel column using EtOAc/hexanes (3:7 to 2:3 v/v) as eluent to yield 89 mg (55%) of viscous liquid as product: 1H NMR (300 MH, CDCl3) δ7.85-7.80 (m, 2H), 7.77-7.71 (m, 2H), 7.38-7.27 (m, 5H), 6.98 (d, J=8.65 Hz, 2H), 6.82 (d, J=8.65 Hz, 2H), 5.19 (d, J=8.16 Hz, 1H), 5.09 (s, 2H), 4.61 (m, 1H), 4.40 (t,J=6.22, 2H), 4.19 (t, J=6.11 Hz, 2H), 3.71 (s, 3H), 3.08-2.96 (m, 2H), 2.23 (quintet, J=6.15 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O[N:17]1[C:21]2C=CC=[CH:25][C:20]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.C(N)C=C>ClCCl>[CH2:21]([NH:17][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH3:14])[CH:20]=[CH2:25]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C=CCN
Solvent: CCN(CC)CC
Product: C=CCNC(=O)[C@H](CC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A 500 mL round bottom flask was charged with (S)-2-(tert-butoxycarbonylamino)butanoic acid (5.0 g, 0.025 mol), 1-hydroxybenzotriazole hydrate (3.4 g, 0.025 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.2 g, 0.038 mol), and dichloromethane (125 mL). Triethylamine (7.6 mL, 0.055 mol) and allylamine (1.9 g, 0.025 mol) were added and the resulting mixture stirred at room temperature for 22 h. The resulting mixture was then diluted with dichlormethane (300 mL), washed 1× with 1N HCl (200 mL), 1× with 1N NaOH (200 mL), and 1× with water (200 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo to yield (S)-tert-butyl 1-(allylamino)-1-oxobutan-2-ylcarbamate. 1H NMR (300 MHz, CDCl3) δ 5.77-5.88 (m, 1H), 5.15-5.23 (m, 2H), 4.03-4.19 (m, 1H), 3.88-3.92 (m, 2H), 1.82-1.94 (m, 1H), 1.60-1.72 (m, 1H), 1.45 (s, 9H), and 0.96 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:2]1([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OCC1CCNCC1
Reactant: Clc1nccc2ccccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: OCC1CCN(c2nccc3ccccc23)CC1

Procedure:
The process is performed as described in Example 2 (step 2.1). Starting with 2.50 g (15.28 mmol) of 1-chloroisoquinoline, 1.94 g (136.6 mmol) of 4-piperidylmethanol, 3.53 g (36.67 mmol) of sodium tert-butoxide, 0.285 g (0.46 mmol) of BINAP and 0.140 g (0.15 mmol) of tris(dibenzylideneacetone)dipalladium, and after chromatography on silica gel, eluting with a 98/2/0.2 and then 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia, 2.40 g of pure product are obtained in the form of a viscous orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH3:17])=[C:8]([N+:18]([O-])=O)[CH:7]=1.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O.O.Cl[Sn]Cl>CC(O)=O.CO>[CH3:1][O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]([CH2:13][CH2:14][NH:15][CH2:16][CH3:17])[C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:18][C:8]=2[CH:7]=1
Reactant: CCCCCCC=O
Reactant: CCNCCNc1ccc(C=CC(=O)OC)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCc1nc2cc(C=CC(=O)OC)ccc2n1CCNCC
Temperature: 40 °C

Procedure:
To a stirred solution of 3-[4-(2-ethylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester (8.174 g, 27.87 mmol) and heptaldehyde (4.85 g, 42.47 mmol, 1.52 eq) in AcOH and MeOH (1:9 v/v, 300 mL) was added SnCl2.2H2O (31.45 g, 139.4 mmol, 5 eq) in portions. The resulting mixture was heated to 40° C. with stirring. The progress of the reaction was monitor by LC/MS. When the reaction was completed, solvent was removed under reduced pressure below 40° C. The resultant residue was diluted with EtOAc (50 mL) then basified (pH>10) with saturated aqueous Na2CO3 and extracted with dichloromethane (×3). Filtration may be needed to remove the white precipitates or suspension derived from Tin in order to get clearly separated layers. The organic extracts were combined, dried (Na2SO4), filtered, and evaporated to dryness. The resulting oily residue was purified by flash column chromatography (silica, φ67×65 mm, solvent MeOH/DCM gradient from 0 to 10%). 3-[1-(2-ethylamino-ethyl)-2-hexyl-1H-benzoimidazol-5-yl]-acrylic acid methyl ester was obtained as yellow solid (4.445 g, 44.6%). HPLC purity at 254 nm: 98.8%, tR=1.71 min. LCMS (ESI) m/z: 358 ([M+H]+). 1H NMR (CDCl3) δ 7.88 (1H, d, J=1.2 Hz), 7.83 (1H, d, J=16.0 Hz), 7.43 (1H, dd, J=8.4, 1.4 Hz), 7.33 (1H, d, J=8.4 Hz), 6.43 (1H, d, J=15.9 Hz), 4.22 (2H, t, J=6.6 Hz), 3.80 (3H, s), 3.01 (2H, t, J=6.6 Hz), 2.89 (2H, t, J=7.9 Hz), 2.65 (2H, q, J=7.1 Hz), 1.91 (2H, pentet, J=7.8 Hz), 1.46 (2H, m), 1.35 (4H, m), 1.07 (3H, t, J=7.1 Hz), 0.90 (3H, t, J=7.0 Hz). The solid could be recrystallized from Hexanes-ether to give a white or pale yellow solid with HPLC purity at 254 nm: 99.2%.