Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.ClCCl.Cl.ClCCl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:4]1(/[CH:3]=[CH:2]/[C:1]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:1](=[O:10])/[CH:2]=[CH:3]/[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:15][CH:14]=2)=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccccc1)Nc1ccc(OC(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Cinnamoyl chloride (16.79 g, 100.8 mmoL) was added to a solution of 4-aminophenol (5.00 g, 45.8 mmol) and DMAP (0.56 g, 4.58 mmol) in pyridine (50 mL). The reaction mixture was stirred at room temperature for 30 min whereupon a solid mass formed. Dichloromethane (50 mL) was added and the resultant suspension was stirred at room temperature for 2 h. The reaction mixture was poured into 10% hydrochloric acid/dichloromethane and shaken. The precipitated white solid was removed by filtration, washed with dichloromethane, 10% hydrochloric acid and then dichloromethane again. The organic layer of the filtrate was separated and washed with 10% hydrochloric acid (×2) and brine, dried (Na2SO4) and evaporated to give the title compound (15.1 g, 89%). 1HNMR (300 MHz) (CDCl3) δ 6.55 (1H, d, J=16 Hz), 6.64 (1H, d, J=16 Hz), 7.18 (2H, d), 7.35-7.45 (6H, m), 7.58 (4H, m), 7.67 (2H, m), 7.78 (1H, d, J=16) and 7.88 (1H, d, J=16).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:30][C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([O:36][CH3:37])=[O:35]>CS(C)=O.O>[CH3:1][C:2]1[N:6]([CH2:30][C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([O:36][CH3:37])=[O:35])[N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:8]=2)[N:3]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a solution of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (311 mg, 1.0 mmol) in DMSO (5 mL), Cs2CO3 (652 mg, 2.0 mmol) and methyl 3-(bromomethyl)benzoate (252 mg, 1.1 mmol) were added at RT. The mixture was stirred at RT for 2 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4×40 mL). The combined organic layers werewashed with H2O (20 mL) and brine (2×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by a silica gelchromatography (EtOAc/Hexane 10% to 60% EtOAc) to give methyl 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzoate as a white solid (310 mg, 68%). MS (ES+) C21H16F3N5O4 requires: 459. found: 460 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.29 (d, J=8.8 Hz, 2H), 8.04 (d, J=7.4 Hz, 1H), 7.95 (s, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 5.51 (s, 2H), 3.92 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [OH:1][CH:2](/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:3]#[C:4][C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:2](=[O:1])[C:3]#[C:4][C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:6])=[CH:22][CH:21]=1
Reactant: COCCOCCOC(=O)C#CC(O)/C=C/c1ccc(OC)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COCCOCCOC(=O)C#CC(=O)/C=C/c1ccc(OC)cc1
Reaction time: 2 h

Procedure:
A solution of 2.4 g (7.2 mmol) of 2-(2-methoxyethoxy)-ethyl (E)-4-hydroxy-6-(4-methoxyphenyl)-5-hexen-2-ynoate in 40 ml of methylene chloride was added dropwise at 0° to a suspension of 9.4 g (108 mmol) of manganese dioxide in 30 ml of methylene chloride. The reaction mixture was stirred at 0° for 2 hours, filtered over magnesium sulphate and concentrated. Crystallization of the residue from ether/hexane yielded 2-(2-methoxyethoxy)ethyl (E)-6-(4-methoxyphenyl)-4-oxo-5-hexen-2-ynoate of melting point 41°-42°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1.[CH2:30]([CH2:32][NH2:33])[OH:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:33][CH2:32][CH2:30][OH:31])=[O:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NCCO)cc2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-[1-(4-chloro-2-fluoro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-benzoic acid was coupled with ethanolamine using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a colourless foam, MS (ESI+): m/z=457.1 [M+H]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[C:16]([O:22][CH3:23])=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:3]=1.[CH2:24](N(CC)CC)[CH3:25].[B-](F)(F)(F)C=C.[K+]>C(O)(C)C.O1CCCC1>[CH3:23][O:22][C:16]1[C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH:24]=[CH2:25])=[N:3]2)=[CH:20][CH:19]=[C:18]([CH3:21])[N:17]=1
Reactant: COc1nc(C)ccc1Cn1nc(I)c2c([N+](=O)[O-])cccc21
Reactant: CCN(CC)CC
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=Cc1nn(Cc2ccc(C)nc2OC)c2cccc([N+](=O)[O-])c12
Temperature: 90 °C
Yield: 52.7 %

Procedure:
A solution of 3-iodo-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (982 mg, 2.31 mmol) in a 4:1 mixture of isopropyl alcohol/tetrahydrofuran (10 mL) was stirred under an argon atmosphere. Argon was bubbled through the solution for 20 minutes. Triethylamine (968 μL, 6.94 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (189 mg, 0.231 mmol) and potassium trifluoro(vinyl)borate (659 mg, 6.94 mmol) were added to the solution. The reaction mixture was heated at 90° C. for 24 hour. The mixture was allowed to cool and then filtered through Celite®, rinsing with ethyl acetate. The filtrate was concentrated under reduced pressure. The material was dissolved in ethyl acetate (50 mL), transferred to a reparatory funnel and washed with water and brine. The solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was purified using column chromatography on silica, eluting with 15-20% ethyl acetate in hexanes to give 1-((2-methoxy-6-methylpyridin-3-yl)methyl)-4-nitro-3-vinyl-1H-indazole (395 mg).
Reaction SMILES: CN(C)C(=O)C.[N:7]1[C:12]2[NH:13][CH:14]=[CH:15][C:11]=2[C:10]([NH2:16])=[N:9][CH:8]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>O>[C:17]1(=[O:22])[N:16]([C:10]2[C:11]3[CH:15]=[CH:14][NH:13][C:12]=3[N:7]=[CH:8][N:9]=2)[C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12
Reactant: Nc1ncnc2[nH]ccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1ncnc2[nH]ccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
To a 250 mL three-neck round bottom flask equipped with an overhead stirrer, nitrogen inlet, and thermocouple was charged 50 mL of dry N,N-dimethylacetamide followed by 5.0 g of 7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (3-1) [J. Davoll, J. Chem. Soc., 131-138 (1960)] and 11.6 g of phthalic anhydride. The resulting mixture was heated to 80° C. for 8 h and then cooled to 10° C. Water (40 mL) was added while maintaining the temperature below 15° C. The resulting slurry was aged for 4 h, then filtered, and the filter washed with 20 mL of 1:1 (v/v) dimethylacetamide/water followed by 30 mL of water. The cake was sucked dry, then washed with 50 mL of ethyl acetate. The solid was dried at 40° C. under vacuum with a nitrogen sweep to give 8.1 g of 4-phthalimido-7H-pyrrolo[2,3-d]pyrimidine (3-2); m.p. 276-277° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=3)[N:10]([CH:20]([CH3:22])[CH3:21])[CH:9]=2)=[CH:6][C:5]([C:23]#[N:24])=[N:4]1)[CH3:2].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([C:23]#[N:24])[CH:6]=3)=[CH:9][N:10]2[CH:20]([CH3:21])[CH3:22])=[CH:15][CH:14]=1
Reactant: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc([N+](=O)[O-])ccc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc(N)ccc12
Reaction time: 0.25 h
Yield: 109.3 %

Procedure:
Stir a solution of 1-Ethyl-5-(1-isopropyl-6-nitro-1H-indol-3-yl)-1H-pyrazole-3-carbonitrile (0.127 g, 0.393 mmol) and tin(II) chloride dihydrate (0.887 g, 3.93 mmol) in DMF (2.5 mL) at 70° C. for 1 h. After this time, Pour the reaction carefully into a stirring solution of saturated aqueous sodium bicarbonate (50 mL), diluted with ethyl acetate (50 mL) and stir for 15 min. Filter the resulting mixture through diatomaceous earth. Separate the organic layer of the filtrate and wash with water (3×50 mL) then brine (50 mL). Dry the resulting solution over sodium sulfate, filtered and concentrate the filtrate under reduced pressure to afford 5-(6-Amino-1-isopropyl-1H-indol-3-yl)-1-ethyl-1H-pyrazole-3-carbonitrile (0.126 g, quant.) as a yellow foam. Use the foam without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].C([Li])CCC.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]C.C(Br)CCCC>CN1C(=O)N(C)CCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#CCCCOC1CCCCO1
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: CCCCCBr
Solvent: CN1CCCN(C)C1=O
Product: CCCCCC#CCCCOC1CCCCO1
Yield: 58 %

Procedure:
1-(Tetrahydopyran-2-yloxy)-4-pentyne (1) (0.66 g, 3.90 mmol) was metallated with n-butyllithium solution (2.5M) in hexane (1.87 ml, 1.2 eq.). Addition of a solution of n-pentyl bromide (0.725 ml, 1.5 eq.) in DMPU (2 ml) produced 0.54 g (58% yield) of the title compound (15). 1H NMR (200 MHz) δ: 4.60 (m, 1H, CH-2'), 3.65 (m, 4H, CH2 -1, 6'), 2.26 (tt, J=7.0, 7.0, 2.0, 2.0 Hz, 2H, CH2 -3), 2.13 (tt, J=7.0, 7.0, 2.5, 2.5 Hz, 2H, CH2 -6), 1.77 (tt, J=6.8, 6.8, 7.07 7.0 Hz, 2H, CH2 -2), 1.33 (m, 6H, CH2 -7, 8, 9), 1.52 (m, 6H, CH2 -3', 4', 5'), 0.89 (t, J=7.0 Hz, 3H, CH3). MS [FAB, m/z(%)] 237 (M+ -1), 85 (100). IR (CCl4, cm-1) 2229, 1322, 1331, 1201, 1138, 1121, 1034.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2([C:26]#N)[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13]1.Cl.C([O:32]C(C)C)(C)C>C1(C)C=CC=CC=1.CO>[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2([CH:26]=[O:32])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13]1
Reactant: CC(C)OC(C)C
Reactant: Cn1cc(C2(C#N)CCCC2)c2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cn1cc(C2(C=O)CCCC2)c2ccccc21

Procedure:
The reaction is performed under a dry nitrogen atmosphere. 94.4 cm3 (0.0944 mol) of a 1N toluene solution of diisobutylaluminium hydride are added at -60° C. to a solution of 13.3 g (0.059 mol) of 1-(1-methyl-3-indolyl)-cyclopentanecarbonitrile in 230 cm3 of toluene. The temperature of the mixture is thereafter allowed to rise to room temperature, and the reaction is then stopped by adding 50 cm3 of methanol and then 230 cm3 of 3N hydrochloric acid to the reaction mixture. The mixture is extracted with dichloromethane, the organic extract is washed with water, dried over sodium sulphate and filtered and the filtrate is evaporated. In succession, the residue obtained is taken up with diisopropyl ether, some insoluble matter is removed by filtration, the solvent is evaporated and the residue is crystallised in hexane.
Reaction SMILES: [F:1]C1C=CC(OC)=C(C2C(C(O)=O)=CC([N+]([O-])=O)=CC=2)C=1.C[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[C:32]([C:41]([O:43]C)=[O:42])=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][C:36]=1C>>[F:1][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[C:32]([C:41]([OH:43])=[O:42])=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1-c1cc(OC)ccc1C
Reactant: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1ccc(F)c(-c2ccc([N+](=O)[O-])cc2C(=O)O)c1
Yield: 99 %

Procedure:
This compound was prepared in a manner similar to that of 5′-fluoro-2′-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 2′-methyl-5′-methoxy-6-methyl-4-nitro-2-biphenylcarboxylate (0.77 g) to afford 0.73 g (99%) of 2′-fluoro-5′-methoxy-4-nitro-2-biphenylcarboxylic acid as a white solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C(Cl)Cl>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:10]=[O:11])=[CH:5][CH:4]=1)#[CH:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C#Cc1ccc(N)cc1
Solvent: ClCCl
Product: C#Cc1ccc(N=C=O)cc1

Procedure:
4-Ethynylphenylisocyanate was prepared from reaction of 4-ethynylaniline with one equivalent of carbonyldiimidazole in CH2Cl2.
Reaction SMILES: S1C=C(N)C2C=CC=CC1=2.FC1C=C(F)C=CC=1S(C)(=O)=O.C(N(CC)C(C)C)(C)C.F[C:33]1[CH:34]=[CH:35][C:36]([S:49]([CH3:52])(=[O:51])=[O:50])=[C:37]([NH:39][C:40]2[C:41]3[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=3[S:43][CH:44]=2)[CH:38]=1.[NH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>CN(C)C=O.C(#N)C.O>[CH3:52][S:49]([C:36]1[CH:35]=[CH:34][C:33]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:38][C:37]=1[NH:39][C:40]1[C:41]2[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=2[S:43][CH:44]=1)(=[O:51])=[O:50]
Reactant: CS(=O)(=O)c1ccc(F)cc1Nc1csc2ccccc12
Reactant: C1CNCCN1
Agent: CS(=O)(=O)c1ccc(F)cc1F
Agent: Nc1csc2ccccc12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1Nc1csc2ccccc12
Temperature: 25 °C
Yield: 16 %

Procedure:
A solution of benzo[b]thiophen-3-amine (1.1 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (1.1 mmol) and N,N-diisopropylethylamine (4.00 mmol) in N,N-dimethylformamide (2 mL) was stirred at 110° C. for 16 h. The reaction was cooled to room temperature, poured over water and extracted with diethyl ether. The solvent was concentrated in vacuo and the residue was used without further purification for the following reaction. N-(5-fluoro-2-(methylsulfonyl)phenyl)benzo[b]thiophen-3-amine (0.3 mmol), piperazine (8.0 mmol), N,N-diisopropylethylamine (4.00 mmol) were stirred at 80° C. in dry acetonitrile (3 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (16% yield). 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.88 (m, 1H), 7.71 (d, 1H), 7.71 (m, 1H), 7.66 (m, 1H), 7.14 (s, 1H), 6.46 (d, 1H), 6.41 (dd. 1H), 3.13 (s, 3H), 3.11 (m, 4H), 2.91 (m, 4H); MS (ESI) m/z: 388.2 (M++1).
Reaction SMILES: COC[O:4][C:5]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]2[C:6]=1[CH2:7][N:8](C(C)(C1C=CC=CC=1)C)[C:9]2=[O:15].C(Cl)(Cl)Cl>Cl.CO>[OH:4][C:5]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]2[C:6]=1[CH2:7][NH:8][C:9]2=[O:15]
Reactant: COCOc1ccc(I)c2c1CN(C(C)(C)c1ccccc1)C2=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1NCc2c(O)ccc(I)c21
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
4-Methoxymethoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (463 mg, 1.06 mmol) was dissolved in 10% hydrogen chloride-methanol solution (14 mL), and the solution was stirred at 70° C. for 2.5 hours. Then, the solution was added with 10% hydrogen chloride-methanol solution (4.3 mL) and further stirred at 2.5 hours. The reaction mixture was added with chloroform and purified by slurry. The solid was collected by filtration and washed with chloroform/methanol (9/1). The obtained solid was dried under reduced pressure to obtain 4-hydroxy-7-iodoisoindolinone (248 mg, yield 85%).
Reaction SMILES: [CH2:1]([O:13][CH2:14][C@@H:15]([OH:18])[CH2:16]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>Br.CC(O)=O.C(Cl)Cl.CCOCC>[CH2:1]([O:13][CH2:14][C@@H:15]1[CH2:16][O:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOC[C@@H](O)CO
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCCCCCCOC[C@@H]1CO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-3-(dodecyloxy)propane-1,2-diol (1 eq) in HBr/AcOH (33 wt %, 0.4 M) was stirred at 35° C. for 30 minutes. The reaction mixture was cooled down to 0° C., diluted with DCM and tuned to pH 7 by adding saturated Na2CO3. The organic layer was separated, dried over Na2SO4 and concentrated en vaccuo. The residue was dissolved in MeOH (0.5 M), cooled down to 0° C. and treated with NaOH (3N in MeOH, 2.5 eq). The reaction mixture was stirred for 30 minutes and diluted with Et2O. The organic layer was separated, washed with H2O and brine, dried over Na2SO4 and concentrated en vaccuo to give the title product as a colorless viscous oil without further purification.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:21]([O:23][C:24](=[O:30])[CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])[CH3:22].CCN(C(C)C)C(C)C>ClCCl>[CH2:21]([O:23][C:24](=[O:30])[CH2:25][N:26]([C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12])[CH:27]([CH3:29])[CH3:28])[CH3:22]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: CCOC(=O)CNC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CN(C(C)C)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 3 h
Yield: 87.8 %

Procedure:
At room temperature, 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (4.57 g, 12.3 mmol) and Isopropylamino-acetic acid ethyl ester (2.15 g, 14.8 mmol), DIPEA (2.14 ml) were mixed in about 40 ml dichloromethane. After stirred for about 3 h, the solution was concentrated and the crude product was purified by chromatography to obtain 4.7 g solid rac-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-acetic acid ethyl ester. MS: 435 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([NH2:17])=[O:16])[CH:9]=1>C(O)(=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([NH2:17])=[O:16])[CH:9]=1
Reactant: Cn1cccc1Cc1cccc(NC(N)=O)c1
Solvent: CC(=O)O
Product: CN1CCCC1Cc1cccc(NC(N)=O)c1
Reaction time: 1 h
Yield: 42.9 %

Procedure:
A solution of 2 g (8.7 mmol) of 1-methyl-2-(3-ureidobenzyl)pyrrole, prepared, for example, as described in Preparation 3E, in 80 ml of glacial acetic acid was hydrogenated at 45 p.s.i. in the presence of 1.5 g of 5% rodium on activated alumina as catalyst, for 1 hour. The catalyst was then separated by filtration and the filtrate evaporated in vacuo. The residue was suspended in 100 ml of methylene chloride and 20 ml of ammonium hydroxide was added. The mixture was dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from acetone-ether afforded 870 mg (43%) of the title compound, 1-methyl-2-(3'-ureidobenzyl)pyrrolidine. M.P. 133°-135° C. (ether)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][CH2:8][CH2:9]I.C[O:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)=[O:14].[Cl-].[NH4+]>C(OCC)C.O.CN(C)C=O>[Cl:7][CH2:8][CH2:9][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([OH:14])=[O:12])=[CH:16][CH:17]=1
Reactant: ClCCI
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc(OCCCl)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 10.6 %

Procedure:
Potassium carbonate (7.27 g, 52.6 mmol) and commercially available 1-chloro-2-iodoethane (3.6 mL, 39.5 mmol) were added to a liquid mixture of commercially available methyl p-hydroxybenzoate (2.0 g, 13.1 mmol) and N,N-dimethylformamide (50 mL) under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 60° C. for 12 hours. The mixture was cooled to mom temperature and then a saturated aqueous ammonium chloride solution, water, and diethyl ether were added to the reaction mixture for partition. The organic layer was washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate, and then filtered and concentrated under vacuum. Tetrahydrofuran (25 mL), methanol (10 mL), and a 2 M sodium hydroxide solution (10 mL) were added to the residue at morn temperature, and the mixture was heated and stirred at 80° C. for 4 hours. The reaction mixture was cooled to 0° C., acidified with 5 M hydrochloric acid, and then the mixture was diluted with ethyl acetate for partition. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated, the precipitate was separated by filtration with a liquid mixture of ethyl acetate and tetrahydrofuran, the resultant was washed, and the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=3:1-2:1-1:1) and the target fraction was concentrated under vacuum to obtain the title compound (278 mg, 11%).