Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15]O)[N:14]=2)[CH:9]=[CH:10][CH:11]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][Cl:25])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CO)nc12
Solvent: ClCCl
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(CCl)nc12
Temperature: 5 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 8-(2,6-dimethylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine (1.0 g, 3.4 mmol) in methylene chloride (50 ml) was added dropwise thionyl chloride (0.5 g, 3.4 mmol) solved in methylene chloride (10 ml) at 5° C. The reaction mixture was stirred 2 h. at 5° C. To the mixture was washed with a saturated bicarbonate solution, the organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure to give 1.0 g (93%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:28][CH2:29][CH2:30]Cl)[CH3:27]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:26][O:28][CH2:29][CH3:30])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCCCl
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 2-chloroethyl ethyl ether (0.056 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (1% methanol/chloroform) to give the subject compound (19 mg, yield 11%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[CH:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32](Cl)Cl)=[CH:27][CH:26]=1.O>ClCCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:32]([NH:31][C:28]3[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=3)[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Reactant: ClC(Cl)=Nc1ccccc1
Solvent: ClCCCl
Solvent: O
Product: COC(=O)CCCCCOc1ccc2nc(Nc3ccccc3)n(-c3ccccc3)c2c1

Procedure:
200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was dissolved in 1 ml of 1,2-dichloroethane, the solution was mixed with 85 μl of phenylisocyanide dichloride, and the mixture was heated for 6 hours to 65° C. After cooling, it was mixed with water, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 55 mg was obtained.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.BrCC1C=[CH:42][C:43](C#N)=[C:44]([CH2:46][C:47]([O-])=[O:48])[CH:45]=1.[CH3:52][C:53]#[N:54]>>[NH2:54][CH2:53][C:52]1[CH:42]=[CH:43][C:44]([CH2:45][N:18]([CH2:17][C:9]2[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:46][C:47]=1[OH:48]
Reactant: N#Cc1ccc(CBr)cc1CC(=O)[O-]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1O
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.375 g, 0.99 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.35 mL, 2.00 mmol) followed by a solution of (5-bromomethyl-2-cyano-phenyl)acetate (0.318 g, 1.25 mmol) in CH3CN (5 mL). The resultant mixture was heated to 60° C. for 15 hours then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (40 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2—CH3OH) followed by radial chromatography on silica gel (2 mm plate, 2:1 hexanes-EtOAc) provided 0.28 g (51%) of a tan foam.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:30]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:9]2[CH2:10][C:11]3[C:2]([F:1])=[N:3][C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:13][CH:14]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCOc1cc2c(c(F)n1)CC(c1ccc(O)cn1)CC2
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2)nc1
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyridin-2-yl)-3-octyloxy-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 7.55 mmol of 7-[5-(octyloxy)pyridin-2-yl]-1-fluoro-3-octyloxy-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.Cl.C[O:16][C:17](=[O:26])[C@@H:18]([NH2:25])[CH2:19][S:20][CH2:21][CH:22]1[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+:31].[K+]>C(O)(C)C>[CH:22]1([CH2:21][S:20][CH2:19][C@H:18](/[N:25]=[C:3](/[C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)\[C:2]([F:13])([F:12])[F:1])[C:17]([O-:26])=[O:16])[CH2:24][CH2:23]1.[K+:31]
Reactant: COC(=O)[C@@H](N)CSCC1CC1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C([O-])[C@H](CSCC1CC1)/N=C(/c1ccc(F)cc1)C(F)(F)F
Temperature: 55 °C
Reaction time: 46 h
Yield: 89.8 %

Procedure:
A suspension of 2,2,2,4′-tetrafluoroacetophenone (48 g; 250 mmol) and (R)-methyl2-amino-3-((cyclopropylmethyl)thio)propanoate hydrochloride (56.4 g; 250 mmol) in isopropanol (IPA; 1100 mL) was added potassium carbonate (69.1 g; 500 mmol; 200 mole %) and the mixture heated at 50-60° C. under a nitrogen atmosphere. After 46 h, the reaction mixture was filtered hot through a pad of celite that was prewashed with hot IPA. The filter was washed with hot IPA (2×) and the combined filtrate and washes were distilled to about 90% of the original volume. Acetonitrile (ACN) was added and the solvent was distilled. This process was repeated two more times with ACN and the product was evaporated to dryness. Potassium (R,Z)-3-((cyclopropylmethyl)thio)-2-((2,2,2-trifluoro-1-(4-fluorophenyl)ethylidene)-amino)propanoate (87 g; 90%) was obtained after drying under high vacuum (1 mm Hg) for 2 hours. This material was used in the next reaction without further purification.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH2:24]([C:28]1[CH:33]=[C:32](Cl)[N:31]=[C:30]([N:35]2[CH:39]=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([F:50])([F:49])[F:48])=[CH:42][CH:41]=3)[N:37]=[CH:36]2)[N:29]=1)[CH2:25][CH2:26][CH3:27]>CS(C)=O>[C:2]([O:6][C:7](=[O:14])[CH:8]([NH:9][C:32]1[CH:33]=[C:28]([CH2:24][CH2:25][CH2:26][CH3:27])[N:29]=[C:30]([N:35]2[CH:39]=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([F:48])([F:49])[F:50])=[CH:42][CH:41]=3)[N:37]=[CH:36]2)[N:31]=1)[CH2:10][CH:11]([CH3:12])[CH3:13])([CH3:5])([CH3:4])[CH3:3]
Reactant: CCCCc1cc(Cl)nc(-n2cnc(-c3ccc(OC(F)(F)F)cc3)c2)n1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cc(NC(CC(C)C)C(=O)OC(C)(C)C)nc(-n2cnc(-c3ccc(OC(F)(F)F)cc3)c2)n1
Temperature: 80 °C
Yield: 84.9 %

Procedure:
L-Leucine tert-butyl ester hydrochloride (291 mg) was dissolved in DMSO (5 mL) under an argon atmosphere and treated with diisopropylethylamine (450 μL, 2.6 mmol, 4 eq.) followed by 4-Butyl-6-chloro-2-[4-(4-trifluoromethoxy-phenyl)-imidazol-1-yl]-pyrimidine (274 mg). The mixture was heated to 80° C. for 48 h. DMSO and the volatiles were removed in vacuo to give a crude residue from which 2-{6-butyl-2-[4-(4-trifluoromethoxyphenyl) imidazol-1-yl] pyrimidin-4-ylamino}-4-methyl-pentanoic acid tert-butyl ester (321 mg) was isolated by flash chromatography (n-hexanes/ethyl acetate 4/1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:11]#[N:12])=[CH:6][C:5]=1[Cl:13].[N:15]([Sn](CCCC)(CCCC)CCCC)=[N+:16]=[N-:17]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5]([Cl:13])=[CH:6][C:7]([C:11]2[NH:17][N:16]=[N:15][N:12]=2)=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)c1c(Cl)cc(C#N)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Cl)cc(-c2nnn[nH]2)cc1Cl
Temperature: 100 °C
Reaction time: 72 h

Procedure:
The mixture of 185 mg of 2,6-dichloro-4-cyanobenzoic acid methylester, 266 mg of azidotributyltin and 5 ml of toluene was stirred at 100° C. for 3 days. The reaction mixture was concentrated and diluted with ethyl acetate. After Celite filtration, the filtrate was concentrated and the residue was purified by reverse phase HPLC to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=2[O:20][CH3:21])[CH:8]=[CH:9][CH:10]=1)[CH3:3].Cl>CCO.O.CCO.[Fe]>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=2[O:20][CH3:21])[NH2:17])[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(CN(C)C)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1-c1cccc(CN(C)C)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
2-(3-(N,N-Dimethylamino)methylphenyl)-4-nitroanisole (200 mg, 0.70 mmol) was dissolved in EtOH/H2O (5 mL:2.5 mL). concentrated HCl (40 uL) was added, followed by iron powder (314 mg). The reaction mixture was refluxed for 1 h, allowed to cool to room temperature, and diluted with EtOH (10 mL). The slurry was filtered and the filtrate evaporated. The resultant oil was taken up in 1 M NaOH (10 mL) and extracted with CH2Cl2 (2×10 mL). The combined organic phases were dried (Na2SO4) and evaporated to afford 3-[3-(N,N-dimethylamino)methylphenyl]-4-methoxyaniline as a brown oil (102 mg, 0.40 mmol, 57%)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[H+].[B-](F)(F)(F)F.[N+](=C[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-].[CH2:26](Cl)Cl>>[CH2:24]([O:23][C:21]([C:4]1[C:3]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=2[O:1][CH:26]=1)=[O:22])[CH3:25]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: ClCCl
Agent: F[B-](F)(F)F
Agent: [H+]
Product: CCOC(=O)c1coc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.2 %

Procedure:
To a solution of 2-hydroxy-4-methoxybenzaldehyde (45 g, 295.76 mmol) in DCM (80 mL) was added catalytic HBF4 etherate (4 mL, 29.4 mmol) and stirred (rt, 10 min). The reaction mixture was cooled (0° C.) and slowly treated drop wise with ethyl diazoacetate (86 ml, 704.7 mmol) over a 30 minute period while maintaining a controlled temperature (0° C. to 23° C.). The resulting mixture was stirred (rt, 1 h). The reaction mixture was concentrated in vacuo and the resulting dark oil was azeotroped with toluene (200 mL) via rotovap (60° C.). Using a Dean Stark trap, the crude mixture was refluxed (24 h). The reaction was cooled (rt) and concentrated in vacuo. The resulting dark oil was purified by flash column chromatography using EtOAc:hexanes (10%) to provide the title compound as a white solid (24.9 g, 38.2%). MS (ESI): mass calcd. for C12H12O4, 220.2; m/z found, 221.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.16 (s, 1H), 7.90 (d, J=8.6, 1H), 7.03 (d, J=2.2, 1H), 6.98 (dd, J=6.4, 2.3, 1H), 4.39 (q, J=7.2, 2H), 3.86 (s, 3H), 1.41 (t, J=7.2, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]([OH:16])[CH2:14][F:15])(=O)=O)=CC=1.[N:17]1([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CO>[F:15][CH2:14][CH:13]([OH:16])[CH2:12][N:20]1[CH2:21][CH2:22][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:18][CH2:19]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CF)cc1
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCN(CC(O)CF)CC1
Temperature: 25 °C
Yield: 18.7 %

Procedure:
To the crude 3-fluoro-2-hydroxypropyl 4-methylbenzenesulfonate (1.98 g, 7.98 mmol) in methanol (40 mL) was added benzyl piperazine-1-carboxylate (1.76 g, 7.98 mmol). The reaction was stirred at RT over the weekend. After being evaporated to dryness, the residue was purified on silica gel, eluting with 0 to 10% MeOH in DCM to yield the desired product (443 mg, 18.7%). LCMS calculated for C15H22FN2O3(M+H)+: m/z=297.2; Found: 297.4.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3C=CC([CH:4]2C=[CH:2]1)C3.[CH3:11][O:12][C:13](=[O:16])[CH:14]=[CH2:15].C1(C=CC(O)=CC=1)O>>[CH3:11][O:12][C:13]([CH:14]1[CH2:4][CH:5]2[CH2:6][CH:15]1[CH:2]=[CH:1]2)=[O:16]
Reactant: C=CC(=O)OC
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: Oc1ccc(O)cc1
Product: COC(=O)C1CC2C=CC1C2
Temperature: 220 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
Dicyclopentadiene (DCPD, available from Aldrich, 256.5 mL, 1.9 mol), methylacrylate (available from Aldrich, 405 mL, 4.5 mol) and hydroquinone (3.2 g, 0.03 mol) were charged into a 2 L high pressure reactor and heated to 220° C. The mixture was stirred at 300 rpm for 5 hours. After the reaction was completed, the resultant was cooled and transferred to a distiller. Vacuum distillation was carried out at 50° C. using a vacuum pump at 1 torr to obtain the product (yield: 57.6%, exo/endo=58/42).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[O:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=[N:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29]([C:28]5[O:24][N:25]=[CH:26][CH:27]=5)=[O:30])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)c1ccno1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccno4)nc3cc21

Procedure:
Isoxazole-5-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and isoxazole-5-carbonyl chloride (78 μl, 0.87 mmol). The title compound was obtained as light brown powder (76 mg, 23%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C[O:17][C:18]1C=CC=C[C:19]=1N1CCN(CCO)CC1>>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:19][CH2:18][OH:17])[CH2:12][CH2:11]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: COc1ccccc1N1CCN(CCO)CC1
Agent: Cl
Product: OCCN1CCN(c2cccc(Cl)c2Cl)CC1
Yield: 97 %

Procedure:
2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]ethanol (35A) is prepared from 1-(2,3-dichloro-phenyl)-piperazine hydrochloride as described for 28A.
Reaction SMILES: CO[C:3](=O)[C@@H:4]1[CH2:8][C:7](=[CH2:9])[CH2:6][N:5]1[C:10](OCC1C=CC=CC=1)=O.[CH2:21]([O:28]C(N1C2C(=CC=CC=2)CC1C(OC)=O)=O)[C:22]1C=CC=CC=1>>[CH2:9]=[C:7]1[CH2:6][N:5]2[C@H:4]([CH2:3][C:21](=[O:28])[CH2:22][CH2:10]2)[CH2:8]1
Reactant: COC(=O)C1Cc2ccccc2N1C(=O)OCc1ccccc1
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Product: C=C1C[C@H]2CC(=O)CCN2C1
Yield: 61 %

Procedure:
In a similar manner to the procedures described in Preparative Examples 5(i)′ and 5(ii) above, reduction, methanesulfonylation and cyanogenation were conducted, using (S)-1-benzyloxycarbonyl-4-methylideneproline methyl ester [obtained as described in Preparative Example 8(i)′ above], instead of methyl 1-benzyloxycarbonylindoline-2-carboxylate, to give the title compound as a colorless oil (yield: 61%).
Reaction SMILES: Cl.[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[SH:11][CH2:12][C:13](OCC)=O.[OH-].[K+]>>[OH:5][C:4]1[CH:6]=[C:12]([CH3:13])[S:11][C:3]=1[C:2]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)c1sc(C)cc1O
Temperature: 0 °C
Reaction time: 96 h

Procedure:
Dry hydrogen chloride gas was bubbled through a mixture of ethyl acetoacetate (0.2 moles) and ethyl 2-mercaptoacetate (b 0.4 moles) at -10° C. until saturated. The oil was allowed to stand 4 days at room temperature. Then, 350 ml of 2N ethanolic KOH, was added drop-wise. The resultant mixture was added to 2 liters of ice-water, and acidified with 6M HCl until the pH was approximately 1. The precipitated oil was extracted with benzene, washed with water and dried with sodium sulphate. After removal of solvent the residue was distilled, b.p. 70°-75° C. (0.5 mm).
Reaction SMILES: [CH2:1]([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:11]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=[CH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:33]=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[BH4-].[Na+].CCCCCC>C(Cl)Cl.CO>[CH2:11]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=[CH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:33][NH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:7][CH2:8][CH2:9][NH2:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: NCCCCCCCCN
Reactant: CCCCCCCCC=CCCCCCCCCOc1ccc(C=O)cc1OCCCCCCCCC=CCCCCCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCC=CCCCCCCCCOc1ccc(CNCCCCCCCCN)cc1OCCCCCCCCC=CCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a vigorously stirred solution of diaminooctane (0.23 g, 1.56 mmol, 5 equiv) in CH2Cl2/MeOH (3:1, 5 mL) was added a solution of the aldehyde 8a (0.20 g, 0.33 mmol) in CH2Cl2/MeOH (3:1, 5 mL), dropwise over 1 hour. The resulting mixture was stirred at RT under an atmosphere of nitrogen overnight. NMR showed the reaction to be complete when there was no aldehyde peak present in the NMR spectrum. The solvent was removed in vacuo and the crude imine dissolved in CH2Cl2/MeOH (1:1, 10 mL). The solution was cooled to 0° C. and sodium borohydride (60 mg, 1.58 mmol) was added in 15 mg portions over 30 minutes. TLC (10% EtAc/hexane) showed the reaction to be complete after stirring overnight. The solvent was removed in vacuo and the crude solid dissolved in CH2Cl2 (50 mL) and washed with sodium carbonate (10% aq, 3×40 mL). The CH2Cl2 layer was dried over sodium sulfate, filtered, the solvent removed in vacuo and the solid residue purified by flash column chromatography (1:10:89 NH4OH:MeOH:CHCl3) to give the product 16 as a white solid (0.15 g, 63%), Rf=0.5 (1:10:89 NH4OH:MeOH:CHCl3). 1H NMR (CDCl3) d 6.85 (s, 1H, aryl), 6.80 (m, 2H, aryl), 5.34 (t, 4H, olefinic), 3.97 (q, 4H, OCH2), 3.69 (s, 2H, benzylic), 2.67 (t, 2H, CH2NH2), 2.60 (t, 2H, CH2NH2), 2.01 (m, 8H, CH2C═C), 1.80 (m, 4H, CH2CH2O), 1.54-1.18 (m, 56H, 28×CH2), 0.88 (t, 6H, CH3); 13C NMR (CDCl3) d 149.31, 148.20, 133.55, 130.11, 130.00, 120.59, 114.14, 114.07, 69.70, 69.50, 54.24, 49.83, 42.60, 34.20, 32.28, 30.46, 30.16, 29.92, 29.81, 29.71, 29.67, 27.73, 27.60, 27.22, 26.44, 23.08, 14.53; HRMS (FAB): theory for C51H95N2O2 (M+1), 767.7394; found (M+1), 767.7377. Anal. (C51H94N2O2.0.3H2O): C, H, N.
Reaction SMILES: C([O:4][C@@H:5]([CH3:9])[C:6](Cl)=[O:7])(=O)C.C([O:13][CH2:14][CH:15]([NH:21][C:22]([C:24]1[C:29]([I:30])=[C:28]([NH2:31])[C:27]([I:32])=[C:26]([C:33]([NH:35][CH:36]([CH2:42][O:43]C(=O)C)[CH2:37][O:38]C(=O)C)=[O:34])[C:25]=1[I:47])=[O:23])[CH2:16][O:17]C(=O)C)(=O)C.[OH-].[Na+]>CN(C)C(=O)C>[CH3:9][C@H:5]([OH:4])[C:6]([NH:31][C:28]1[C:29]([I:30])=[C:24]([C:22]([NH:21][CH:15]([CH2:16][OH:17])[CH2:14][OH:13])=[O:23])[C:25]([I:47])=[C:26]([C:33]([NH:35][CH:36]([CH2:42][OH:43])[CH2:37][OH:38])=[O:34])[C:27]=1[I:32])=[O:7]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: C[C@H](O)C(=O)Nc1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Reaction time: 15 h
Yield: 86.7 %

Procedure:
(S)-2-(Acetyloxy)propanoyl chloride (16.5 g, 110 mmol) is added, over 20 min, to a stirred solution of N,N′-bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (53.3 g, 61.1 mmol) in N,N-dimethylacetamide (75 mL) while keeping the temperature of the reaction mixture below 30° C. A further amount of (S)-2-(acetyloxy)propanoyl chloride (0.9 g, 6.0 mmol) is added after 24 and 30 hours and the reaction mixture is stirred at the same temperature for additional 15 hours. 5 M NaOH (90 mL, 450 mmol) is dripped over a period of 2 hours into the reaction mixture vigorously stirred at 45° C. After two hours the mixture is concentrated under vacuum and reintegrated with additional N,N-dimethylacetamide (200 mL). After two hours at room temperature the resulting suspension is filtered and the solid washed with N,N-dimethylacetamide (2×20 mL). The mother liquors, combined with the washings, are concentrated to an oily residue, which is diluted with water (200 mL) and nanofiltered. The retentate is loaded onto an Amberlite® XAD-16.00 resin column (160 mL) that is eluted with water. The eluate is concentrated and loaded onto two ion exchange resin columns (Dowex® C350 15 mL, Relite® MG1 10 mL). The eluate is concentrated and the solid residue is crystallized from ethanol to afford Iopamidol (41.2 g, 53 mmol).