Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:22]C(Cl)C>>[ClH:22].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC3(CCc4ccccc43)CC2)cc1
Reactant: CC(Cl)Cl
Product: Cl
Product: c1ccc2c(c1)CCC21CCNCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1'-Benzyl-2,3-dihydrospiro[1H-indene-l,4'-piperidine](0.50 g, 1.80 mmol) was dissolved in dichloroethane (6 mL). The resulting solution was cooled to 0° C. and 1-chloro-ethylchloroformate (0.258 g, 1.80 mmol) was added in one batch. Cooling was continued for 10 min after which the reaction mixture was refluxed for 1 h, cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in MeOH (10 mL) and refluxed for 2 h. The resulting solution was concentrated under reduced pressure to obtain (0.40 g, quant.) of a pale yellow crystalline solid; m.p. 256°-257° C. (lit. 288-290); 1H NMR (CDCl3):δ1.74 (br d, 2, piperidyl β-Heq), 2.10 (td, 2, piperidyl β-Hax), 2.13 (t, 2, Ph-CH2 --CH2--, J= 6 Hz), 2.94 (t, 2, J=6 Hz, Ph-CH2 --), 3.12-3.38 (m, 4, piperidyl αHax,eq), d=7.19 (br s, 4, phenyl). MS (EI) m/e 187.2 (M+ of free base).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:34])[CH2:18][C:17](=[O:19])[C:16]([CH3:21])([CH3:20])[C:15]2[CH:14]=[C:13](/[C:22](/C)=[CH:23]/[C:24]3[CH:32]=[CH:31][C:27](C(O)=O)=[CH:26][CH:25]=3)[CH:12]=[CH:11][C:10]1=2.ClC([O:38][CH2:39][CH3:40])=O.[N-:41]=[N+:42]=[N-:43].[Na+]>CC(C)=O.O>[CH3:8][C:9]1([CH3:34])[CH2:18][C:17](=[O:19])[C:16]([CH3:21])([CH3:20])[C:15]2[CH:14]=[C:13]([CH2:22][CH:23]=[CH:24][C:25]3[CH:26]=[CH:27][CH:31]=[CH:32][C:40]=3[C:39]([N:41]=[N+:42]=[N-:43])=[O:38])[CH:12]=[CH:11][C:10]1=2
Reactant: CCOC(=O)Cl
Reactant: [N-]=[N+]=[N-]
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)C(=O)CC2(C)C
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)CC(=O)C(C)(C)c2cc(CC=Cc3ccccc3C(=O)N=[N+]=[N-])ccc21
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
A solution of 6 ml of triethylamine in 30 ml of acetone is allowed to run into a suspension of 12.7 g (35 mmol) of (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-7-oxo-naphth-2-yl)-1-propenyl]-benzoic acid (Example 2) in 60 ml of acetone and 20 ml of water, at 0°-5° C. At 0° C. 4.5 ml (5.2 g, 55 mmol) of ethyl chloroformate are added dropwise, the solution is stirred for a further 10 minutes and a solution of 3.5 g (55 mmol) of sodium azide in 7.5 ml of water is then added dropwise. The solution is stirred at 0° C. for a further 2 hours, the finely crystalline solid is filtered off under suction and the residue is washed with a little water and ethanol and dried, to give 10.8 g of the title compound which is processed further without purification (see Example 11).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14](OC)=[O:15])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][OH:23].[OH-].[K+]>C1COCC1.CO.CCOCC>[CH2:1]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([NH:22][OH:23])=[O:15])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NCc1ccccc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NO)c1ccccc1S(=O)(=O)NCc1ccccc1
Temperature: 0 °C
Yield: 36.7 %

Procedure:
In a 50 mL round-bottomed flask was added methyl 2-(N-benzylsulfamoyl)benzoate 43 (49 mg, 0.160 mmol) in THF (321 μl) and MeOH (321 μl) and the solution was cooled to 0° C. Then, a 50% aqueous solution of hydroxylamine (530 mg, 8.02 mmol) was added, followed by a 4M aqueous solution of KOH (80 μl, 0.321 mmol) and the resulting colorless solution was stirred at 0° C., allowing to slowly warm to rt and stirred for 18 h. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc and combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide a colorless oil. A solid was obtained by successive dissolution in Et2O/Hex mixture and concentration which was triturated in Et2O to afford title compound 44 (18 mgs, 37% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.25 (s, 1H), 9.34 (s, 1H), 7.83 (dd, J=7.6, 1.2 Hz, 1H), 7.67 (td, J=7.4, 1.4 Hz, 1H), 7.61 (td, J=7.6, 1.6 Hz, 1H), 7.50 (dd, J=7.4, 1.6 Hz, 1H), 7.49 (bs, 1H), 7.27-7.18 (m, 5H), 4.05 (d, J=5.9 Hz, 2H). LRMS (ESI): (calc.) 306.34 (found) 307.14 (MH)+
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[N:5]12[CH2:8][CH:7]1[CH2:6]2.[O:9]1CC[CH2:11][CH2:10]1>>[C:10]([N:5]1[CH2:6][CH:7]([S:3][C:1](=[O:4])[CH3:2])[CH2:8]1)(=[O:9])[CH3:11]
Reactant: C1C2CN12
Reactant: CC(O)=S
Reactant: C1CCOC1
Product: CC(=O)SC1CN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.8 %

Procedure:
With use of 2.00 g of 2-bromomethylaziridine hydrobromide (2) obtained in the above Example 1, there was produced a solution of 1-azabicyclo[1.1.0]butane (4) dissolved in tetrahydrofuran by the same method as in the above Example 7. Next, to a 5 ml solution of dried tetrahydrofuran containing 1.32 ml of thioacetic acid, there was added dropwise a solution of compound (4) dissolved in tetrahydrofuran at a temperature of -40° C. or lower, and the resulting mixture was stirred at a room temperature for 18 hours. After the reaction was over, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography (eluent: chloroform-acetone), and, thus, there was obtained 828 mg (yield: 51.8%) of 1-acetyl-3-acetylthioazetidine (11).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:16]3[C:17](=[O:25])[N:18]([CH3:24])[C:19]([S:22][CH3:23])=[N:20][CH:21]=3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[CH3:24][N:18]1[C:17](=[O:25])[C:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:30]4[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)=[CH:21][N:20]=[C:19]1[S:22][CH3:23]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CSc1ncc(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(=O)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)n1C
Temperature: 90 °C
Yield: 34.3 %

Procedure:
A mixture of 5-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (0.52 g, 0.97 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.22 g, 1.07 mmol), and K2CO3 (0.40 g, 2.9 mmol) in 5:1 dioxane/water (6 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.12 g, 0.10 mmol), sparged again with Ar and heated at 90° C. overnight. The solids were removed via filtration, the filtrate treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(methylthio)pyrimidin-4(3H)-one (140 mg, 34%). MS (ESI) m/z: 421.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:23][CH3:24])([CH2:20][CH:21]=[CH2:22])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[CH2:13][C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:38])[C:35](Cl)=[O:36].[CH2:40]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH3:41]>C(Cl)Cl.O>[F:15][C:14]([F:16])([F:17])[CH2:13][C:12]([N:11]([CH2:10][C@@:9]([N:23]([CH3:24])[C:34](=[O:38])[C:35]([N:42]([CH2:40][CH3:41])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:36])([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:20][CH:21]=[CH2:22])[CH3:19])=[O:18]
Reactant: CCNc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CC[C@](CN(C)C(=O)CC(F)(F)F)(NC)c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C=CC[C@@](CN(C)C(=O)CC(F)(F)F)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)C(=O)N(CC)c1ccccc1
Yield: 75.8 %

Procedure:
N-[2-(S)-(3,4-Dichlorophenyl)-2-(methylamino)-4-pentenyl]-3,3,3-trifluoro-N-methylpropanamide (200 mg) was dissolved in anhydrous methylene chloride (1 mL). Under cooling with ice, N,N-diisopropylethylamine (109 μL) and oxalyl chloride (109 μL) were added thereto, and the mixture was stirred for 30 minuites. A solution of N-ethylaniline (127 mg) in anhydrous methylene chloride (1 mL) was added to the reaction mixture, and the resultant mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, extracted with methylene chloride, washed with saturated brine, and dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=3:1 to 1:1), to thereby give the title compound (221 mg, 75.8%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]=[C:3]1[C:8](=[NH:10])[NH2:9].C(O[C@@H:15]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]1[O:17][C:18](=[O:20])[CH3:19])(=O)C.FC(F)(F)C(O)=O.O>C[Si](C)(C)N[Si](C)(C)C.C(#N)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[C:23]([O:22][C@H:21]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:8]([NH2:9])=[NH:10])[C:2]2=[O:1])[O:27][C@@H:26]1[CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:25])[CH3:24]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N=C(N)c1ncc[nH]c1=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC[C@H]1O[C@@H](n2ccnc(C(=N)N)c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
In 2.0 mL of 1,1,1,3,3,3-hexamethyldisilazane were suspended 0.20 g of 3-oxo-3,4-dihydro-2-pyrazinecarboximidamide and 10 mg of ammonium sulfate. Under a stream of nitrogen gas, the suspension was heated under reflux for 10 minutes. After adding 9.0 mg of ammonium sulfate, the mixture was heated under reflux for an additional 2 hours. The reaction mixture was allowed to cool, and the solvent was removed under reduced pressure. The residue thus obtained was dissolved in 4.0 mL of acetonitrile, 0.46 g of β-D-ribofuranose-1,2,3,5-tetraacetate and 0.34 mL of stannic (IV) chloride were successively added, and the mixture thus obtained was stirred at room temperature for 3 hours. Then, 10 μL of trifluoroacetic acid and 1.0 mL of water were added to the reaction mixture, and the solvent was removed under reduced pressure. Further, the same reaction as above was repeated by using 0.05 g of 3-oxo-3,4-dihydro-2-pyrazinecarboximidamide. The reaction mixture thus obtained was united with the reaction mixture obtained above, and the product was purified by reversed phase silica gel column chromatography [eluent: acetonitrile:water=1:4] to obtain 0.34 g of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[3-[amino(imino)methyl]-2-oxo-1(2H)-pyrazinyl]tetrahydro-3-furanyl acetate as a light yellow-colored solid product.
Reaction SMILES: [CH3:1][C:2]([OH:5])([CH3:4])[CH3:3].Cl[S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>C(Cl)Cl>[CH:13]1([NH:16][S:7]([NH:10][C:11](=[O:12])[O:5][C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:9])=[O:8])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.33 ml of t-BuOH were dissolved in 50 ml of anhydrous CH2Cl2 and, at RT, 2.00 g of chlorosulfonyl isocyanate were added dropwise. During this, the internal temperature rose to 30° C. Stirring at RT for 1 hour was followed by dropwise addition of 1.96 ml of cyclopropylamine and leaving the reaction mixture to stand at RT for 16 hours. It was then washed 3 times with 15 ml of water each time. After drying over Na2SO4, the solvent was removed in vacuo. 1.3 g of an amorphous solid were obtained.
Reaction SMILES: N1C2C(=CC=CC=2)[C:3]([C:10](O)=[O:11])=[CH:2]1.CN1CCC(CN)CC1.[CH2:22]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH:33][C:34]([C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)=[O:35])[CH2:28][CH2:27]1)CCC>>[CH3:22][N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH:33][C:34]([C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)=[O:35])[CH2:28][CH2:27]1.[CH3:22][N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH:33][C:34]([C:36]2[C:44]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[N:38]3[CH2:2][CH2:3][CH2:10][O:11][C:37]=23)=[O:35])[CH2:28][CH2:27]1
Reactant: CCCCN1CCC(CNC(=O)c2c[nH]c3ccccc23)CC1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: CN1CCC(CN)CC1
Product: CN1CCC(CNC(=O)c2c3n(c4ccccc24)CCCO3)CC1
Product: CN1CCC(CNC(=O)c2c[nH]c3ccccc23)CC1

Procedure:
N-[(1-Methyl-4-piperidyl)methyl] indole-3-carboxamide was prepared from indole-3-carboxylic acid and N-(1-methyl-4-piperidyl)methylamine using an analogous method to Description 1b and then converted to the title compound using an similar procedure to Example 3 (method 2).
Reaction SMILES: [CH2:1](OC1C=CC(CCC(OCC)=O)=CC=1)[CH:2]=[CH2:3].[CH3:18][CH:19]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]=[CH2:37])=[CH:30][CH:29]=1)[C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:21].C(C1C=C(CCC(OCC)=O)C=CC=1O)C=C>>[CH3:18][CH:19]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH:36]=[CH2:37])=[CH:32][CH:33]=1)[C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:21].[CH3:18][CH:19]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[C:32]([CH2:3][CH:2]=[CH2:1])[CH:33]=1)[C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:21]
Reactant: C=CCOc1ccc(CCC(=O)OCC)cc1
Agent: C=CCOc1ccc(CC(C)C(=O)OCCOC)cc1
Agent: C=CCc1cc(CCC(=O)OCC)ccc1O
Product: C=CCc1cc(CC(C)C(=O)OCCOC)ccc1O

Procedure:
Methoxyethyl 2-methyl-3-(4-allyloxyphenyl)propionate was prepared using the procedure used to prepare ethyl 3-(4-allyloxyphenyl)propionate (see Example 1). Methoxyethyl 2-methyl-3-(3-allyl-4-hydroxyphenyl)propionate was prepared from methoxyethyl 2-methyl-3-(4-allyloxyphenyl)propionate using the method described in Example 1 for the preparation of ethyl 3-(3-allyl-4-hydroxyphenyl)propionate. The product was isolated as a yellow oil; microanalysis; found: C, 69.0 H, 7.70%; C16H22O4 requires C, 69.0 H. 7.97%; m/z 279 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])=O.[BH4-].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:15][CH:17]([CH2:18][CH2:19][CH3:20])[CH3:22].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(N[C@H]1CCN(C(=O)OC(C)(C)C)C1)c1ccc(Cl)cc1Cl
Product: CCCC(C)C
Yield: 56.7 %

Procedure:
Stir a mixture of (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (10.4 g, 55.7 mmol) and 2,4-dichloroacetophenone (10.5 g, 55 mmol) in dry toluene (400 mL) at 110° C. for 48 h. Concentrate and dissolve the residue in methanol (160 mL), add sodium borohydride (3.37 g, 89 mmol) slowly and stir for 20 min. Add 1 N sodium hydroxide (200 mL) and extract with diethyl ether. Combine the organic layers, wash with water, dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with 0:100 to 40:60 ethyl acetate:2-methylpentane to give (S)-3-[1-(2,4-dichlorophenyl)-ethylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (5.6 g, 28%). 1H NMR (300 MHz, CDCl3) δ 7.41-7.51 (1H, m), 7.34 (1H, s), 7.24 (1H, dd, J=8.38, 1.98 Hz), 4.21-4.36 (1H, m), 3.42-3.57 (2H, m), 3.21-3.33 (1H, m), 3.04-3.15 (1H, m), 2.88-3.03 (1H, m), 1.96-2.05 (1H, m), 1.63-1.72 (1H, m), 1.37-1.47 (9H, m), 1.30 (3H, dd, J=6.59, 1.51 Hz), MS (ES): m/z=359[M+].
Reaction SMILES: [NH2:1][C@@H:2]1[C:19]2[CH:20]=[C:15]([CH:16]=[CH:17][N:18]=2)[C:14]2[CH:13]=[CH:12][C:11]([NH:21][C:22](=[O:25])[O:23][CH3:24])=[CH:10][C:9]=2[NH:8][C:7](=[O:26])[C@H:6]([CH3:27])[CH2:5][CH2:4][CH2:3]1.C(C1C=CC(C2O[N:37]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=CC=1)#N>ClCCl>[C:42]([O:41][C:39]([NH:37][NH:1][C@@H:2]1[C:19]2[CH:20]=[C:15]([CH:16]=[CH:17][N:18]=2)[C:14]2[CH:13]=[CH:12][C:11]([NH:21][C:22](=[O:25])[O:23][CH3:24])=[CH:10][C:9]=2[NH:8][C:7](=[O:26])[C@H:6]([CH3:27])[CH2:5][CH2:4][CH2:3]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](N)c1cc-2ccn1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](NNC(=O)OC(C)(C)C)c1cc-2ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A modified procedure described by Vidal (Chem. Eur. J., 1997, 3(10), 1691) was used. To a cooled (0° C.) pink suspension of 11A (0.060 g, 0.163 mmol) in dichloromethane (1.30 mL) was added dropwise a clear, colorless solution of tert-butyl 3-(4-cyanophenyl)-1,2-oxaziridine-2-carboxylate (0.050 g, 0.204 mmol) in dichloromethane (0.651 ml). The resulting suspension was allowed to warm to rt and stir overnight. After 24 h, the majority of the solid went into solution and the solution had become a yellow color. The reaction was concentrated. Purification by normal phase chromatography gave 11B (0.033 g, 42%) as a pale yellow solid. MS (ESI) m/z: 484.2 (M+H)+. 1H NMR (500 MHz, CD3OD) δ 8.58 (d, J=5.0 Hz, 1H), 7.57 (s, 1H), 7.51-7.46 (m, 3H), 7.35 (dd, J=5.0, 1.7 Hz, 1H), 4.29 (dd, J=8.5, 5.2 Hz, 1H), 3.78 (s, 3H), 2.57-2.48 (m, 1H), 1.92-1.80 (m, 1H), 1.73-1.59 (m, 3H), 1.41 (s, 9H), 1.23-1.11 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.79-0.65 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:21])[CH2:14][C:15]([CH2:17][O:18][CH2:19][CH3:20])=O)[CH3:11].[CH2:22]([O:24][C:25](=[O:30])/[CH:26]=[C:27](\[NH2:29])/[CH3:28])[CH3:23]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:30])=[C:27]([CH3:28])[NH:29][C:15]=1[CH2:17][O:18][CH2:19][CH3:20])=[O:21])[CH3:11]
Reactant: CCOCC(=O)CC(=O)OCC
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1ccccc1Cl
Solvent: CCO
Product: CCOCC1=C(C(=O)OCC)C(c2ccccc2Cl)C(C(=O)OCC)=C(C)N1
Yield: 55 %

Procedure:
After heating a solution of 14 g of 2-chlorobenzaldehyde, 17.4 g of γ-ethoxyacetoacetic acid ethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 80 ml of ethanol under reflux for several hours, 2-ethoxymethyl-6-methyl-4-(2'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained, after cooling, in the form of light yellow crystals of melting point 115° C, in a yield of 55% of theory.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8]C(=O)CC(C)(C)C)[CH2:4]1.C(Cl)Cl.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.[C:30]([O-:33])(O)=[O:31].[Na+]>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][C@H:3]2[CH2:7][CH2:6][C@@H:5]([NH:8][C:30]([O:33][C:3]([CH3:7])([CH3:4])[CH3:2])=[O:31])[CH2:4]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CC(C)(C)CC(=O)N[C@@H]1CC[C@H](CO)C1
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of N-((1R,3S)-3-(hydroxymethyl)cyclopentyl)-3,3-dimethylbutanamide (Intermediate 16-step 2, 4.5 g, 21.12. mmol) in DCM (50 ml) triethyl amine (about 9.5 ml, 68.1 mmol) was added at room temperature and cooled to about 0° C. After ten minutes, 4-methylbenzene-1-sulfonyl chloride (about 6.0 g) was added and stirred the reaction at room temperature for about 6 hours and completion of the reaction was monitored by TLC. Reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (5.5 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.45 (s, 9H); 2.46-2.55 (m, 4H); 2.90-2.91 (m, 1H); 3.95-3.98 (m, 2H); 4.59-4.70 (m, 2H); 5.66-5.77 (m, 2H); 7.34-7.37 (d, J=9 Hz, 2H); 7.77-7.80 (d, J=9 Hz, 2H).
Reaction SMILES: [123I-].[I:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C(O)C.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C-:21]#[N:22].[Na+]>C(O)(=O)C.O>[NH:14]([CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[I:2])[C:21]#[N:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [C-]#N
Reactant: O=Cc1ccccc1I
Reactant: Nc1ccccc1
Agent: [123I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: N#CC(Nc1ccccc1)c1ccccc1I
Reaction time: 0.33 h

Procedure:
A solution of 1 mg of I-123-o-iodobenzaldehyde prepared in accordance with example 15 in 100 mcl ethanol was placed in a small test tube. One lambda of aniline was added and the mixture allowed to stand for ten minutes. A solution of 2 mg of sodium cyanide in 10 lambda of deionized water was then added and the mixture allowed to stand for an additional ten minutes. Three lambda of acetic acid was then added and the mixture allowed to stand 20 minutes to yield α-anilino-o-iodophenylacetonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)[CH:15]=1)(=[O:13])=[O:12].[CH2:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])C.C(O[N:48]1[C:52](=[O:53])[CH2:51][CH2:50][C:49]1=[O:54])(=O)CCC([O-])=O>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][CH:20]2[C:16]1[CH:15]=[C:14]([S:11]([NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:49](=[O:54])[CH2:50][CH2:51][C:52]([NH:48][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:37]3[C:29]4[C:39](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:38][N:35]([CH3:33])[CH2:36]3)[CH:15]=2)(=[O:13])=[O:12])=[O:53])(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCN)c2)C1
Reactant: O=C([O-])CCC(=O)ON1C(=O)CCC1=O
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCNC(=O)CCC(=O)NCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Reaction time: 8 h

Procedure:
To N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (intermediate 168.2) (150 mg, 0.30 mmol, 1.00 equiv) in DMF (2 mL) was added triethylamine (60 mg, 0.59 mmol, 1.98 equiv) and intermediate 177.1 (47 mg, 0.15 mmol, 0.50 equiv) and the resulting solution was stirred overnight. The mixture was then concentrated under vacuum and the crude product (150 mg) was purified by Flash-Prep-HPLC with the following conditions: column, C18 silica gel; mobile phase, methanol/water=0.05/100 increasing to methanol/water=90/100 within 25 min; Detector, UV 254 nm. This resulted in 53.1 mg (33%) of N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)succinamide as a white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.77-7.80 (m, 2H), 7.71 (s, 2H), 7.48-7.57 (m, 4H), 7.36-7.37 (m, 2H), 6.82 (s, 2H), 4.39-4.44 (m, 2H), 3.79 (d, J=15.9 Hz, 2H), 3.66 (d, J=16.2 Hz, 2H), 3.45-3.57 (m, 16H), 3.35-3.37 (m, 4H), 3.03-3.08 (m, 6H), 2.65-2.71 (m, 2H), 2.49-2.50 (m, 10H). MS (m/z): 1089 [M+H]+