Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3]C1C=CC(F)=C(F)C=1CCN)C.[CH2:15]([O:17][C:18]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[C:19]=1[CH2:20][CH2:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1)=S)[CH3:16].C1C(=O)N(Br)C(=O)C1>>[CH2:15]([O:17][C:18]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[C:19]=1[CH2:20][CH2:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1)=[O:3])[CH3:16]
Reactant: CCOc1ccc(F)c(F)c1CCN
Reactant: CCOc1ccc(F)c(F)c1CCNC(=S)Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Product: CCOc1ccc(F)c(F)c1CCNC(=O)Nc1ccc(Br)cn1

Procedure:
The methods described in Example 151 of WO 93/03022 was then used to transform this compound to 2-ethoxy-5,6-difluoro-phenethylamine. The method described in Example 411 of WO 93/03022 was then used to prepare N-(2-ethoxy-5,6-difluorophenethyl)-N'-(5-bromopyrid-2-yl)-thiourea. This product was then oxidised with NBS as Example 4 to provide N-(2-ethoxy-5,6-difluorophenethyl)-N'-(5-bromopyrid-2-yl)-urea. 1H-NMR (250 MHz, CDCl3): 1.4 (t, 3H), 3.0 (q, 2H), 3.95 (q, 2H), 6.5 (m, 1H), 6.8 (d, 1H), 6.95 (dd, 1H), 7.68 (dd, 1H), 8.90 (d, 1H) 8.9 (s, 1H), 9.0 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][CH2:15][CH3:16])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:36]=[CH:35][C:26]2[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=2[CH:24]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][CH2:15][CH3:16])=[O:12])=[N:7][C:2]([NH:22][C:23]2[CH:36]=[CH:35][C:26]3[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CCCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Yield: 37.6 %

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-propyl-benzamide (50.0 mg, 0.000154 mol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (31.4 mg, 0.000154 mol) and 10-Camphorsulfonic acid (35.7 mg, 0.000154 mol) were dissolved in Isopropyl alcohol (3.00 mL, 0.0392 mol) and the reaction was microwaved on 300 watts, 140° C. for 20 minutes. The reaction mixture was reduced under nitrogen. The crude residue was isolated and purified by prep HPLC to afford 28.57 mg (38%) of the title compound. LC/MS (ESI): 493.17. 1H NMR (400 MHz, DMSO, d6) δ 9.44 (s, 1H), 9.37 (s, 1H), 8.76 (m, 2H), 8.21 (s, 1H), 7.76 (d, 1H, J=7.83 Hz), 7.65 (d, 1H, J=8.08 Hz), 7.48 (m, 2H), 7.14 (t, 1H, J=7.33 Hz), 6.88 (d, 1H, J=8.34 Hz), 3.25 (m, 2H), 2.17 (m, 2H), 1.97 (m, 2H), 1.55 (m, 2H), 1.29 (s, 6H), 0.90 (t, 3H, J=7.33 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@H:16]([C:17](OCC)=[O:18])[CH2:15][C:14]3[NH:22][N:23]=[CH:24][C:13]=3[C@@H:12]2[C:25](OCC)=[O:26])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li+].[BH4-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@H:16]([CH2:17][OH:18])[CH2:15][C:14]3[NH:22][N:23]=[CH:24][C:13]=3[C@@H:12]2[CH2:25][OH:26])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1Cc2[nH]ncc2[C@H](C(=O)OCC)N1S(=O)(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Product: O=S(=O)(c1ccc(Cl)cc1)N1[C@H](CO)Cc2[nH]ncc2[C@@H]1CO

Procedure:
Prepared by reduction of cis-diethyl 5-(4-chlorophenylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-4,6-dicarboxylate using LiBH4 as shown in Example 14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:8]=1
Reactant: [H][H]
Reactant: COc1ccccc1CNc1ccc2c(/C=C/c3ccccc3)cccc2n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1CNc1ccc2c(CCc3ccccc3)cccc2n1

Procedure:
(2-Methoxy-benzyl)-[5-((E)-styryl)-quinolin-2-yl]-amine (example 2, 102 mg, 0.279 mmol) was dissolved in 20 mL ethanol. Palladium on charcoal (10%, 30 mg, 0.028 mmol) was added and the reaction mixture war hydrogenated with a hydrogen balloon overnight. The palladium was filtered off and the solvent was evaporated. The title compound was obtained as a light brown oil (97 mg, 95%), MS: m/e=369.0 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[Cl:30])[CH2:14][CH2:13]2)=[N:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:30][C:21]1[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:20]=1[C:19]([NH:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=2)[CH2:13][CH2:14]1)=[O:31]
Reactant: COC(=O)c1ccc(NC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(NC[C@H]2CC[C@H](NC(=O)c3cc(C(F)(F)F)ccc3Cl)CC2)nc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Trans-6-{[4-(2-Chloro-5-trifluoromethyl-benzoylamino)-cyclohexylmethyl]-amino}-nicotinic acid methyl ester (Example 19.15) (30 mg, 0.06 mmol) is placed in a vial with MeOH (2 mL). 1M NaOH (1 mL) is added and the reaction mixture is stirred at RT for 3 days. The reaction mixture is acidified and the resulting precipitate in the aqueous layer which was filtered and dried to afford the title compound. [MH+456.31], NMR: δH (400 MHz, DMSO); 12.29 (1H, s), 8.53 (1H, d), 8.48 (1H, d), 7.78 (4H, m) 7.35 (1H, m), 6.50 (1H, d), 3.71 (1H, m), 3.19 (2H, m), 1.96 (2H, m), 1.83 (2H, m), 1.52 (1H, m), 1.23 (2H, m), 1.08 (2H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([NH2:15])=[C:13]([Cl:16])[C:8]2[N:9]([CH3:12])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>>[NH2:15][C:14]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]2[N:11]=[CH:10][N:9]([CH3:12])[C:8]=2[C:13]=1[Cl:16]
Reactant: COC(=O)c1cc2ncn(C)c2c(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Product: Cn1cnc2cc(C(=O)O)c(N)c(Cl)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
See step d) of example H2 using 6-amino-7-chloro-1-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester as starting material and 1.5 equivalents of NaOH (1 N aqueous solution). After 5 h of stirring at ambient temperature and for 18 hours reaction at a temperature of 50° C., the solvents is evaporated and the work-up is made as already described. A total amount of 614 mg (2.72 mmol, 87%) of a pink-red solid were obtained. LC/MS: 226/228 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[OH:11])=[O:3].[CH3:12][C:13]([CH3:15])=O.N1CCCC1>CO>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]2[C:2](=[O:3])[CH2:1][C:13]([CH3:15])([CH3:12])[O:11][C:5]=2[CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1O
Reactant: CC(C)=O
Solvent: CO
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2ccc(Cl)cc2O1

Procedure:
A solution of 4-chloro-2-hydroxyacetophenone (20 g, 0.1176 mol), acetone (13.3 mL, 0.1811 mol) and pyrrolidine (15 mL, 0.18 mol) in methanol (475 mL) was stirred at 25° C. overnight. The mixture was then concentrated to a red oil. Water was added and the solution was adjusted to pH 1 with concentrated hydrochloric acid. The product was extracted with diethylether. The organic layer was dried over magnesium sulfate and diethylether was evaporated under reduced pressure. The residue was dissolved in a small volume of methanol. The solution was treated with charcoal, filtered and water was added to the filtrate. The resulting precipitate was collected by filtration, washed with water and dried (79%). mp: 63-66° C., IR (KBr): υ: 3086 (C—H aromatic), 2976, 2931 (C—H aliphatic), 1693 (C=0) cm−1, Anal. (C11H11O2Cl) C, H.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[S:15][C:14]([CH3:16])=[C:13]([C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][CH:33]=3)[O:25][CH2:26][C:27]([O:29]C)=[O:28])[N:21]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[S:15][C:14]([CH3:16])=[C:13]([C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][CH:33]=3)[O:25][CH2:26][C:27]([OH:29])=[O:28])[N:21]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1cccc(-c2csc(-c3cc(C=NNC(=O)OC(C)(C)C)sc3C)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C=NNC(=O)OC(C)(C)C)cc1-c1nc(-c2cccc(OCC(=O)O)c2)cs1
Yield: 84.5 %

Procedure:
A stirred solution of 50 mg (0.11 mmol) of methyl 2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate was dissolved in tetrahydrofuran (10 mL) and treated 2M aqueous sodium hydroxide solution (2 mL) at room temperature for 1 h 10 min. The solvents were removed in vacuo. Purification by passing the solid through silica gel (1 inch in a 60 mL scintered-glass Büchner funnel) eluting with dichloromethane:methanol 8/2 (v:v) gave 2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (44 mg, 88%) as a yellow solid. 1H-NMR (DMSO-d6; 300 MHz) δ9.38 (br s, 2H), 8.94 (br s, 2H), 8.51 (s, 1H), 8.31 (s, 1H), 7.62 (m, 2H), 7.41 (m, 1H), 6.96 (m, 1H), 4.89 (s, 2H), 3.72 (s, 3H), 2.92 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H23N3O5S2 474.1 (M+H), 374.1 ((M-BOC)+H) found 374.2, 473.7.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:35]=[CH:34][C:33]([CH2:36][CH2:37]C(O)=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.C(O[C:57]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)=[O:58])(C)(C)C>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:57]([N:59]5[CH2:60][CH2:61][NH:62][CH2:63][CH2:64]5)=[O:58])=[CH:32][CH:31]=4)[C:17]=3[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=2)=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCC(=O)O)cc3)cn2)cc1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(CCC(=O)N3CCNCC3)cc2)cn1
Yield: 30.6 %

Procedure:
Using 3-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-propionic acid (61 mg) and piperazine-1-carboxylic acid tert-butyl ester (20 mg) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, 3-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-tert-butyl-piperazin-1-yl)-propan-1-one was obtained, and further PMB group and BOC group were removed according to the above Deprotection method 2, to obtain the desired compound (D-168) as a pale yellow powder (14 mg, 31%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2O[C:10]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]#[N:24])=[CH:18][C:17]=3[CH3:25])=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.CC1(C)OO1.O.[NH2:32][NH2:33]>CC(C)=O.CO>[CH3:1][C:2]1([C:7]2[N:33]=[N:32][C:10]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]#[N:24])=[CH:18][C:17]=3[CH3:25])=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: NN
Reactant: Cc1cc(C#N)cc(C)c1OCCCc1ccc(C2(C)OCCO2)o1
Agent: CC1(C)OO1
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: Cc1cc(C#N)cc(C)c1OCCCc1ccc(C2(C)OCCO2)nn1
Yield: 47 %

Procedure:
Following a procedure similar to that described in Example 3c, 5-(2-methyl-1,3-dioxolan-2-yl)-2-[3-(2,6-dimethyl-4-cyanophenoxy)propyl]furan; (1.05 g; 3.08 mmol), 48 mL (0.06M) of dimethyldioxirane in acetone, and 10 mL of acetone were reacted. The resulting product was dissolved in methanol and reacted with 85% hydrazine hydrate (0.15 mL; 4.49 mmol) then purified by chromatography on silica gel with 65% ethyl acetate/hexane to afford 0.511 g (47%) of 6-(2-methyl-1,3-dioxolan-2-yl)-3-[3-(2,6-dimethyl-4-cyanophenoxy)propyl]-pyridazine.
Reaction SMILES: [I:1]I.C(=O)(O)[O-].[Na+].[F:8][C:9]([F:18])([F:17])[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.NC(N)=S>C1COCC1.O>[F:8][C:9]([F:17])([F:18])[C:10]1[CH:11]=[C:12]([I:1])[C:13]([OH:16])=[CH:14][CH:15]=1
Reactant: II
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(C(F)(F)F)cc1I
Reaction time: 8 h

Procedure:
a,a a-Trifluoro-o-iodo-p-cresol. A mixture of iodine (91.6 mmol, 23.2 g) and sodium bicarbonate (91.6 mmol, 7.7 g) was added to a solution of α,α,α-trifluoro-p-cresol (83.3 mmol, 13.5 g) in THF (90 mL) and H2O (90 mL) and the reaction mixture was allowed to stand at room temperature overnight. Sufficient thiourea (5% solution) was added to remove the excess iodine as indicated by the color change of the reaction from deep violet to brown. The reaction mixture was extracted with ether (3×100 mL), the extract was dried, filtered and the filtrate was concentrated to obtain a brown oil. This oil was distilled (bp 105° C. at 44 mm Hg) to obtain α,α,α-trifluoro-o-iodo-p-cresol (4.1 g, 75% pure, admixed with the starting α,α,α-trifluoro-p-cresol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=2)[NH:25][CH:24]=1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:25]3[C:26]4[C:31](=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=4)[C:23]([CH3:22])=[CH:24]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1c[nH]c2ccc(S(C)(=O)=O)cc12
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: Cc1cn(-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c2ccc(S(C)(=O)=O)cc12

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 3-methyl-5-(methylsulfonyl)-1H-indole (intermediate-23).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[N:28]=[N:29][C:30]([O:33][CH2:34][CH3:35])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@H:6]1[CH2:36][O:37]C(=O)C)(=O)C.C[O-].[Na+]>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:36][OH:37])[O:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[N:28]=[N:29][C:30]([O:33][CH2:34][CH3:35])=[CH:31][CH:32]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)nn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-((6-ethoxypyridazin-3-yl)methyl)phenyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate (74 mg, 0.13 mmol) in MeOH (3 mL) was added NaOMe (0.2 mL), and the mixture was stirred for 1 h at room temperature. The mixture was neutralized with Amberlite IR-120 (H) resin, and filtered, the resin was washed with MeOH, and the combined filtrate and washings were concentrated as pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([N:9]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[Cl:8][C:5]1[N:4]=[C:3]2[C:2]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][CH2:10][N:9]2[CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:7][N:6]=1
Reactant: CNC(=O)CCN(CC1CC1)c1nc(Cl)ncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1C(=O)CCN(CC2CC2)c2nc(Cl)ncc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a partial solution of 3-[(5-bromo-2-chloro-pyrimidin-4-yl)-(cyclopropylmethyl)amino]-N-methyl-propanamide (Intermediate 94; 426 mg, 1.18 mmol) in anhydrous 1,4-dioxane (15 mL) was added Caesium Carbonate (790 mg, 2.42 mmol). Nitrogen was bubbled through the reaction mixture for 10 minutes, prior to addition of Tris(dibenzylideneacetone)dipalladium(0) (69 mg, 0.075 mmol) and XANTPHOS (62 mg, 0.107 mmol). The reaction was heated to 100° C. and stirred under nitrogen for 18 hrs.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([N:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][C@@H:13]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:33])([CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][C:20]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O)C>C(OCC)C>[CH3:10][N:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][C@@H:13]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:33])([CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][C:20]=1[O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C(=O)OCC)c(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a 25° C. slurry of 267 mg (7.04 mmole) of lithium aluminum hydride in 12 ml ethyl ether is added dropwise over 30 minutes a solution of 1.50 g (3.11 mmole) of N-ethoxycarbonyl-cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol. The reaction is stirred for 0.5 hour at 25° C., then two hours at reflux. The reaction is quenched by addition of wet magnesium sulfate followed by decantation and washing of the salts with two 30 ml portions of ether. The ether extract is washed with 10 ml saturated sodium chloride, dried over magnesium sulfate and evaporated to give 1.19 g (91%) of the title compound as a solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH3:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]([CH2:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][CH:11]=3)[CH3:16])[CH2:18][CH2:19]2)=[CH:28][CH:27]=1)#[N:30]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCc1ccc(N)cc1)C1CCN(c2ccc(C#N)cc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)C1CCN(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
0.34 g (3 mmol) of methanesulfonyl chloride dissolved in tetrahydrofuran was added dropwise at 0° C. to 1.0 g (3 mmol) of the product from Example 3 and 0.6 g (6 mmol) of triethylamine in 100 ml of anhydrous tetrahydrofuran. The mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The residue was partitioned between aqueous sodium bicarbonate solution and methylene chloride, and the organic phase was dried and concentrated under reduced pressure. The resulting oil was purified by chromatography (eluent: methylene chloride/methanol 10:1). 0.73 g of 1-(4-cyanophenyl)-4-(2-(4-methanesulfonylaminophenyl)-N-methylethylamino) piperidine was obtained. 1H NMR (d -DMSO) δ=1.3-1.5 (2H); 1.7 (2H); 2.1 (3H); 2.5-2.7 (4H); 2.7-3.0 (5H); 3.3 (1H); 3.9 (2H); 6.9 (2H); 7.0-7.2 (4H); 7.5 (2H) and 9.6 (1H) ppm.
Reaction SMILES: IC1C=C(I)C=C(I)C=1C1C=CC(C)=CC=1.[I:17][C:18]1[C:23]([C:24](=O)[CH3:25])=[C:22]([I:27])[CH:21]=[C:20]([I:28])[C:19]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[C:31]([N+:38]([O-:40])=[O:39])[CH:30]=1.Cl>>[I:17][C:18]1[C:23]([CH2:24][CH3:25])=[C:22]([I:27])[CH:21]=[C:20]([I:28])[C:19]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[C:31]([N+:38]([O-:40])=[O:39])[CH:30]=1
Reactant: CC(=O)c1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Agent: Cc1ccc(-c2c(I)cc(I)cc2I)cc1
Agent: Cl
Product: CCc1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I

Procedure:
Freidel-Crafts acylation is performed on 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) in the presence of AlCl3 and CH3COCl to yield 2′,4′,6′-triiodo-3′-acetyl-3-nitrobiphenyl-4-carboxylic acid (12). C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → C ⁢   ⁢ H 3 ⁢   ⁢ C ⁢   ⁢ O ⁢   ⁢ Cl Al ⁢   ⁢ Cl 3 ⁢ C 15 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 5 2′,4′,6′-triiodo-3′-acetyl-3-nitrobiphenyl-4-carboxylic acid (12) is then reacted with a zinc mercury amalgam and hydrochloric acid and heated to yield 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13). C 15 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 5 ⁢ → Δ Zn ( Hg ) ,   ⁢ H ⁢   ⁢ Cl ⁢ C 15 ⁢ H 10 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carbonyl chloride (14). C 15 ⁢   ⁢ H 10 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → S ⁢   ⁢ O ⁢   ⁢ Cl 2 ⁢ C 15 ⁢   ⁢ H 9 ⁢ Cl ⁢ I 3 ⁢ N ⁢   ⁢ O 3 1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carbonyl chloride (14) to yield 2-nitro-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (15). C14H21NO9+C15H9ClI3NO3→C29H29I3N2O12 2-nitro-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (15) is treated with stannous chloride and hydrochloric acid to yield 2-amino-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-D-glucosamine (16). C 29 ⁢   ⁢ H 29 ⁢ I 3 ⁢ N 2 ⁢ O 12 ⁢ → Sn ⁢   ⁢ Cl 2 ,   ⁢ H ⁢   ⁢ Cl ⁢ C 21 ⁢   ⁢ H 23 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 6 Example 2 is similar in general structure to Example 1, with the additional presence of a short alkyl chain attached to the radio-opaque tri-iodophenyl moiety at the C-3′ position to further increase lipophilicity of the molecule and enhance cell membrane permeability. The computed logP of Example 2 is 5.31.
Reaction SMILES: [CH:1]1([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[C:13]([CH2:24][O:25][C:26]2[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=2)=[C:12]3[C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.[NH2:54][C:55]1[CH:56]=[C:57]([CH:62]=[CH:63][CH:64]=1)[C:58]([O:60]C)=[O:59].C1COCC1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH:1]1([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21]([NH:54][C:55]2[CH:56]=[C:57]([CH:62]=[CH:63][CH:64]=2)[C:58]([OH:60])=[O:59])=[O:22])[C:13]([CH2:24][O:25][C:26]2[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=2)=[C:12]3[C:36]([N:38]2[CH2:39][CH2:40][CH2:41][CH2:42]2)=[O:37])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCCn1c(COc2ccc3ccccc3c2)c(C(=O)N2CCCC2)c2cc(NC(=O)C3CCCC3)ccc21
Reactant: COC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCn1c(COc2ccc3ccccc3c2)c(C(=O)N2CCCC2)c2cc(NC(=O)C3CCCC3)ccc21)Nc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
The compound of Example 50 (1 eq) was weighed into a flask and to this was added EDCI (3 eq), DMAP (1.2 eq), methyl 3-aminobenzoate (1.2 eq) followed by anhydrous THF (0.04M) and the reaction mixture was then stirred at 25° C. for 2 d. Worked up with ethyl acetate/water followed by washing the organic layer with 1N HCl, saturated bicarbonate and brine. Recrystallization from ethyl acetate/hexane afforded the desired product in 88% yield.