Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([O:10][C:11]2[CH:33]=[CH:32][C:14]3[C:15]4[N:19]([CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH:18]=[C:17]([C:23]2[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=2)[N:16]=4)[CH3:9])[CH2:3][CH2:2]1.[CH3:34][C:35]([CH3:37])=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O.CO>[CH:29]([N:24]1[C:23]([C:17]2[N:16]=[C:15]3[C:14]4[CH:32]=[CH:33][C:11]([O:10][CH:8]([CH:4]5[CH2:5][CH2:6][CH2:7][N:1]([CH:35]([CH3:37])[CH3:34])[CH2:2][CH2:3]5)[CH3:9])=[CH:12][C:13]=4[O:22][CH2:21][CH2:20][N:19]3[CH:18]=2)=[N:27][C:26]([CH3:28])=[N:25]1)([CH3:30])[CH3:31]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)C4CCCNCC4)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)C4CCCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.6 %

Procedure:
To a solution of 8-(1-azepan-4-ylethoxy)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 10 (50 mg, 0.11 mmol) in a 10:1 mixture of DCM:MeOH (2.2 mL) were added acetone (81 uL, 1.1 mmol), AcOH (0.011 mmol) and sodium triacetoxyborohydride (47 mg, 0.22 mmol). The reaction mixture was stirred for 24 h at RT, then diluted with DCM and poured into water. The aqueous layer was extracted with DCM (×3) and the combined organic phases were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 217 as a white solid (48 mg, 81%). LCMS: RT 3.16 min [M+H]+ 493.2. 1H NMR (CDCl3, 400 MHz): δ 8.40 (1H, d, J=8.95 Hz), 7.56 (1H, s), 6.71 (1H, d, J=9.07 Hz), 6.52 (1H, s), 5.98-5.86 (1H, m), 4.52-4.44 (2H, m), 4.43-4.36 (2H, m), 4.33-4.23 (1H, m), 2.92-2.80 (1H, m), 2.76-2.48 (5H, m), 2.41 (3H, s), 2.02-1.74 (5H, m), 1.63-1.40 (7H, m), 1.30-1.23 (3H, m), 1.03-0.95 (6H, m)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][N:14]=[C:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:23]([OH:27])(=[O:26])(=[O:25])=[O:24]>Cl.C(Cl)(Cl)Cl>[Cl:23]([OH:27])(=[O:26])(=[O:25])=[O:24].[CH3:1][N:2]1[C:6]([C:15](=[N:14][CH3:13])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1cc(C)cn1C
Reactant: CN=C(Cl)c1ccccc1
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)Cl
Product: CN=C(c1ccccc1)c1c(C)cc(CC(=O)OC)n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
Methyl 1,4-dimethyl-1H-pyrrole-2-acetate (1.66 g, 10 mmole) was placed in a 25 ml round bottom flask and treated with alcohol free chloroform (2 ml) and N-methyl benzimidoyl chloride (1.78 g, 12 mmole). The solution was treated with several drops of ethereal hydrogen chloride--mild exotherm. The reaction was protected with a calcium chloride drying tube and stirred at room temperature for about four hours. The reaction was diluted with chloroform, quenched into saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated. The viscous residue was dissolved in absolute ethanol (6 ml) and treated with 70% perchloric acid (1.42 g, 10 mmole). The resulting crystalline solid was isolated by filtration and washed with ethanol/ether (1 to 3 by volume) and air dried to yield 2.39 g (62%) of the title compound as a bright yellow solid, m.p. 149°-150° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH:6]=[CH:5]2.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.C(OCC)(=O)C>[CH3:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[CH:3]=2)[N:8]=1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3ccc(C#N)cc3)ccc2n1
Temperature: 25 °C

Procedure:
The product from Example 42D (160 mg, 0.5 mmol), 4-cyanophenylboronic acid (0.75 mmol), and dichlorobis(triphenylphosphine) palladium (II) (35.1 mg, 0.05 mmol) were combined in isopropyl alcohol (5.0 mL) and 0.2 M K3PO4 aq. solution (5.0 mL, 1.0 mmol) and heated at 60° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (20 mL). The organic phase was separated, washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with one equivalent of L-tartaric acid in IPA:ethanol to give the tartrate salt. mp 164° C.; MS (ESI) 342 (M+H)+; 1H NMR (DMSO-d6) δ 8.40 (1H, d), 8.38 (1H, d), 8.12 (1H, d), 8.06 (1H, d), 8.04 (2H, d), 7.98 (2H, d), 7.58 (1H, d), 4.05 (2H, s), 3.63 (1H, m), 3.50 (1H, m), 3.33 (2H, t), 3.15 (2H, m), 2.88 (1H, m), 2.09 (1H, m), 1.86 (2H, m), 1.55 (1H, m), 1.29 (3H, d).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([NH:13][NH2:14])[C:7]([C:8]([O-])=[O:9])=[CH:6][N:5]=1.Cl>C(O)C>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:8](=[O:9])[NH:14][NH:13][C:11]=2[CH:12]=1
Reactant: NNc1cc(Cl)ncc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1[nH][nH]c2cc(Cl)ncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-L reactor was placed ethanol (22 L), sodium hydroxide (800 g, 20.00 mol), and 6-chloro-4-hydrazinylnicotinate (2700 g, 13.39 mol). The resulting solution was stirred for 2 h at room temperature. The pH value of the solution was adjusted to 7 with HCl. The solid was filtered out. The filtrate was concentrated in vacuo to give 6-chloro-1H-pyrazolo[4,3-c]pyridin-3(2H)-one, which was carried onto the next step without further purification. MS ESI calc'd. for C6H4ClN3O [M+1]+ 170. found 170.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CN1CCNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3)CC2)c(C)c1
Yield: 85.3 %

Procedure:
Using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (348 mg) described in Preparation Example 133 and 1-methylimidazolidin-2-one (96 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (278 mg) was obtained.
Reaction SMILES: [ClH:1].C(OC(N1[C@@H](C)CC[C@H]1C1NC(C2C=CC([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31](C3NC([C@@H]5CC[C@H](C)N5C(OC(C)(C)C)=O)=NC=3)[CH:30]=[CH:29]4)=CC=2)=CN=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[N:32]1[C:33]2[C:28](=[CH:27][CH:26]=[CH:35][CH:34]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc(-c4ccc5nc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)OC(C)(C)C)[nH]6)ccc5c4)cc3)[nH]2)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2ncccc2c1
Yield: 778.5 %

Procedure:
4M HCl (0.2 mL, 0.8 mmol) in dioxane was added to a solution of (2S,5S)-tert-butyl 2-(5-(6-(4-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinolin-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (12.7 mg, 0.018 mmol) in dioxane (1 mL) and the mixture was stirred at rt for 3d. The reaction mixture was concentrated to yield a crude HCl salt of 2-(2-((2S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-6-(4-(242S,5S)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)quinoline (18.1 mg) as yellow solid. LC-MS retention time 2.597 min; m/z 504.46 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 9.09 (d, J=9.0 Hz, 1 H), 8.66 (s, 1 H), 8.54-8.61 (m, 2 H), 8.51 (d, J=9.0 Hz, 1 H), 8.50 (d, J=8.8 Hz, 1 H), 8.00-8.08 (m, 4 H), 7.99 (s, 1 H), 5.14 (t, J=8.5 Hz, 1 H), 5.07 (t, J=8.0 Hz, 1 H), 3.90-4.04 (m, 2 H), 2.52-2.75 (m, 4 H), 2.39-2.53 (m, 2 H), 1.98-2.14 (m, 2 H), 1.59 (dd, J=9.7, 6.7 Hz, 6 H).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.[CH3:34][NH:35]C(=O)CN.CN1CCOCC1>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][C:16]([NH:35][CH3:34])=[O:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: CNC(=O)CN
Agent: Cl
Solvent: CN1CCOCC1
Product: CNC(=O)CNC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Yield: 33 %

Procedure:
The title compound was prepared by a procedure similar to the one described for (±) 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide using glycine methyl amide HCl (1.77 g, 14.25 mmol) as the amine and with an addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (1.55 g, 33%) as white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.97 (dd, 1H, J=1.6 Hz), 7.73 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.57 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.98 (s, 2H), 2.74 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H); ES-HRMS m/z 491.1262 (M+H C23H22ClF2N4O4 requires 491.1292). Both (+) and (−) atropomers will be resolved and characterized.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:21][CH:20]=2)[O:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH2:1]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:32]3[CH2:33][CH2:34][CH2:35][CH:31]3[CH3:30])=[CH:21][CH:20]=2)[O:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCCN1
Reactant: COC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1oc(-c2ccc(OCCCN3CCCC3C)cc2)nc1CNCc1ccccc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 4-[(benzylamino)methyl]-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-5-carboxylate i94 (0.11 g, 0.27 mmol, 1 eq), 2-methylpyrrolidine (30 μl, 0.32 mmol, 1.2 eq) and potassium carbonate (0.15 g, 1.06 mmol, 4 eq) in acetonitrile (5 ml) is stirred at 110° C. overnight. The mixture is then poured into ethyl acetate (50 ml) and washed with water. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. Two successive purifications over silicagel (eluent: dichloromethane, methanol, ammonia 90/10/1) and one purification by preparative liquid chromatography (gradient: acetonitrile/water/trifluoroacetic acid 95:5:01 to 5:95:01) yield 6 mg of methyl 4-[(benzylamino)methyl]-2-{4-[3-(2-methyl-1-pyrrolidinyl)propoxy]phenyl}-1,3-oxazole-5-carboxylate 99.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11]O)[C:5]=2[O:4][CH2:3][CH2:2]1.S(Cl)([Cl:15])=O>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][Cl:15])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc2c1OCCO2
Solvent: ClCCl
Product: ClCc1cccc2c1OCCO2
Yield: 100.3 %

Procedure:
Dissolve (2,3-Dihydrobenzo[1,4]dioxin-5-yl)methanol (1.8 g, 10.8 mmol) in dichloromethane (15 mL). Add neat thionyl chloride (2 mL, 27.4 mmol) dropwise to the stirring reaction mixture at 25° C. under nitrogen. Stir the reaction for 15 minutes and concentrate under reduced pressure to obtain 2.0 g (100%) of the desired compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=2)=[C:6]([CH:14]=1)[C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.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>[Cl:22][C:18]1[CH:17]=[C:16]([O:15][C:5]2[CH:4]=[CH:3][C:2]([C:27]3[CH:28]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:14][C:6]=2[C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])[CH:21]=[CH:20][N:19]=1
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccnc(Cl)c1
Reactant: OB(O)c1cncnc1
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: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)c1cc(-c2cncnc2)ccc1Oc1ccnc(Cl)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A resealable tube was charged with a mixture of 5-bromo-2-(2-chloropyridin-4-yloxy)-N,N-diethylbenzamide (2.500 g, 6.52 mmol), pyrimidin-5-ylboronic acid (2.018 g, 16.29 mmol), and potassium carbonate (4.50 g, 32.6 mmol) in THF (40.0 mL) and water (10.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.376 g, 0.326 mmol) was added, the system was purged with argon, and the tube was sealed. The reaction mixture was stirred at 100° C. for 4.0 h. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown solid. This material was purified via column chromatography on silica gel (RediSep 120 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford 2-(2-chloropyridin-4-yloxy)-N,N-diethyl-5-(pyrimidin-5-yl)benzamide as an off-white solid. MS m/z=383.2 [M+H]+. Calcd for C20H19ClN4O2: 382.1.
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C:4](=[O:5])[S:3][CH2:2]1.[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[C:10]=1/[CH:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[CH:21]=[CH:22]/[C:23](/[CH3:28])=[CH:24]/[C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>O.C(Cl)Cl>[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[C:10]=1/[CH:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[CH:21]=[CH:22]/[C:23](/[CH3:28])=[CH:24]/[C:25]([NH:7][CH:6]1[C:4](=[O:5])[S:3][CH2:2][CH2:1]1)=[O:26]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Reactant: N[C@H]1CCSC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)NC2CCSC2=O)C(C)(C)CCC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
McCully (U.S. Pat. No. 4,618,685; “the '685 patent”, incorporated herein by reference) attempted to synthesize thioretinamide, the precursor to the compound of the invention, from homocysteine thiolactone free base and retinoic acid. McCully's synthesis of thioretinamide involves the conjugation of homocysteine thiolactone to retinoic acid using dicyclohexylcarbodimide as a coupling agent. The process in that patent starts with the preparation of the free base of homocysteine thiolactone. This is done by dissolving sodium hydroxide (NaOH) in water, adding methylene chloride and rapidly mixing. Homocysteine thiolactone hydrochloride is then slowly added to the mixture. After 15 minutes of mixing, the methylene chloride layer is separated, dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure at 37° C. The resulting clear liquid (homocysteine thiolactone free base) is immediately added to tetrahydrofuran (or any other non-polar solvent) containing all-trans-retinoic acid. Then, dicyclohexylcarbodiimide is added, and the reaction mixture is stirred 16 hours at 20° C., protected from light. The tetrahydrofuran is removed at 37° C. under reduced pressure, and the yellow-white residue is added to 500 ml of water and 500 ml of ethyl acetate. The mixture is stirred vigorously for one hour, and the ethyl acetate layer is separated and dried over anhydrous sodium sulfate. The ethyl acetate is concentrated to about 20 ml at 50° C. under reduced pressure and cooled. The resulting N-homocysteine thiolactonyl retinamide, (a yellow powder) was produced with a 69% theoretical yield and a melting point of 172° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:12]=[C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Reactant: NC(=O)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc(C3CCNCC3)co2)cc1
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A solution of 4-fluorobenzamide (4.54 g, 32.7 mmol) and t-butyl 4-(bromoacetyl)-piperidine-1-carboxylate (5.0 g, 16.3 mmol) in DMF (40 mL) was heated at 145° C. for 16 h. Upon completion of the reaction, the solution was allowed to cool to rt and concentrated to a dark oil. The oil was purified by reverse phase HPLC to afford the title compound (760 mg). LC/MS: m/e 247.08 (M+H)+.
Reaction SMILES: Cl.N[C@H](C)CSC1SC2C=C(OCC)C=CC=2N=1.C(OC1C=CC2N=C(S)SC=2C=1)C.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C.C([O:64][C@@H:65]1[C@H:69]([O:70]C(=O)C)[C@@H:68]([CH2:74][O:75]C(=O)C)[O:67][C@H:66]1[N:79]1[C:104]2[N:103]=[C:102]([Cl:105])[N:101]=[C:83]([NH:84][C@H:85]([CH3:100])[CH2:86][S:87][C:88]3[S:89][C:90]4[CH:96]=[C:95]([O:97][CH2:98][CH3:99])[CH:94]=[CH:93][C:91]=4[N:92]=3)[C:82]=2[N:81]=[CH:80]1)(=O)C.C[O-].[Na+]>CO>[CH2:98]([O:97][C:95]1[CH:94]=[CH:93][C:91]2[N:92]=[C:88]([S:87][CH2:86][C@H:85]([NH:84][C:83]3[C:82]4[N:81]=[CH:80][N:79]([C:104]=4[N:103]=[C:102]([Cl:105])[N:101]=3)[C@@H:66]3[O:67][C@H:68]([CH2:74][OH:75])[C@@H:69]([OH:70])[C@H:65]3[OH:64])[CH3:100])[S:89][C:90]=2[CH:96]=1)[CH3:99]
Reactant: CCOc1ccc2nc(SC[C@@H](C)Nc3nc(Cl)nc4c3ncn4[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)sc2c1
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCOc1ccc2nc(S)sc2c1
Agent: CCOc1ccc2nc(SC[C@@H](C)N)sc2c1
Solvent: CO
Product: CCOc1ccc2nc(SC[C@@H](C)Nc3nc(Cl)nc4c3ncn4[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)sc2c1
Yield: 17 %

Procedure:
The title compound was prepared according to general method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]-6-ethoxybenzothiazole hydrochloride [prepared by a Mitsunobu reaction as described in Example 1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (3.5 g, 20 mmol) and 6-ethoxy-2-mercaptobenzothiazole (4.23 g, 20 mmol) followed by acidic hydrolysis] (3.8 g, 11.1 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.1 g, 2.5 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(6-ethoxy-2-benzothiazolyl)thio-2-propyl]adenosine using sodium methoxide in methanol to provide the title N[(R)-1-(6-ethoxy-2-benzothiazolyl)thio-2-propyl]-2-chloroadenosine (0.22 g, 17%) as a foam (following column chromatography), 1H NMR (DMSO-d6) δ1.32-1.40 (6H, m, --CH2CH3 and --CHCH3), 3.44-3.81 (4H, m, H-5'a and H-5'b and --CH2 --), 3.97 (1H, d, H-4'), 4.08 (2H, q, --CH2CH3), 4.14 (1H, d, H-3'), 4.53 (1H, q, H-2'), 4.68 (1H, m, --CH), 5.09 (1H, t, 5'-OH), 5.23, 5.51 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.06, 7.57, 7.74 (3H, 3d, Ar--H), 8.42 (1H, s, H-8), 8.53 (1H, d, N--H). HPLC retention time 22.4 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([C:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)[S:15][CH:16]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][S:27]([O:23][CH:20]1[CH2:21][CH2:22][N:17]([C:14]2[S:15][CH:16]=[C:12]([C:10]([O:9][CH2:8][C:7]3[CH:24]=[CH:25][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[N:13]=2)[CH2:18][CH2:19]1)(=[O:29])=[O:28]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)c1csc(N2CCC(O)CC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)CC1
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
To a solution of 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (0.75 g, 2.06 mmol) (obtained as described in Reference Example 14(4)) in anhydrous methylene chloride (38 ml) were added methanesulfonyl chloride (0.18 ml, 2.33 mmol) and triethylamine (0.35 ml, 2.51 mmol) in an ice bath. The mixture was brought to room temperature in 10 minutes, and then stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1) as the eluant to afford 4-methanesulfonyloxy-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)piperidine (0.87 g, yield 96%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: Oc1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Oc1ccccc1)c1ccc(O)cc1O
Yield: 54.5 %

Procedure:
A 1.5 l sulfonating flask equipped with stirrer, condenser, dropping funnel and gas outlet is charged with 154.1 g (1.0 mol) of 2,4-dihydroxybenzoic acid, 141.2 g (1.5 mol) of phenol, 500 ml of toluene and 1 ml of dimethylformamide. 178.5 g (1.5 mol) of thionyl chloride are then added dropwise at an internal temperature of 100°-105° C. over a period of 2.5 hours. The reddish clear solution is then refluxed overnight (110°-115° C.). The toluene and the phenol are distilled off in vacuo, the highly viscous residue (271.5 g) is stirred in 300 ml of 7:3 toluene/cyclohexane, and the product is allowed to crystallize overnight. The precipitate is filtered off with suction while cold (10° C.) and washed with 3×50 ml of 7:3 toluene/cyclohexane. It is dried at 80° C. in vacuo to give 125.5 g (54.4% of theory) of phenyl 2,4-dihydroxybenzoate (m.p. 135°-137° C.).