Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([SiH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][N:3]=1.[Br-].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Zn+].N>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.O1CCCC1>[CH:11]1([C:5]2[CH:6]=[C:7]([SiH:8]([CH3:10])[CH3:9])[C:2]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[N:3][CH:4]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[SiH](C)c1cc(C2CCCCC2)cnc1Br
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [Br-]
Solvent: C1CCOC1
Product: C[SiH](C)c1cc(C2CCCCC2)cnc1-c1ccccn1
Temperature: 25 °C

Procedure:
To a reaction container equipped with a cooling apparatus, 2.61 g of tetrakis(triphenylphosphine)palladium, 6.75 g of 2-bromo-5-cyclohexyldimethylsilylpyridine obtained in the above-mentioned Example 2-1 and 135 mL of tetrahydrofuran were added. To the obtained mixture, 45.26 mL of 2-pyridyl zinc bromide (0.5 M/tetrahydrofuran solution) was added with stirring at room temperature. The obtained mixture was stirred at 50° C. for 9 hours to effect reaction. The reaction mixture was cooled until room temperature and then, 200 mL of 28% aqueous ammonia solution was added thereto. The obtained mixture was extracted three times with 230 mL of chloroform. The obtained organic layers were mixed and dried with magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated to obtain a crude product. The crude product was purified with silica gel column chromatography followed by further distillation to obtain 4.04 g of 5-cyclohexyldimethylsilyl-2,2′-bipyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(C)cc(-c2ccsc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)cc(-c2ccsc2)c1
Reaction time: 2 h

Procedure:
Methyl 3-methyl-5-(3-thienyl)benzoate (257 mg, 1.1 mmol) is treated with lithium hydroxide (186 mg, 4.4 mmol) in tetrahydrofuran/methanol/water (8 ml, 2:1:1) and the mixture is stirred for 2 hours at 20–25 degrees C. The mixture is acidified and concentrated to give the title compound, MS [M+H]+=217.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](C)(C(OCC)=O)[C:9](OCC)=O)[C:5]([F:20])=[CH:4][N:3]=1.CC(O)=O.Cl.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH3:9])[C:5]([F:20])=[CH:4][N:3]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1nc(Cl)ncc1F
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc(Cl)ncc1F
Temperature: 100 °C
Yield: 20.7 %

Procedure:
Diethyl 2-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylmalonate (3.00 g, 9.85 mmol) was treated with glacial HOAc (25 mL) and 5N HCl (10 mL) and fitted with a reflux condenser and heated to 100° C. for 18 h. The reaction was cooled to RT and treated with H2O (30 mL) and DCM (45 mL) and the DCM layer separated and dried over MgSO4, filtered and concentrated. The crude residue was purified with flash chromatography (eluting with 100% DCM) affording 2-chloro-4-ethyl-5-fluoropyrimidine (328 mg, 21%) as a viscous pale yellow oil. MS (ESI, pos. ion) m/z: 161.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.34 (1H, s), 2.87 (2H, qd, J=7.6, 2.0 Hz), 1.29-1.37 (3H, t).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([CH2:21][C@@H:20]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[OH:23])=[N+:25]=[N-:26]
Reactant: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 65 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
8-Benzyloxy-5-((R)-2-bromo-1-hyroxyethyl)-1H-quinolin-2-one (20.8 g, 55.6 mmol) and sodium azide (3.61 g, 55.5 mmol) were suspended in N,N-dimethylformamide (100 mL) and the mixture was stirred at 65° C. for 3 hours. Sodium azide (1.81 g, 27.8 mmol) was added thereto and the mixture was stirred at the same temperature overnight. To the reaction solution was added purified water and stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with purified water. By drying under reduced pressure, 5-((R)-2-azido-1-hyroxyethyl)-8-benzyloxy-1H-quinolin-2-one (16.8 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].N12CCCN=C1CCCC[CH2:17]2.IC.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15]
Reactant: O=C1CCc2c(Br)cc([N+](=O)[O-])c(O)c21
Reactant: C1CCC2=NCCCN2CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c([N+](=O)[O-])cc(Br)c2c1C(=O)CC2
Temperature: 25 °C
Reaction time: 40 h
Yield: 78.9 %

Procedure:
4-Bromo-7-hydroxy-6-nitroindan-1-one (8.07 g, 29.7 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.33 mL, 35.6 mmol) were dissolved in N,N-dimethylformamide (150 mL), iodomethane (18.5 mL, 297 mmol) was added, and the mixture was stirred at room temperature for 40 hr. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with diethyl ether, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→60/40) to give the title compound (6.70 g, yield 79%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.OO.O.O.O.O.O.S([O-])([O-])(=[O:33])=S.[Na+].[Na+].O>C(O)(=O)C>[CH3:23][O:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:10]=2)=[O:33])=[CH:14][CH:15]=1
Reactant: O=S([O-])([O-])=S
Reactant: COCCOc1ccc(Sc2ccc(OCCOC)cc2)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1ccc(S(=O)c2ccc(OCCOC)cc2)cc1
Reaction time: 15 h
Yield: 984.4 %

Procedure:
In 200 g of acetic acid was dissolved 28.5 g of bis[4-(2-methoxyethoxy)phenyl]sulfide obtained in Synthesis Example 1-33. While the solution was maintained at an internal temperature of 40° C., 7.87 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 15 hours, after which under ice cooling, a mixture of 2.0 g sodium thiosulfate pentahydrate and 10 g water was added dropwise to quench the reaction. The solution was concentrated in vacuum and combined with 100 g of toluene, 50 g of ethyl acetate and 50 g of water. The organic layer was separated, washed with water, and concentrated in vacuum. The concentrate was crystallized from 20 g of ethyl acetate and 300 g of hexane, obtaining 27.8 g of the target compound, bis[4-(2-methoxy-ethoxy)phenyl]sulfoxide as white crystals. Yield 91%.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.Cl.N[C:32](N)=N.ClC1C2C(=CC=C(S(NC3(C(OC)=O)CCCCC3)(=O)=O)C=2)C(Cl)=CN=1.O>CS(C)=O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:23]([O:25][CH3:32])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1
Reactant: N=C(N)N
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCCCC3)cc12
Agent: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCCCC1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCCC1
Temperature: 60 °C
Yield: 5.8 %

Procedure:
1-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylic acid hydrochloride ##STR54## NaH (22.3 mg, 80% dispersion by wt in mineral oil, 0.743 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (117 mg, 1.98 mmol) in DMSO (5 mL) and the mixture was heated at 50-70° C. under N2 for 25 min. Methyl 1-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}-cyclohexanecarboxylate (124 mg, 0.30 mmol) was added in one portion and the mixture heated at 80° C. for 8 h. The cooled mixture was poured into water (50 mL), extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with water, brine, dried (MgSO4) and evaporated in vacuo. The residue was crystallised from a minimum of hot EtOAc to give methyl 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (12 mg, 0.043 mmol) as yellow solid. Evaporation of the mother liquors and trituration of the residue with Et2O gave a second crop (7 mg).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[C:24]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:24]3[C:23]([Cl:22])=[CH:28][C:27]([Cl:29])=[CH:26][C:25]=3[Cl:30])[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Clc1cc(Cl)c(N2CCNCC2)c(Cl)c1
Product: CCc1cc(NC(=O)N2CCN(c3c(Cl)cc(Cl)cc3Cl)CC2)c(OC)nc1C
Yield: 54 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,4,6-trichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[H-].[Na+].[C:12]1([C:22]([C:24]2[C:31]([CH3:32])=[CH:30][C:27]([CH2:28]Br)=[CH:26][C:25]=2[CH3:33])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O.C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH2:28][C:27]2[CH:26]=[C:25]([CH3:33])[C:24]([C:22]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[O:23])=[C:31]([CH3:32])[CH:30]=2)[N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1nn[nH]c1N
Reactant: Cc1cc(CBr)cc(C)c1C(=O)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(Cn2nnc(C(N)=O)c2N)cc(C)c1C(=O)c1cccc2ccccc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A solution of 5-amino-l,2,3-triazole-4-carboxamide (182 mg, 1.43 mmol) in 5 ml of dry dimethylformamide (DMF) is treated with 50% sodium hydride dispersion in mineral oil (70mg). The reaction mixture is warmed to 45° C. and stirred for 1 hour. To this mixture, a solution of 4-(1-naphthoyl)-3,5dimethylbenzyl bromide (0.43 g, 1.2 mmol) in 5 ml of dry DMF is added. The reaction mixture is stirred at 45° C. for an additional 20 minutes and then stirred at room temperature for 1 hour. The reaction mixture is added slowly to water containing a small quantity of glacial acetic acid. The mixture is extracted with methylene chloride and the combined extracts washed with brine and dried with anhydrous sodium sulfate. Solvent is removed and the crude mixture of two triazoles is chromatographed on silica gel to give the titled compound.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.[Br:15]C1CC1>CS(C)=O.CCOCC>[Br:15][C:12]1[CH:13]=[CH:8][C:9]([CH:5]2[CH2:2][CH2:1]2)=[CH:10][C:11]=1[SH:14]
Reactant: BrC1CC1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: Sc1cc(C2CC2)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a degassed solution of potassium tert-butoxide (2.08 g, 18.51 mmol) in dry dimethylsulphoxide (6 mL), 4-bromo-benzenethiol (3.5 g, 18.5 mmol) was added and the mixture was stirred for 15 min at ambient temperature under nitrogen. Bromocyclopropane (4.4 mL, 55.5 mmol) was added afterwards and the reaction mixture was heated at 80° C. for 24 h in a sealed vessel. The mixture was cooled, diluted with ether (150 mL) and washed with water (100 mL). The aqueous layer was extracted with ether (3×50 mL). Combined organic extracts were finally dried with anhydrous magnesium sulfate. 1-Bromo-4-cyclopropyl-sulfanyl-benzene was obtained after evaporation of the solvent as yellow liquid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[C:15]1([C:21]2[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:63]([Cl:65])[Cl:64]>>[NH3:5].[CH2:63]([Cl:65])[Cl:64].[C:15]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=[CH:19][C:18]([O:1][CH:2]2[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N
Product: c1ccc(-c2ccc(OC3CCNCC3)cc2)cc1
Reaction time: 16 h

Procedure:
A suspension of tert-butyl 4-hydroxy-1-piperidine carboxylate (497 mg), 4-phenylphenol (300 mg), and polymer-supported triphenylphosphine (1.2 g) in DCM (10 mL) was treated with di-tert-butyl azodicarboxylate (608 mg). The resulting mixture was shaken for 16 h, and filtered through a pad of celite. The pad was washed with DCM (3×5 mL) and the combined filtrates were evaporated. The residue was dissolved in dioxane (5 mL) and treated with hydrogen chloride (5 mL of a 4 N solution in dioxane). After 16 h, solvent was removed and the residue was treated with 10% aqueous sodium hydroxide (20 mL). The resulting mixture was extracted with DCM (2×500 mL), and the combined organic phases were dried (magnesium sulfate) and evaporated. Chromatography of the residue (1–6% 2M methanolic ammonia/DCM) gave the title compound as a white solid (107 mg). 1H NMR (400 MHz, CDCl3): 7.56–7.49 (m, 4H), 7.42–7.39 (m, 2H), 7.31–7.27 (m, 1H), 6.99–6.96 (m, 2H), 4.43–4.37 (m, 1H), 3.18–3.13 (m, 3H), 2.77–2.70 (m, 2H), 2.07–2.01 (m, 2H), 1.73–1.64 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N([C:16]([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@H](C=O)CCS(C)=O.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O:18][CH2:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17]
Reactant: C1CCNCC1
Reactant: CS(=O)CC[C@@H](C=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCCC1
Reaction time: 4 h

Procedure:
The resin was deprotected using a 20% solution of piperidine in DMF (1×3 min, 1×7 min, 20 ml each) and subsequently washed with DMF (1×20 ml). Acylation was carried out by addition of FmocMetOH (2.4 g, 3 eq), DMF (10 ml), HOBt (990 mg, 3 eq), and DIC (1.01 ml, 3 eq) and DMAP (260 mg, 0.1 eq). The coupling was left for 4 h and the resin was washed with DMF (7×20 ml). A small sample was dried carefully and deprotected with DCM/piperidine (1:1) for 30 min. Photometric determination of the resulting Fmoc-piperidine adduct (absorption at 301 nm) gave a resin loading of 0.43 m mol/g. The remaining resin was capped using a solution of acetic anhydride (2 M) and DMAP (0.1 M) in DMF (20 ml, 1×10 min) and subsequently washed with DMF (12×20 ml), methanol (3×40 ml) and diethyl ether (3×40 ml), and dried in vacuo to yield 3.9 g FmocMet-Rinkamide resin.
Reaction SMILES: O.N1CCCC1.C([O:10][C:11](=[O:44])[CH:12]([CH2:31][CH2:32][N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])[N:13]([CH3:30])[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])C=C.Cl>O1CCOCC1>[CH3:30][N:13]([S:14]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:22]=1)(=[O:15])=[O:16])[CH:12]([CH2:31][CH2:32][N:33]1[C:34](=[O:43])[C:35]2=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]2[C:37]1=[O:38])[C:11]([OH:44])=[O:10]
Reactant: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCNC1
Product: CN(C(CCN1C(=O)c2ccccc2C1=O)C(=O)O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Yield: 94.8 %

Procedure:
Water (1.75 ml), tetrakis(triphenylphosphine)palldium(0) (8.2 mg. 0.007 mmol) and pyrrolidine (0.45 ml, 5.3 mmol) were successively added to a solution of (±)-N-methyl-N-(4-phenoxybenzenesulfonyl)-2-(2-phthalimidoethyl)glycine allyl ester (1.88 g, 3.5 mmol), the product of (3) above, in dioxane (33 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was acidified with hydrochloric acid (1N) and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was washed with diethyl ether to give the title compound (1.64 g, yield 94%) as a white powder.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](=[O:33])[CH3:32])=[CH:23][N:22]=4)[C@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:34]=1)(=O)C.[Li+].[OH-]>C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](=[O:33])[CH3:32])=[CH:23][N:22]=4)[C@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:34]=1.[OH:4][CH2:5][C:6]1[C:7]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](=[O:33])[CH3:32])=[CH:23][N:22]=4)[C@@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:34]=1
Reactant: CC(=O)OCc1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)[C@@H]3C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cnc(N2CCn3c(nc4cc(CO)c(S(C)(=O)=O)cc43)[C@@H]2C(C)C)nc1C(F)(F)F
Product: CC(=O)c1cnc(N2CCn3c(nc4cc(CO)c(S(C)(=O)=O)cc43)[C@H]2C(C)C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (R)-(2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methyl acetate (100 mg, 0.181 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH (38 mg, 0.905 mmol). The mixture was stirred at rt for 10 min. The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by basic preparative HPLC to afford the crude product (53.1 mg, 55.9% yield). The crude product was separated by SFC to afford (R)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (32.90 mg, isomer 1) as a white solid and (S)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (16.90 mg, isomer 2) as a white solid. Isomer 1: (R)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone. Analytical chiral HPLC: tR=7.280 min in 15 min chromatography (Method: AS-H—5—5—40—2.35 ML). LC-MS m/z 512.1 [M+H]+. 1H NMR (CD3OD 400 MHz): δ 9.00 (s, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 6.11-6.07 (m, 1H), 5.49-5.32 (m, 1H), 5.10 (s, 2H), 4.54 (dd, J=3.6 Hz and 12.4 Hz, 1H), 4.24 (dt, J=4.8 and 12.0 Hz, 1H), 3.98-3.90 (m, 1H), 3.25 (s, 3H), 2.61-2.57 (m, 1H), 2.56 (s, 3H), 1.29 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.8 Hz, 3H). Isomer 2: (S)-1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone
Reaction SMILES: C([O:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[CH:10]1)C1C=CC=CC=1.C([O:29][N:30]1[C:42]2[C:41]3[N:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N:35]=[CH:34][C:33]=2[N:32]=[CH:31]1)C1C=CC=CC=1>>[NH:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[OH:29].[NH:30]1[C:42]2[C:41]3[N:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N:35]=[CH:34][C:33]=2[N:32]=[C:31]1[OH:8]
Reactant: c1ccc(COn2cnc3cnc4cccnc4c32)cc1
Reactant: c1ccc(COn2cnc3cnc4ccccc4c32)cc1
Product: Oc1nc2cnc3ccccc3c2[nH]1
Product: Oc1nc2cnc3cccnc3c2[nH]1

Procedure:
In step (11) of Reaction Scheme IV, the benzyl group of a benzyloxy-1H-imidazo[4,5-c]quinoline or benzyloxy-1H-imidazo[4,5-c][1,5]naphthyridine of Formula XLV is cleaved to provide a 1H-imidazo[4,5-c]quinolinol or 1H-imidazo[4,5-c][1,5]naphthyridinol of Formula XLVI. The cleavage is conveniently carried out on a Parr apparatus under hydrogenolysis conditions using a suitable heterogeneous catalyst such as palladium on carbon in a solvent such as ethanol. Alternatively, the reaction can be carried out by transfer hydrogenation in the presence of a suitable hydrogenation catalyst. The transfer hydrogenation is conveniently carried out by adding ammonium formate to a solution of a compound of Formula XLV in a suitable solvent such as ethanol in the presence of a catalyst such as palladium on carbon. The reaction is carried out at an elevated temperature, for example, the reflux temperature of the solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH2:29]1OC(O)C[O:31][CH:30]1O>C(Cl)Cl.C(OCC)(=O)C>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[C:12]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=3[NH:1][CH2:29][CH2:30][OH:31])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: OC1COC(O)CO1
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2NCCO)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared from the compound of Example 32 and glycolaldehyde dimer as described for Example 58, with stirring at room temperature for 2 hours. Following workup, chromatography on silica gel with 4:1 methylene chloride/ethyl acetate afforded the title compound as a white solid, mp 45-53° C.