Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:34][C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28](=[N:31][OH:32])[CH2:29][CH3:30])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:33])[CH2:10][CH2:9]1)(C)(C)C.[ClH:46].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:46].[O:39]1[C:38]2[CH:43]=[CH:44][C:35]([CH2:34][NH:7][CH:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[C:21]([C:28](=[N:31][OH:32])[CH2:29][CH3:30])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=5)[CH:19]=[CH:18][C:17]4=[O:33])[CH2:12][CH2:13]3)=[CH:36][C:37]=2[O:42][CH2:41][CH2:40]1
Reactant: CCC(=NO)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(=NO)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C

Procedure:
To 1 mL of an ethyl acetate solution containing 83 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(1-(hydroxyimino)propyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature. The resulting solid was filtered to give 51 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-5-(1-(hydroxyimino)propyl)-1,2-dihydro-2-oxoquinoline hydrochloride as a green solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[NH:10][C:11]1[N:16]=[C:15]([C:17]2[N:21]3[CH:22]=[CH:23][N:24]=[C:25]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:13][N:12]=1)(C)(C)C.Cl>C(O)C>[Cl:39][C:35]1[CH:34]=[C:33]([CH:9]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[N:21]4[CH:22]=[CH:23][N:24]=[C:25]([N:26]5[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]5)[C:20]4=[N:19][CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH2:8][NH2:7])[CH:38]=[CH:37][CH:36]=1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(NC(CNC(=O)OC(C)(C)C)c5cccc(Cl)c5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CN)c5cccc(Cl)c5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of crude (2-(3-chloro-phenyl)-2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester (150 mg, 0.266 mmol) in ethanol (5 mL) was added concentrated hydrochloric acid (5 mL) slowly. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and then the solid was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford 1-(3-chloro-phenyl)-N1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-ethane-1,2-diamine; hydrochloride. (Yield 28 mg, 10.7%). 1H NMR (300 MHz, CD3OD): δ 8.79 (brs, 1H), 8.59 (s, 1H), 8.30 (d, 1H, J=6.3 Hz), 7.59-7.45 (m, 4H), 7.37-7.27 (m, 2H), 5.62 (brs, 1H), 5.45 (brs, 2H), 3.64-3.60 (m, 4H), 3.48-3.38 (m, 4H), 2.89 (s, 3H). LC-MS: [M+H]+ 465.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([CH2:20][C:19]4[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH3:15])[CH:18]=4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(CN2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg; 0.24 mmol), 3-methoxybenzyl bromide (0.04 ml; 0.29 mmol), and K2CO3 (0.04 ml; 0.72 mmol) were dissolved in DMF (2 ml) and stirred overnight at room temperature. Prep-LC-MS purification provided 17 as an off-white powder (14 mg, 18% yield). LC-MS (M+H=328, obsd.=328).
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:19])([F:18])[C:8]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:9][CH2:10][CH2:11][OH:12].[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C1COCC1.C(OCC)C>[C:20]([O:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([F:15])([F:16])[F:17])([OH:13])[C:7]([F:18])([F:19])[F:6])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: OCCCC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C(=O)OCCCC(O)(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a 3-necked, 2-L round-bottomed flask equipped with an overhead stirrer, digital thermometer and a 1-L constant-pressure addition funnel with a nitrogen inlet was added 590 mL (0.944 mol) of n-butyllithium (1.6 M in hexane). The addition funnel was charged with a solution of 107 g (0.47 mol) of 1,1,1-trifluoro-2-trifluoromethyl-2,5-pentanediol (4) in 300 mL of anhydrous THF. The flask was cooled and the diol was added dropwise with stirring while maintaining a temperature below 15° C. The resulting yellow-orange solution was stirred for an additional 2 hours at which time a solution of 54.5 g (0.52 mol) of methacryloyl chloride in 200 mL of anhydrous THF was added dropwise over 1 h at 10° C. The reaction mixture was allowed to reach room temperature overnight after which it was diluted with 500 mL of diethyl ether and washed with 2×500 mL of saturated ammonium chloride and brine, dried over MgSO4, evaporated and distilled at 74° C. at 1.0 mm Hg (0.5 g of phenothiazine was added to the pot prior to distillation) to yield 109 g (79%) of the title compound. The identity of the product was confirmed using 1H NMR spectroscopy and HRMS.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10](=O)[CH:11]=1)=[CH:8][CH:7]=[C:6]([CH3:13])[N:5]=2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:10]1[C:9]2[C:4](=[N:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(=O)cc(C)[nH]c2n1
Product: Cc1ccc2c(Cl)cc(C)nc2n1

Procedure:
The product from Example 14a (500 mg, 2.87 mmol) was reacted with 10 mL of POCl3 for 2 h following the procedure from Example 1d giving the title compound, which was used without purification.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH3:28])([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:28])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: CC(C)CC(C)(N)C(N)=O
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CC(C)CC(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-amino-2,4-dimethylpentanamide (CAN 113509-60-7) as starting materials and isolated (41 mg, 32%) as a white solid; MS (ESI, m/z): 388.2 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:7][N:8]=1)[CH2:2][CH3:3].[OH-].[K+]>CO>[CH2:1]([C:4]1[S:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1ncc(CC(=O)OCC)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1ncc(CC(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A mixture of 2.13 g of ethyl 2-propyl-5-thiazole acetate, 11 ml of methanol and 1.1 ml of potassium hydroxide was stirred for 1 hour under a nitrogen atmosphere at room temperature and the methanol was distilled under reduced pressure. The residue was dissolved in 5 ml of water and 2 ml of concentrated hydrochloric acid and then 2.1 g of sodium acetate were added thereto. The mixture was extracted with methylene chloride and the organic extracts were dried and evaporated to dryness. The residue was crystallized from toluene to obtain 1.24g of 2-propyl-5-thiazole-acetic acid melting at 95° C.
Reaction SMILES: C1COCC1.CO.[OH-].[Na+].[Cl:10][C:11]1[C:12]([NH:24][C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]([CH3:37])[CH:28]=2)=[O:26])=[CH:13][C:14]([F:23])=[C:15]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:16]=1>Cl>[Cl:10][C:11]1[C:12]([NH:24][C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]([CH3:37])[CH:28]=2)=[O:26])=[CH:13][C:14]([F:23])=[C:15]([CH2:17][C:18]([OH:20])=[O:19])[CH:16]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2cn(C)c3ccc(F)cc23)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2cc(F)c(CC(=O)O)cc2Cl)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.2 %

Procedure:
THF/methanol (1/1, 60 ml) and 0.25N NaOH (43 ml, 10.6 mmol) were added to ethyl (5-chloro-2-fluoro-4-(((5-fluoro-1-methyl-3-indolyl)carbonyl)amino)phenyl)acetate (865 mmol, 2.13 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured in 1N HCl, followed by extraction with a chloroform/methanol (10/1) mixture. The extract was dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was solidified with methanol/chloroform/hexane. The crystals thus precipitated were collected by filtration under reduced pressure and dried under reduced pressure to give (5-chloro-2-fluoro-4-(((5-fluoro-1-methyl-3-indolyl)carbonyl)amino)phenyl)acetic acid (736 mg, 91%) as a white crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:9]([CH3:20])=[C:10]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:9]([CH3:20])=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([Cl:25])=[O:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Product: Cc1c(CCCC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
A mixture of 8 g of 4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid (Example V) and 80 ml of thionyl chloride was refluxed for 45 minutes and after removal of excess thionyl chloride under reduced pressure, 60 ml of benzene were added thereto. The traces of thionyl chloride were removed by entrainment with benzene. This operation was repeated 3 times. The residue was taken up in tetra-hydrofuran to obtain a solution of 4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid chloride which was used as is for the next step.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([CH3:19])([CH3:18])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15].[NH2:22][C:23](=[N:37]O)[C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][N:28]2[CH2:33][C:34]([NH2:36])=[O:35].CC(C)N=C=NC(C)C>O1CCOCC1>[F:20][C:2]([F:1])([F:21])[C:3]([CH3:18])([CH3:19])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:37]=[C:23]([C:24]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:25]=3[CH:26]=[CH:27][N:28]4[CH2:33][C:34]([NH2:36])=[O:35])[N:22]=2)=[CH:7][C:6]=1[C:14]([F:16])([F:15])[F:17]
Reactant: CC(C)(Oc1ccc(C(=O)O)cc1C(F)(F)F)C(F)(F)F
Reactant: NC(=O)Cn1ccc2c(C(N)=NO)cccc21
Agent: CC(C)N=C=NC(C)C
Solvent: C1COCCO1
Product: CC(C)(Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
To a solution of 4-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-(trifluoromethyl)benzoic acid (118 mg) and 2-{4-[amino(hydroxyimino)methyl]-1H-indol-1-yl}acetamide (104 mg) in dioxane (5 ml) was added DIC (69 μl), followed by stirring at room temperature for 3 hours, and then heating under reflux for 20 hours. The reaction solution was concentrated, and then to the residue was added water (15 ml), followed by extraction with chloroform (15 ml). The organic layer was washed with a saturated aqueous NaHCO3 solution and saturated brine, dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: CAPCEL PAK, C18, MG, S-5, 30×50 mm; solvent: 50-90% acetonitrile/10 mM ammonium carbonate-ammonia (pH 9.2); 40 ml/min), and crystallized with diisopropyl ether to obtain 2-(4{5-[4-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (40 mg) as a white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:34])=[O:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:36].[K+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:34])(=[O:36])=[O:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CS(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (412 mg, 0.84 mmol) in methanol (46 mL) at 0° C. was added a solution of potassium permanganate (133 mg, 0.84 mmol) in water (23 mL) dropwise. After stirring for 2 h at 0° C., the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered through a short silical gel pad (QingDao silica gel, 200-300 mesh), and concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (370 mg, 87%): LC/MS m/e calcd for C26H25N3O4S2 [M+H]+ 508.63, observed 508.2.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([CH3:10])[CH:3]=1.[CH:11]([Sn](CCCC)(CCCC)CCCC)=[CH2:12].[F-].[K+]>C1(C)C=CC=CC=1.CCOC(C)=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>[CH3:10][C:4]1[CH:3]=[C:2]([CH:11]=[CH2:12])[CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: Cc1cc(Br)ccc1CO
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(CO)c(C)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 91.1 %

Procedure:
A solution of 4-bromo-2-methylbenzyl alcohol (M. I. Dawson, et al., J. Med. Chem. 1984, 27, 1516-1531; 0.81 g, 4.0 mmol) in toluene (10 mL) was charged successively with Pd(PPh3)4 (0.13 g, 0.11 mmol), BHT (few crystals, catalytic), and vinyltributyltin (1.3 mL, 4.4 mmol). The mixture was heated at 110° C. for 3.5 h, cooled, charged with aqueous KF and stirred for 12 h at RT. The mixture was diluted with EtOAc and the resultant white precipitate was removed via filtration. The organic phase was separated, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified via flash chromatography to afford 2-methyl-4-vinylbenzyl alcohol (0.54 g). A portion (0.27 g) of this product in methylene chloride (5 mL) was added to a precooled (−78° C.) mixture of oxalyl chloride (1.3 mL, 2.6 mmol) and DMSO (0.3 mL, 4.3 mmol) in methylene chloride (10 mL). The reactoin was charged with triethylamine (1.0 mL, 7.2 mmol) and stirred in the cold bath for 2 h, at which point the bath was at RT. The reaction was stirred for an additional hour at RT and then quenched with sat. NaHCO3. The mixture was extracted with EtOAc (2×), and the organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to afford pure 2-methyl-4-vinylbenzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5C(OCC5C=CC=CC=5)=O)=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[N:22][CH:23]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[N:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][NH:36]5)=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[N:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OCc5ccccc5)[nH]4)cc3)nc2)[nH]1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)nc2)[nH]1
Reaction time: 3 h
Yield: 56.4 %

Procedure:
A solution of (S)-2-[5-(2-{4-[2-((S)-1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (317.1 mg, 0.48 mmol) in MeOH (1 mL) was added to a stirred suspension of 10% palladium on carbon (60 mg) and K2CO3 (70 mg) in a solution of MeOH (5 mL) and H2O (0.1 mL) at room temperature under N2. The flask was charged and evacuated three times with H2 and stirred for 3 h at atmosphere pressure. Additional catalyst (20 mg) was then added and the reaction mixture was stirred further for 3 h before it was suction-filtered through diatomaceous earth (Celite®) and concentrated. The residue was diluted with MeOH, filtered through a PVDF syringe filter (13 mm×0.45 m), distributed into 4 pHPLC vials and chromatographed (gradient elution from 20% B to 100% B over 10 min on a Phenomenex-Gemini C18 column (30×100 mm, 10 μm) where A=95% water, 5% acetonitrile, 10 mM NH4OAc, B=10% water, 90% acetonitrile, 10 mM NH4OAc). After concentration of the selected test tubes by speed vacuum evaporation, there was isolated the title compound as a yellow solid (142.5 mg, 56% yield).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[C:10](O)[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3]1.BrC[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>CC#N.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[C:10]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(SC)c(O)cc2S(=O)(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(SC)c(C(=O)OCC)cc2S(=O)(=O)C1
Yield: 106.8 %

Procedure:
To a suspension of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 3; 12.85 g, 28.71 mmol) in MeCN (150 ml) was added ethyl bromoacetate (3.85 ml, 34.6 mmol), tetrabutylammonium bromide (0.925 g, 2.869 mmol) and sodium carbonate (12.85 g, 121.2 mmol). The mixture was heated under reflux for 5 hours. The solvent was removed under reduced pressure and the residue was partitioned between DCM and 0.5 M HCl. The organic layer was washed with brine, dried (MgSO4) and concentrated. Chromatography using DCM/EtOAc (9:1) as eluent gave the desired product (15.45 g) as a tan oil. NMR 0.70–0.85 (m, 6H), 1.00–1.55 (m, 15H), 2.15 (s, 3H), 3.10 (s, 2H), 3.70 (brs, 2H), 4.25 (q, 2H), 4.70 (s, 2H), 6.65 (s, 1H), 6.90-7.30 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH2:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH:19][S:30]([CH3:29])(=[O:32])=[O:31])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@H](N)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](NS(C)(=O)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 575.9 %

Procedure:
A solution of 39 (0.10 g, 0.26 mmol), methanesulfonyl chloride (0.08 mL, 1.03 mmol), NEt3 (0.04 mL, 0.28 mmol) and a catalytic amount of DMAP in CH2Cl2 (50 mL) was stirred at room temperature for 2 h. The mixture was washed with 2N HCl (30 mL), 2N NaOH (30 mL), and H2O (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a crude solid. The crude solid was purified by column chromatography (eluent: 2% MeOH/CH2Cl2) to afford 0.7 g (56%) of 42 as a white crystalline solid, mp 262-265° C. (EtOAc/n-hexanes); 1H NMR (CDCl3); δ 1.09 (3H, s); 1.46 (3H, s); 1.60 (3H, m); 1.79 (1H, dd, J=2.7, 9.6); 2.07 (2H, m); 2.18 (1H, m); 2.21 (1H, s); 2.50 (2H, m); 2.75 (1H, dd, J=3.6, 13.2); 2.99 (3H, s); 3.72 (3H, s); 4.15 (1H, m); 5.34 (1H, d, J=5.4); 5.55 (1H, dd, J=5.1, 11.4); 6.38 (1H, dd, J=0.9, 1.2); 7.41 (1H, dd, J=1.5, 1.8); 7.43 (1H, dd, J=0.9, 1.5).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Br:21])[NH:10]/[C:11]/2=[N:12]\[OH:13])[N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:30][CH2:31][C@H:32]1[CH2:36][O:35][C:34]([CH3:38])([CH3:37])[O:33]1>CN(C=O)C>[CH3:37][C:34]1([CH3:38])[O:33][C@@H:32]([CH2:31][CH2:30][O:13]/[N:12]=[C:11]2\[NH:10][C@@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Br:21])[CH2:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:22])[C:5]\2=3)[CH2:36][O:35]1
Reactant: CC1(C)OC[C@H](CCI)O1
Reactant: Cc1nc(N)nc2c1/C(=N/O)N[C@@H](c1ccc(F)cc1Br)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1/C(=N/OCC[C@H]1COC(C)(C)O1)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (85c, 9.2 mg, 0.025 mmol) in dry DMF (1 mL) was added Cs2CO3 (12.2 mg, 0.0375 mmol) and the reaction mixture stirred at ambient temperature for 30 minutes. Then, (S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (85d, 7.68 mg, 0.03 mmol) was added and the reaction mixture stirred overnight. LCMS showed complete consumption of the starting material. The reaction mixture was poured onto crushed ice and the resulting solid was filtered and rinsed with cold water. Drying afforded (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (7.8 mg, 63%) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 3H) 1.41 (s, 3H) 2.02 (qd, J=6.32, 3.03 Hz, 2H) 2.75 (s, 3H) 2.94 (dd, J=16.42, 8.84 Hz, 1H) 3.17 (dd, J=16.42, 4.55 Hz, 1H) 3.59 (dd, J=8.08, 7.07 Hz, 1H) 4.09 (dd, J=8.08, 6.06 Hz, 1H) 4.17-4.28 (m, 3H) 4.98 (ddd, J=8.72, 4.55, 1.64 Hz, 1H) 7.07 (td, J=8.27, 2.65 Hz, 1H) 7.34 (dd, J=8.08, 2.78 Hz, 1H) 7.43 (dd, J=8.72, 5.94 Hz, 1H). MS (ES) [M+H] calculated for C21H27BrFN5O3, 495.11. found 495.30.