Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8](#[N:11])[CH:9]=[CH2:10].[CH2:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]O.[C:22]1(C(C)C)[CH:27]=CC=[CH:24][CH:23]=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na].[Na].[Na].S([O-])[O-].C=O.[Na+].[Na+].C([O-])(=O)CCCCCCC/C=C\CCCCCCCC.[K+].[OH-].[Na+]>O>[C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8](#[N:11])[CH:9]=[CH2:10].[CH2:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:27]=[CH:22][CH:23]=[CH2:24]
Reactant: CC(C)c1ccccc1
Agent: C=C(C)C(=O)OC
Agent: C=O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Solvent: C=Cc1ccccc1
Solvent: O
Solvent: C=CC#N
Product: C=CC=C
Temperature: 71.11111111111111 °C
Reaction time: 1 h

Procedure:
To a mixture of 65.0 parts of the latex product of Example 1 and 178 parts of water at 140° F., there is added, separately and portionwise over a period of one hour, (1) a mixture of 17.5 parts of methyl methacrylate, 2.0 parts of acrylonitrile and 15.5 parts of styrene; (2) 0.275 part of 80% aqueous cumene hydroperoxide; and (3) a solution of 0.015 part of ferrous sulfate heptahydrate, 0.045 part of 48% aqueous trisodium ethylene diamine tetraacetic acid, and 0.15 part of sodium formaldehyde sulfoxylate in 1.50 parts of water. After 10 minutes of this one-hour period at 140° F., the temperature is raised to 160° F. and held there for the remaining 50 minutes and for an additional two hours. At the end of this period a solution of 2.0 parts of 15% aqueous potassium oleate and 0.45 part of sodium hydroxide in 30 parts of water is added. The polymerization mixture is agitated mildly throughout and then filtered through cheesecloth to yield 306 parts of latex (a graft copolymer of methyl methacrylate, acrylonitrile and styrene on a substrate copolymer of styrene and butadiene). Its pH is 10.3; total solids: 33.6%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:12][C:13]1[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[S:16][CH:17]=1>C(O)(C)C>[CH:18]([C:15]1[S:16][CH:17]=[C:13]([CH2:12][NH:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[N:14]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)c1nc(CCl)cs1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)c1nc(CNNC(=O)OC(C)(C)C)cs1

Procedure:
A solution of 7.5 g (57 mmol) to t-butylcarbazate in 200 ml of isopropyl alcohol was treated with a solution of 1.0 g (57 mmol) of 4-(chloromethyl)-2-isopropylthiazole hydrochloride in 10 ml of isopropyl alcohol. The resulting solution was heated at reflux for 16 h, allowed to cool, and concentrated in vacuo. The residue was diluted with 1N HCl, washed with three portions of ethyl acetate, basified to pH 12 with aqueous NaOH, and extracted with three portion of ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by silica gel chromatography using 20% ethyl acetate in hexane provided 0.32 g (21%) of the desired compound (Rf 0.4, 5% methanol in chloroform). 1H NMR (CDCl3) δ 1.40 (d, J=7 Hz, 6H), 1.47 (s, 9H), 2.53 (br, 1H), 3.33 (heptet, J=7 Hz, 1H), 4.11 (s, 2H), 6.22 (br, 1H), 7.01 (s, 1H). Mass spectrum: (M+H)+ =272.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([N:32]1[CH:36]=[C:35](CO)[C:34]([N+:39]([O-:41])=[O:40])=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([N:32]1[CH:36]=[C:35]([CH2:1][Br:5])[C:34]([N+:39]([O-:41])=[O:40])=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1nn(Cc2ccccc2)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1nn(Cc2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Carbon tetrabromide (3.67 g, 11.1 mmol) and triphenylphosphine (2.43 mL, 11.1 mmol) were added to a solution of C3 (1.29 g, 5.53 mmol) in dichloromethane (150 mL), and the reaction was allowed to stir at RT for 18 hours. After being washed with water, the reaction mixture was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 100% EtOAc in heptane) afforded C4 as a solid. Yield: 951 mg, 3.21 mmol, 58%. LCMS m/z 297.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 4.60 (d, J=0.6 Hz, 2H), 5.32 (s, 2H), 7.28-7.32 (m, 2H), 7.36-7.41 (m, 3H), 7.52 (br s, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Na].[Cl:11][C:12]1[C:22]([Cl:23])=[C:21]([C:24](=O)[CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:20]=[CH:19][C:13]=1[O:14][CH2:15][C:16]([OH:18])=[O:17]>C(O)C>[C:16]([CH2:15][O:14][C:13]1[CH:19]=[CH:20][C:21]([C:24]2[CH2:25][CH:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:2]([C:1]([O:7][CH2:8][CH3:9])=[O:6])[C:3](=[O:4])[CH:5]=2)=[C:22]([Cl:23])[C:12]=1[Cl:11])([OH:18])=[O:17]
Reactant: O=C(O)COc1ccc(C(=O)C=Cc2ccccc2)c(Cl)c1Cl
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C(=O)C=C(c2ccc(OCC(=O)O)c(Cl)c2Cl)CC1c1ccccc1

Procedure:
Ethyl acetoacetate (6.85 g, 0.0526M) was added at 70° to a solution of sodium (1.21 g, 0.0526M) dissolved in ethanol (150 ml). After a few minutes [2,3-dichloro-4-(3-phenyl-1-oxo-2-propenyl)phenoxy]acetic acid (8.7 g, 0.0248M) was added and the suspension was stirred at reflux for 3 hours, cooled and concentrated under vacuum. The residue was taken up in water, acidified with hydrochloric acid and extracted with methylene chloride. The organic extracts were washed with water dried over MgSO4 and concentrated. The residue was triturated with toluene and the solid that crystallized filtered. The crude product was taken up in butyl chloride and filtered. The filtrate was concentrated under vacuum and the residue recrystallized from toluene to give ethyl 4-[4-(carboxymethoxy)-2,3-dichlorophenyl]-2-oxo-6-phenyl-3-cyclohexene-1-carboxylate, m.p. 91° C.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[N:30](C)C)=[C:24]([N+]([O-])=O)[CH:23]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2]>CCO.CN(C=O)C>[CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:27]=[C:26]3[C:25]([CH:28]=[CH:29][NH:30]3)=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(/C=C/N(C)C)c([N+](=O)[O-])c3)nc3ccccc3c2=O)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(-n2c(-c3ccc4cc[nH]c4c3)nc3ccccc3c2=O)cc1
Yield: 8.5 %

Procedure:
A solution of (E)-3-(4-sec-butylphenyl)-2-(4-(2-(dimethylamino)vinyl)-3-nitrophenyl)quinazolin-4(3H)-one (0.565 g, 1.20 mmol) in a 3:1 mixture of EtOH/DMF (25 mL) was flushed with N2. Pd/C (0.060 g, 10 wt %) was added and flushed with H2 for 2.5 hours. After filtering through diatomaceous earth, the filtrate was concentrated. Purification was effected by flash chromatography on silica gel, eluting with 5% to 75% EtOAc in heptane, Further purification was effected by reverse-phase chromatography, eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The desired fractions were collected, basified, and extracted with CH2Cl2, to afford the title compound as a white solid (0.040 g, 8%). 1H-NMR (300 MHz, DMSO-d6): δ11.27 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.87-7.90 (m 1H), 7.75 (d, J=7.8 Hz, 1H), 7.56-7.59 (m, 1H), 7.50 (s, 1H), 7.37 (d, J=2.6 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 7.19-7.22 (m, 2H), 7.08-7.10 (m, 2H), 6.89-6.92 (m, 1H), 6.34 (s, 1H), 2.51-2.61 (m, 1H), 1.33-1.20 (m, 2H), 1.11 (d, J=6.9 Hz, 3H), 0.59 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 394 (M+H)+.
Reaction SMILES: C1([CH:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:8]1(=[O:16])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:7]1
Reactant: O=C1c2ccccc2CC1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C1CCc2ccccc21

Procedure:
Racemic 2-phenylindanone VI is the starting material for the process of the invention. As shown in Step B, indanone VI is directly converted to the methylated intermediate VII containing the (+) and (-) enantiomers by treating indanone VI with methyl halide and an aqueous base (e.g., 50% aqueous sodium hydroxide) in an organic solvent (e.g., toluene) in the presence of a chiral catalyst at a temperature, of about 15° C. The 2-methylated (+) and (-) enantiomer of intermediate VII can then be O -demethylated in the presence of a catalyst (A1C13) to obtain the optically active intermediate (+) and (-) enantiomer indanone mixture VIII which, in turn, can then be alkylated, hydrolyzed, and acidified to obtain the pure (+) and (-) enantiomers of indenyl-oxy acetic acid I at a yield of about 65-80%.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][O:6][N:7]=1.[CH2:14]([OH:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([O:18][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][O:6][N:7]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCO
Reactant: Clc1nonc1-c1cccnc1
Agent: [Na]
Product: CCCCOc1nonc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (150 mg, 6.5 mmol) in 1-butanol (5 ml) was added 3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (350 mg, 1.9 mmol). The mixture was stirred at 25° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:3]=1.[CH3:22][N:23]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:42]>>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]([C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:42])[N:23]([CH3:22])[CH:32]=2)=[N:3][C:4]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[N:5][CH:6]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CS(=O)(=O)Cc1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Product: Cn1cc(-c2nc(CS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2ccccc2c1=O

Procedure:
The title compound of Example 146, step 2 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.69-7.68 (m, 2H), 7.58-7.54 (m, 1H), 7.45-7.34 (m, 2H), 7.07-7.03 (m, 1H), 4.83 (s, 2H), 3.58 (s, 3H), 3.17 (s, 3H). LCMS: 458.1 (M+1)+
Reaction SMILES: Cl.[N:2]1([C:8]2[C:9]3[N:10]([N:19]=[N:20][N:21]=3)[C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][N:13]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C=O.[CH2:24](Cl)Cl.C([O-])(O)=O.[Na+]>CO>[CH3:24][N:5]1[CH2:4][CH2:3][N:2]([C:8]2[C:9]3[N:10]([N:19]=[N:20][N:21]=3)[C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][N:13]=2)[CH2:7][CH2:6]1
Reactant: c1csc(-c2cnc(N3CCNCC3)c3nnnn23)c1
Reactant: ClCCl
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CN1CCN(c2ncc(-c3cccs3)n3nnnc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A 2 L round bottom flask was charged with 8-(piperazin-1-yl)-5-(thiophen-2-yl)tetrazolo[1,5-a]pyrazine HCl salt (139 g, 0.429 mol), HCHO (38% aqueous solution, 50 mL), NaBH3(CN) (90.7 g, 1.44 mol), CH2Cl2 (500 mL), and MeOH (200 mL). The resulting solution was stirred at room temperature for 0.5 h. Work-up: the reaction mixture was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2 (500 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 1-10% MeOH in CH2Cl2, to afford 122 g (94%) of the product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.00 (m, 2H), 7.45 (dd, J=5.1, 1.2 Hz, 1H), 7.20 (dd, J=5.1, 3.6 Hz, 1H), 4.39 (br, 4H), 2.60 (t, J=5.1 Hz, 4H), 2.37 (s, 3H). MS m/z: 302 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([OH:30])=[CH:19][N:18]=3)=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([O:30][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:19][N:18]=3)=[N:9]2)=[CH:31][CH:32]=1
Reactant: COc1ccc(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c3ccccc32)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3ncc(OCC(F)(F)F)c(Nc4ccncc4)n3)c3ccccc32)cc1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
143 mg of 2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol (3-2, 0.337 mmol, 1. eq.) were dissolved in 500 μl of dry DMF. Then 117 mg of 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.505 mmol, 1.5 eq.), 93.1 mg of potassium carbonate (0.674 mmol, 2 eq.) and 24 μl of acetonitrile were added. The resulting mixture was stirred at 150° C. for 30 minutes in a microwave. Then the mixture was partitioned between water and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 7.7 mg (0.01 mmol, 3.9%) of the analytically pure target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[C:25]([CH3:26])=[CH:24][C:23]([N:27]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:22]3[C:18]=2[CH2:19][CH2:20][CH2:21]3)[OH:16])=[CH:11][C:10]=1[CH:42]([CH3:44])[CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:25]([CH3:26])=[CH:24][C:23]([N:27]([CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:22]3[C:18]=2[CH2:19][CH2:20][CH2:21]3)=[O:16])=[CH:11][C:10]=1[CH:42]([CH3:44])[CH3:43])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c2c(c1C(O)c1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c2c(c1C(=O)c1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Yield: 88 %

Procedure:
To a solution of (4-benzyloxy-3-isopropylphenyl)-(7-dibenzylamino-5-methylindan-4-yl)methanol (497 mg) in dichloromethane (10 mL) was added manganese (IV) oxide (2.98 g) at room temperature for 3 days. The insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure to dryness to give the title compound (436 mg).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[C:33]([CH2:41]Br)[CH:32]=2)[O:11][C@H:10]1[CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:52]#[N:53].[K+]>CCO.O>[CH2:24]([O:23][C@@H:13]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:10]([CH2:43][O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[O:11][C@H:12]1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]([CH2:41][C:52]#[N:53])[CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1cc([C@@H]2O[C@@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2ccccc2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2ccccc2c1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of the (2S,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(3-(bromomethyl)naphthalen-1-yl)-tetrahydro-2H-pyran in EtOH (80 mL) and water (40 mL) was added potassium cyanide (4.24 g, 65.1 mmol). The reaction mixture was refluxed overnight. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The crude residue was purified by column chromatography to yield 2-(4-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxy-methyl)-tetrahydro-2H-pyran-2-yl)naphthalen-2-yl)acetonitrile (10.9 g, 46%) as a white solid.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].C(C(C([O-])=O)C([O-])=O)C.[K+].[K+].[Br:15][C:16]1[C:17]([O:27][CH3:28])=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22].Cl.[C:30]([O:33][CH2:34][CH3:35])(=[O:32])[CH3:31]>O1CCCC1.C(N(CC)CC)C>[Br:15][C:16]1[C:17]([O:27][CH3:28])=[CH:18][C:19]([O:25][CH3:26])=[C:20]([C:21](=[O:22])[CH2:31][C:30]([O:33][CH2:34][CH3:35])=[O:32])[CH:24]=1
Reactant: COc1cc(OC)c(C(=O)Cl)cc1Br
Reactant: CCOC(C)=O
Agent: CCC(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cc(Br)c(OC)cc1OC
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a suspension of anhydrous magnesium chloride (36.5 g) and ethyl acetate (200 mL) was slowly added dropwise tetrahydrofuran (55.2 g). After completion of the dropwise addition, the mixture was stirred at 75° C. for 2 hr to dissolve anhydrous magnesium chloride. The solution was added dropwise to an ice-cold suspension of potassium ethylmalonate (52.1 g) and triethylamine (46.5 g) in ethyl acetate (200 mL). After the dropwise addition, the suspension was warmed to 70° C. To the suspension was slowly added dropwise at 70° C. a suspension of 5-bromo-2,4-dimethoxybenzoic acid chloride obtained in Step 2 of Example 1 in tetrahydrofuran. After completion of the dropwise addition, the mixture was stirred at 70° C. for 0.5 hr, and the completion of the reaction was confirmed by HPLC. 2N Hydrochloric acid (240 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The organic layer was separated, and washed successively with water (200 mL), twice with 5% sodium hydrogencarbonate (200 mL), and water (200 mL). After washing, the solvent was evaporated under reduced pressure, toluene (200 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. The obtained ethyl 3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropionate (52.8 g) as a white solid was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]([NH2:5])([CH3:4])[CH3:3].[H-].[Na+].Cl[C:9]1[N:14]=[C:13]([C:15]2[CH:27]=[CH:26][C:18]3[N:19]=[C:20]([NH:22][C:23](=[O:25])[CH3:24])[S:21][C:17]=3[CH:16]=2)[CH:12]=[N:11][CH:10]=1.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>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]([NH:5][C:9]1[N:14]=[C:13]([C:15]2[CH:27]=[CH:26][C:18]3[N:19]=[C:20]([NH:22][C:23](=[O:25])[CH3:24])[S:21][C:17]=3[CH:16]=2)[CH:12]=[N:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(=O)Nc1nc2ccc(-c3cncc(Cl)n3)cc2s1
Reactant: CC(C)(C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(-c3cncc(NC(C)(C)C)n3)cc2s1
Reaction time: 0.25 h

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 2-methylpropan-2-amine (0.100 g, 2 mmol) in DMF (3 ml). Then sodium hydride (0.047 g, 2.0 mmol) was added into the mixture and allowed to stir an additional 15 minutes. Then N-(6-(6-chloropyrazin-2-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.30 mmol), palladium(II) acetate (0.007 g, 0.03 mmol) and Xantphos (0.010 g) was added to the mixture. The vial was capped and placed into a CEM Microwave for 10 minutes at 100° C., while 100 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired product in the mixture. The mixture was placed into a round-bottom flask, then diluted with ethyl acetate (20 ml) and stirred 20 minutes. The precipitate was collected by filtration and then purified by reverse-phase HPLC. This gave N-(6-(6-(tert-butylamino)pyrazin-2-yl)benzo[d]thiazol-2-yl)acetamide (0.005 g, 4% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 342 (MH+). Calc'd exact mass for C17H19N5OS: 341. 1H NMR 400 MHz, DMSO-d6): 1.49 (s, 9H), 2.09 (s, 3H), 6.80 (s, 1H), 7.62 (d, J=8.03 Hz, 1H), 7.82 (s, 1H), 7.98 (d, J=8.03 Hz, 1H), 8.24 (s, 1H), 8.43 (s, 1H).
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.Br[CH2:38][C:39]1[CH:40]=[CH:41][C:42]2[S:46][C:45]([CH3:47])=[N:44][C:43]=2[CH:48]=1>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][CH2:38][C:39]5[CH:40]=[CH:41][C:42]6[S:46][C:45]([CH3:47])=[N:44][C:43]=6[CH:48]=5)[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: Cc1nc2cc(CBr)ccc2s1
Product: Cc1nc2cc(COC(C)c3ccc([C@H]4C[C@@]5(C)[C@@H](CC[C@@]5(O)C(F)(F)C(F)(F)F)[C@@H]5CCC6=CC(=O)CCC6=C54)cc3)ccc2s1
Yield: 24 %

Procedure:
In analogy to Example 2, 500 mg (0.98 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using 5-bromomethyl-2-methylbenzothiazole and, after workup and purification, 157 mg (24%) of the title compound were isolated as a colourless foam.
Reaction SMILES: C(NC(C1SC(N2C(O)CN(CC3C=CC(F)=CC=3)C2=O)=NC=1C)=O)C1C=CC=CC=1.[F:32][C:33]1[CH:62]=[CH:61][C:36]([CH2:37][N:38]2[CH2:42][CH:41](O)[N:40]([C:44]3[S:45][C:46]([C:50]([NH:52][CH2:53][C:54]4[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=4)=[O:51])=[C:47]([CH3:49])[N:48]=3)[C:39]2=[O:60])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:38]2[CH:42]=[CH:41][N:40]([C:44]3[S:45][C:46]([C:50]([NH:52][CH2:53][C:54]4[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=4)=[O:51])=[C:47]([CH3:49])[N:48]=3)[C:39]2=[O:60])=[CH:61][CH:62]=1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1cccnc1
Agent: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 81 %

Procedure:
Following the procedure as described in Example 17, making variations as required to replace N-benzyl-2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide with 2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 81% yield: mp 158-159° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=1.5 Hz, 1H), 8.49 (dd, J=4.5, 1.5 Hz, 1H), 7.69-7.65 (m, 1H), 7.26-7.16 (m, 4H), 7.04-6.97 (m, 2H), 6.47 (t, J=5.7 Hz, 1H), 6.29 (d, J=3.3 Hz, 1H), 4.78 (s, 2H), 4.58 (d, J=5.7 Hz, 2H), 2.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 162.2, 153.5, 150.5, 149.2, 149.0, 135.6, 133.7, 131.3, 129.8, 123.6, 119.5, 116.1, 115.8, 113.1, 107.6, 46.7, 41.5, 17.2; MS (ES+) m/z 424.3 (M+1).