Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)=[O:4].Cl[C:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>>[C:15]1([C:14]2([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:11][C:8]3[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][CH3:1])=[CH:6][C:7]=3[O:12]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCC(=O)c1ccc(O)c(O)c1
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCC(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 170 °C

Procedure:
A mixture of 3,4-dihydroxypropiophenone (ICN Biomedicals, Inc., 3300 Hyland Ave., Costa Mesa, Calif., 92626, USA, 5.0 g, 30 mmol) and dichlorodiphenylmethane (10.0 mL, 52.1 mmol) was heated for 7 min at 170° C. The reaction was cooled and poured into 1 N sodium hydroxide. The mixture was extracted with ether (2×) and the combined extracts were washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (2×5 inches packed in hexane) with elution proceeding as follows: 2% ether/hexane (500 mL), 0.84 g of a white solid tentatively identified as 2-chloro-1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-propan-1-one; 5% ether/hexane (250 mL), 1.9 g of an unidentified orange oil; 5% ether/hexane (250 mL), 2.18 g of recovered dichlorodiphenylmethane; 10% ether/hexane (500 mL), 4.82 g (48%) of 1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-propan-1-one as an orange oil which solidified on standing. The product had: mp 69-70.5° C. Analysis calculated for C22H17CIO3: C, 79.98; H, 5.49. Found: C, 80.05; H, 5.34.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].ICC[OH:14]>>[C:1]([OH:9])(=[O:14])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: OCCI
Reactant: CCCC(CCC)C(=O)Cl
Product: CCCC(CCC)C(=O)O
Temperature: 100 °C
Yield: 138.7 %

Procedure:
To the product of Example 21 (4.87 g, 30 mmol), 2-iodoethanol (5.16 g, 30 mmol) was added with stirring and cooling in an ice bath. The neat mixture was then heated to 100° C. in a water bath for 10 minutes, then removed from the heat and stirred for an additional 10 minutes. The reaction mixture was then dissolved in 50 mL of ether, washed with water (1×30 mL), 5% NaOH (2×30 mL), and again with water (2×30 mL). The ether layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. A light yellow liquid product was obtained in 67% yield from valproic acid (6.0 g). Silver nitrate gave a bright yellow precipitate. NMR analysis confirmed the identity of the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1)=[O:4].CCOCC.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1>[OH:12][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 0.2 h

Procedure:
25.2 g (154 mmol) of methyl terephthalaldehydate was dissolved in 200 ml of tetrahydrofuran. 51.2 ml(154 mmol) of a 2M ether solution of phenyl magnesium bromide was added dropwise thereto under cooling in a sodium chloride-ice bath with stirring for 12 minutes and the mixture was stirred for further 20 minutes. Dilute hydrochloric acid was added to the resulting reaction mixture, then the obtained mixture was extracted twice with ethyl acetate. After the organic phase was washed with brine and dried (MgSO4), the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1 (v/v)) to obtain 31.7 g (131 mmol) of methyl α-hydroxy-α-phenyl-p-toluate as a pale yellow oily substance. Its spectroscopic data are as follows:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[N:18]=[N:17][C:16]([C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)=[N:15]2)=[CH:11][CH:10]=1.[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43]Br)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]>O1CCCC1.CN(C)C=O>[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43][O:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:16]4[N:17]=[N:18][N:14]([CH2:13][C:12]5[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:27][CH:26]=5)[N:15]=4)[CH:20]=3)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]
Reactant: COc1ccc(Cn2nnc(-c3cccc(O)c3)n2)cc1
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cccc(-c4nnn(Cc5ccc(OC)cc5)n4)c3)csc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of cesium carbonate (0.60 g, 1.83 mmol), 3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenol (0.38 g, 1.35 mmol) (from Example 26 supra) in tetrahydrofuran-N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70° C. for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.41 g, 1.22 mmol) (from Example 1 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 4-chloro-3-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.17 g, 26%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][NH:21][C:22]2=[O:28].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:27][C:26]1[C:17]([NH:16][C:2]2[C:7]([C:8]3[CH:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:28])[NH:21][CH:20]=[CH:19]2
Reactant: CNc1cc(-c2cccnc2Cl)ncn1
Reactant: Cc1ccc2c(=O)[nH]ccc2c1N
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(=O)[nH]ccc23)ncn1
Temperature: 150 °C
Yield: 25.9 %

Procedure:
6-(2-chloropyridin-3-yl)-N-methylpyrimidin-4-amine (897 mg, 4.1 mmol), 5-amino-6-methylisoquinolin-1(2H)-one (779 mg, 4.5 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (128 mg, 0.33 mmol) and tris(dibenzylideneacetone)dipalladium (0) (149 mg, 0.16 mmol) were added to a microwave tube. The tube was capped and flushed with nitrogen, and then lithium bis(trimethylsilyl)amide (16.9 mL, 1.0 M solution in THF) was added. The mixture was heated in a microwave reactor at 150° C. for 15 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate then extracted with DCM. The DCM extracts were conccentrated and purified by flash chromatography (0-10% 2 M ammonia in methanol) to give the title compound (380 mg, 26%). MS (M+H)+ 359.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH2:22][C@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:24]([OH:26])=[O:25])[CH:18]=[CH:19][C:20]=1[OH:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:14][C:15]1[CH:16]=[C:17]([CH2:22][C@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:24]([O:26][CH2:13][CH:11]([OH:12])[CH2:10][O:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[O:25])[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: O=C(OCC1CO1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)OCC(O)COC(=O)c1ccccc1
Yield: 25.7 %

Procedure:
A solution of oxiran-2-ylmethyl benzoate (3.0 g, 16.8 mmol), (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoic acid (6.0 g, 20.2 mmol), and tetrabutylammonium bromide (542 mg, 1.7 mmol) in anhydrous toluene was heated to 90° C. for 18 hrs. The reaction mixture was concentrated to dryness under reduced pressure, diluted with ethyl acetate, and washed with water twice followed by the addition of a saturated NaHCO3 solution and brine. The organic layer was dried through MgSO4 and concentrated under reduced pressure. Chromatography (silica gel, 1:1 ethyl acetate/hexane) of the residue afforded 2.05 g (26%) of 2-Hydroxy-3-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH:19]1([C:22]2[C:23]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[C:23]([N:31]3[CH2:32][CH2:33][N:34]([C:11]([C:10]4[CH:9]=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:35][CH2:36]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: O=C(c1ccc(N2CCCS2(=O)=O)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 66.9 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (300 mg) described in Preparation Example 25 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (297 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Example 109, the title compound (347 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[Br:7].[CH3:8][S:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Br:7][C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: BrC1=C(Br)CCC1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ccc(C2=C(Br)CCC2)cc1
Yield: 32.6 %

Procedure:
Under nitrogen, 36.4 g (161 mmol) of 1,2-dibromocyclopentene (Aldrich) was reacted with 18.0 g (107 mmol) of 4-methylthiophenylboronic acid (Step 1) in 550 mL of toluene, 365 mL of ethanol, and 235 mL of 2M Na2CO3 in the presence of 6.0 g (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (MgSO4), and reconcentrated. Purification by silica gel chromatography (Waters Prep-500) with hexane gave 9.39 g (22%) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (38 in Synthetic Scheme X when R5 =SCH3 and R1, R2, R3, R4, R6, and R7 =H) as a solid: mp 52°-54° C.; NMR (CDCl3) d 1.98-2.09 (m, 2H) , 2.50 (s, 3H) , 2.70-2.78 (m, 2H) , 2.80-2.89 (m, 2H), 7.24 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([OH:47])=O)([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[CH2:52]([OH:59])[C:53]([NH2:58])([CH2:56][OH:57])[CH2:54][OH:55].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:47])[NH:58][C:53]([CH2:56][OH:57])([CH2:54][OH:55])[CH2:52][OH:59])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:50])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(CO)(CO)CO
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NC(CO)(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and tris(hydroxymethyl)aminomethane instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine, respectively.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[C:18](Cl)=[N:19][CH:20]=1>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[N:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a suspension of sodium hydride (5.08 g, 127 mmol) in N,N-dimethylformamide (75 mL) was added diethyl malonate (19.26 mL, 127 mmol) at 0° C. The solution was then stirred at ambient temperature for 30 minutes and a solution of 5-bromo-2-chloro-3-nitropyridine (30 g, 127 mmol) in N,N-dimethylformamide (75 mL) was added dropwise. The dark brown mixture was then stirred at 100° C. for 2 hours before being cooled to ambient temperature and quenched with a saturated solution of ammonium chloride (500 mL) at 0° C. The mixture was extracted with ethyl acetate (3×500 mL) and the combined organics were dried over magnesium sulfate and filtered. The solvent was removed in vacuo to give a dark brown oil which was purified by flash column chromatography (10% ethyl acetate/hexane) to afford diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate as a brown solid (31.8 g, 69%). 1HNMR (400 MHz, CDCl3, δ): 8.86 (s, 1H), 8.61 (s, 1H), 5.44 (s, 1H), 4.29 (q, 4H), 1.27 (t, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:9])=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:15]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:9])=[CH:4][N+:3]=1[O-:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCc1ccc(Cl)nc1
Solvent: ClCCl
Product: [O-][n+]1cc(CCl)ccc1Cl
Temperature: 25 °C
Reaction time: 168 h
Yield: 90 %

Procedure:
To an icecold solution of 2-chloro-5-(chloromethyl)-pyridine (5 g, 29.6 mmol) in DCM (130 mL) was added dropwise a solution of 3-chlorobenzo-peroxoic acid (10.23 g, 59.3 mmol) in DCM (80 mL). The resulting solution was warmed to RT and stirred for 7 d till all starting material was consumed as judged by TLC. After this the reaction mixture was carefully treated with a saturated K2CO3 solution. The resulting precipitate was removed by filtration and the organic layer was washed with a saturated K2CO3 solution and brine. The organic layer was dried, filtered, and evaporated yielding the titled compound as an oil which slowly crystallizes (5.3 g, 90% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]3[CH2:19][C@@H:14]2[C:15]3([CH3:21])[CH3:20])(=O)=O)=CC=1.[C-:22]#[N:23].[K+]>CS(C)=O.[Cl-].[Na+].O>[CH3:21][C:15]1([CH3:20])[C@H:14]2[CH2:19][C@@H:16]1[CH2:17][CH2:18][C@@H:13]2[CH2:12][C:22]#[N:23]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)[C@H]2CC[C@H](CC#N)[C@@H]1C2
Temperature: 70 °C

Procedure:
To a solution of Example 21A (13.6 g, 44.2 mmol) in DMSO (100 mL) was added potassium cyanide (11.5 g, 177 mmol). The reaction was heated at 70° C. for 48 h. The mixture was diluted with brine and extracted with ether (3×75 mL). The organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on SiO2 (Hexanes/ethyl acetate, gradient 0 to 50%) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and methanesulfonyl chloride as starting materials in 43% yield. LCMS for C25H29ClN7O3S (M+H)+: m/z=542.2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].O.[N-:17]=[N+:18]=[N-].[Na+]>C(O)(C(F)(F)F)=O>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc2ccncc2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc2ccncc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
To a solution of 7-aminoisoquinoline (7.0 g) in TFA (35 mL) at 0° C. was added sodium nitrite (4.02 g) portionwise over a period of 30 minutes. The reaction was stirred at 0° C. to room temperature for 1.5 h. Water (3.5 mL) was added followed by portionwise addition of sodium azide (3.48 g) at 0° C. over a period of 30 minutes. After the addition, the reaction was slowly warmed up to room temperature and stirred for 1 h. Two third of TFA was evaporated and the residue was cooled to 0° C. Sodium bicarbonate (sat. in water) was added dropwisely to the residue until the pH was about 8-9. After extraction with methylene chloride (4×60 mL), the organic phase was combined, washed with water, brine, dried over sodium sulfate, filtered and concentrated to leave 7-azidoisoquinoline (7.5 g) as a dark brown solid. CI mass spectrum z (rel. intensity) 171 (M+H, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CS(O[CH2:27][CH2:28][C@H:29]([F:34])[CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:34][C@H:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH2:27][O:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Oc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Reactant: CCCC[C@@H](F)CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC[C@@H](F)CCOc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
A mixture of 1.12 g of 5-hydroxy-2-(4-benzyloxyphenyl)pyrimidine, 1.30 g of 3-(R)-fluoroheptyl methanesulfonate, 1.2 g of potassium carbonate, and 50 ml of DMF was stirred at 80° C. for 4 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and distilled to remove the solvent to obtain a residue weighing 2.12 g. Recrystallization of the residue from ethanol furnished 1.41 g (percent yield: 87.7%) of 5-[3-(R)-fluoroheptyloxy]-2-(4-benzyloxyphenyl)pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([O:25]CC2C=CC(OC)=CC=2)=[O:24])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:35][CH:36]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)c2ccc(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)cc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(C(=O)O)cc1

Procedure:
4-Methoxybenzyl 4-(N-benzyloxycarbonyl-L-valyloxy)benzoate was de-esterified by the method described in Example A-I-1, step c. The title compound (1.86 g) was obtained after silica gel column chromatography (2, 10, 20% ethanol in dichloromethane). Rf (2%MeOH/CHCl3) 0.20. The compound can be activated and esterifed directly to a drug or further modified as described below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:16][O:13][C:12]([C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C1(c2ccc(OC)cc2)CC1
Yield: 1980.2 %

Procedure:
To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (50.0 g, 0.26 mol) in MeOH (500 mL) was added toluene-4-sulfonic acid monohydrate (2.5 g, 13.1 mmol) at room temperature. The reaction mixture was heated at reflux for 20 hours. MeOH was removed by evaporation under vacuum and EtOAc (200 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (100 mL) and brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (53.5 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 7.25-7.27 (m, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.80 (s, 3H), 3.62 (s, 3H), 1.58 (q, J=3.6 Hz, 2H), 1.15 (q, J=3.6 Hz, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][NH2:20])[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:43][C:44]1[C:45]([C:50](O)=[O:51])=[N:46][CH:47]=[CH:48][CH:49]=1>CC(C)=O.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][NH:20][C:50](=[O:51])[C:45]4[C:44]([CH3:43])=[CH:49][CH:48]=[CH:47][N:46]=4)[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: Cc1cccnc1C(=O)O
Reactant: COc1ccc(-c2nc(CN)co2)cc1OCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OCC1CC1

Procedure:
A 0.2 g quantity of the [2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]methylamine obtained in Reference Example 13 was suspended in 4 ml of acetone. To the obtained suspension were added 0.2 g of 1-hydroxybenzotriazole, 0.29 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.14 g of 3-methylpicolinic acid, and the mixture was heated and refluxed for 30 minutes. The reaction mixture was cooled, water was then added thereto, and extraction was performed with ethyl acetate. The organic layer was washed with water twice, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 0.16 g of white powdery N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.