Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].C(Cl)(Cl)(Cl)Cl.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N+:31]([O-:33])=[O:32])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24]>C(O)C.C1(C)C=CC=CC=1.O1CCCC1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([N+:31]([O-:33])=[O:32])[C:28]=1[O:29][CH3:30])[C:23]([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14])=[O:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1

Procedure:
4.9 g of magnesium are suspended in 15 ml of absolute ethanol and, after adding 1 ml of carbon tetra-chloride, warmed until the reaction starts. A solution of 31.8 g of diethyl malonate in 19.9 ml of absolute ethanol and 80 ml of absolute toluene is then added dropwise while stirring so that the temperature lies between 50° and 60°. The reaction mixture is subsequently stirred at this temperature for an additional 1 hour, whereupon it is cooled to -5° and a solution of 49.3 g of 3,4-dimethoxy-5-nitrobenzoyl chloride (m.p. 82°-85°) in 300 ml of absolute toluene and 50 ml of absolute tetrahydrofuran is added dropwise so that the temperature does not exceed -5°. The mixture is subsequently stirred at room temperature overnight. After distillation of the solvent the residue is dissolved in 500 ml of ethyl acetate. The solution is treated while stirring and cooling with ice with an ice-cold solution of 12 ml of concentrated sulfuric acid in 80 ml of water. The organic phase is washed with sodium chloride solution, dried over magnesium sulfate and evaporated. The oil obtained is chromatographed on a ten-fold amount of silica gel with methylene chloride. The crystalline material obtained is recrystallized from isopropyl ether. There is obtained diethyl 3,4-dimethoxy-5-nitrobenzoylmalonate in the form of pale beige crystals of m.p. 70°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:28])[C:6]=2[CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2cc(Br)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
330 mg of 6-bromo-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of dichloromethane at room temperature and 280 mg of m-chloroperbenzoic acid were added. After stirring at room temperature for 3 days the mixture was washed with sodium bisulphite solution, then with sodium bicarbonate solution and finally with water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 4% (v/v) methanol/ethyl acetate for the elution to give 250 mg of 2-(6-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide as a foam. NMR (300 MHz, CDCl3): 8.35-8.30 (1H, m), 7.26-7.15 (3H, m), 7.13-7.05 (1H, m), 6.95 (1H, broad s), 6.75 (1H, d, 9Hz), 5.28 (1H, broad s), 2.42 (1H, dd, 13Hz, 6Hz), 1.7 (1H, broad s), 1.42 (3H, s), 1.37 (3H, s). MS (EI): 335 (M+ [Br81 ], 333 (H+ [Br79 ]), 318 (M+ [Br81 ]-OH), 316 (M+ [Br79 ]-OH)
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CC[CH2:39][CH2:38]1.C(I)C>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][C:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])([CH2:38][CH3:39])[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CCC(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCI
Product: CCC(CC)(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
5-(2-Benzyloxycarbonylbutyl)thiophene-2-carboxylic acid tert-butyl ester (29.5 g, 78.8 mmol) was dissolved in tetrahydrofuran (200 mL), 1.09 M lithium bis(trimethylsilyl)azanide/tetrahydrofuran solution (94 mL, 102 mmol) was added dropwise at −78° C., and the mixture was stirred for 2 hours. To the reaction mixture was added ethyl iodide (12.3 g, 156 mmol) at −78° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was added to ethyl acetate and 0.5 N-hydrochloric acid solution, the organic layer was extracted, and the aqueous layer was extracted two times with ethyl acetate. The organic layers were collected, washed with sodium thiosulfate solution and brine, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (24.9 g, 61.9 mmol, 78%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH2:28][OH:29])[CH:7]=2)[CH2:3][CH2:2]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]O.Cl>ClCCl.O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][O:29][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CO)c2c1
Reactant: CN(C)CCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(COCCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of the product of step i) (130 mg) in dichloromethane (5 mL) was treated with (−/+)-10-camphorsulfonic acid (680 mg) and N,N-dimethylethanolamine (0.32 mL) and stirred at room temperature for 17 hours. 4N Hydrogen chloride in 1,4-dioxane (0.85 mL) was added and the reaction was stirred at room temperature for 6 hrs. Additional N,N-dimethylethanolamine (0.33 mL), (−/+)-10-camphorsulfonic acid (680 mg) and 4N hydrogen chloride in 1,4-dioxane (0.9 mL) were added and the reaction was stirred at room temperature for 60 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate (100 mL) solution. The organics were evaporated in vacuo, and the crude product was purified by HPLC to yield the title compound as a solid (25.0 mg).
Reaction SMILES: C([Mg]Cl)(C)C.[Si:6]([O:13][CH2:14][C:15]([N:18]1[C:22]2[N:23]=[C:24]([Cl:27])[N:25]=[CH:26][C:21]=2[C:20](I)=[CH:19]1)([CH3:17])[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:29]1([C:35](=[N:42][C:43]2[CH:44]=[N:45][CH:46]=[C:47]([CH:54]=2)[C:48](N(OC)C)=[O:49])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[Si:6]([O:13][CH2:14][C:15]([N:18]1[C:22]2[N:23]=[C:24]([Cl:27])[N:25]=[CH:26][C:21]=2[C:20]([C:48]([C:47]2[CH:46]=[N:45][CH:44]=[C:43]([N:42]=[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:54]=2)=[O:49])=[CH:19]1)([CH3:17])[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnc(Cl)nc21
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cnc(Cl)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Isopropyl magnesium chloride (105 mL, 210 mmol, 2.0 M in THF) was added to 7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (89.0 g, 190 mmol) (see Preparation 44) in THF (450 mL) at 0° C., under nitrogen. The mixture was stirred at 0° C. for 1 hour then a solution of 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (72.6 g, 210 mmol) (see Preparation 23) in THF (200 mL) was added dropwise at 0° C. The mixture was warmed to room temperature and stirred at this temperature for 16 hours. The reaction mixture was quenched with 10% aqueous ammonium chloride (500 mL) and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine (400 mL), dried over sodium sulfate, evaporated in vacuo and the crude material was purified by column chromatography on silica gel (gradient of heptane:EtOAc 100:0 to 60:40) to afford the title compound as a colourless gum in 66% yield, 78.9 g.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:8][NH:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[C:18]([CH:21]=O)[CH:19]=[CH:20][C:14]=2[CH:13]=1)=[O:11])[CH3:7])[CH:2]([CH3:4])[CH3:3].[CH:23]1([O:28][C:29](=[O:48])[C@@H:30]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][NH2:47])=[CH:42][CH:41]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(O)(=O)C>[CH:23]1([O:28][C:29](=[O:48])[C@@H:30]([NH:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][NH:47][CH2:21][C:18]3[CH:19]=[CH:20][C:14]4[CH:13]=[C:12]([C:10](=[O:11])[NH:9][O:8][CH:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH3:7])[S:16][C:15]=4[CH:17]=3)=[CH:44][CH:45]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(C=O)cc2s1
Reactant: NCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)OC2CCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)COC(C)ONC(=O)c1cc2ccc(CNCc3ccc(CN[C@@H](Cc4ccccc4)C(=O)OC4CCCC4)cc3)cc2s1
Reaction time: 3 h
Yield: 17.9 %

Procedure:
6-formyl-benzo[b]thiophene-2-carboxylic acid (1-isobutoxy-ethoxy) amide (Scheme 7) (220 mg, 0.68 mmol) and (S)-2-(4-Aminomethyl-benzylamino)-3-phenyl-propionic acid cyclopentyl ester (263 mg, 0.75 mmol) were dissolved in DCE (10 mL) under an atmosphere of N2. Sodium triacetoxyborohydride (430 mg, 2.04 mmol) and acetic acid (50 μL) were added and the reaction stirred at r.t for 3 h. Sodium hydrogen carbonate (20 mL) was added and the reaction mixture extracted with dichloromethane (3×50 mL). The organic layers were combined and concentrated. The residue was purified by column chromatography (50%-100% EtOAc/heptane) to give the protected compound (80 mg, 21%). m/z 658 [M++H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CO.C(Cl)Cl.CCN(CC)CC>[N:19]1([NH:18][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: NN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CCOCC1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.4 %

Procedure:
A mixture of 4-benzyloxybenzoic acid (0.5 g, 2.19 mmol), 4-aminomorpholine (0.2 mL, 2.13 mmol), Et3N (0.316 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.671 g, 3.5 mmol) and 1-hydroxybenzotriazole hydrate (0.5 g, 3.7 mmol) in N,N-dimethylformamide (17 mL) was stirred at room temperature for 2 days. The reaction was concentrated and diluted in dichloromethane. The organic phase was washed twice with water, dried with MgSO4 and concentrated. The residue was purified on column chromatography (silica gel, 5% MeOH in CH2Cl2) and N-(4-morpholinyl)-4-(phenylmethoxy)-benzamide (0.615 g, yield: 90%) was identified by NMR spectroscopy.
Reaction SMILES: CC([N:5]([C@@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH2:30][CH3:31])[CH:23]=2)=[N:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][C@H:9]([CH2:10][CH3:11])[C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH2:30][CH3:31])[CH:23]=2)=[N:19][CH:20]=1)=[O:13]
Reactant: CCOc1cc(Oc2ncc(NC(=O)[C@@H](CC)N(C(=O)[O-])C(C)(C)C)cn2)ccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(Oc2ncc(NC(=O)[C@H](N)CC)cn2)ccc1C
Temperature: 0 °C
Yield: 105.6 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-1-{[(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)amino]carbonyl}propyl)carbamate (Intermediate 93, 80 mg) in dichloromethane (1 mL) cooled to 0° C., TFA (573 μl, 7.43 mmol) was added dropwise. The mixture reaction was stirred at 0° C. for 1.5. The solvent and the TFA were evaporated. The mixture was diluted with dichloromethane and an aqueous saturated solution of NaHCO3. The organic layer was separated, dried over sodium sulphate, filtered end evaporated to afford the title compound (65 mg) which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]1[NH:6][NH:5][C:4](=[O:7])[C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1.[CH3:21][C:22]1[NH:26][N:25]=[C:24]([O:27][C@@H:28]2[O:36][C@H:35]([CH:37]([C:39](=[O:41])[CH3:40])[OH:38])[C@@:33]([C:42](=[O:44])[CH3:43])([OH:34])[C@:31]([C:45](=[O:47])[CH3:46])([OH:32])[C@@:29]2([C:48](=[O:50])[CH3:49])[OH:30])[C:23]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)=[CH:54][CH:53]=1>>[CH3:21][C:22]1[NH:26][N:25]=[C:24]([O:27][C@@H:28]2[O:36][C@H:35]([CH:37]([C:39](=[O:41])[CH3:40])[OH:38])[C@@:33]([C:42](=[O:44])[CH3:43])([OH:34])[C@:31]([C:45](=[O:47])[CH3:46])([OH:32])[C@@:29]2([C:48](=[O:50])[CH3:49])[OH:30])[C:23]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)=[CH:54][CH:53]=1.[C@@H:28]1([O:7][C:4]2[C:3]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:11][CH:10]=3)=[C:2]([CH3:1])[NH:6][N:5]=2)[O:36][C@H:35]([CH2:37][OH:38])[C@@H:33]([OH:34])[C@H:31]([OH:32])[C@H:29]1[OH:30]
Reactant: Cc1[nH][nH]c(=O)c1Cc1ccc(-c2ccccn2)cc1
Agent: CC(=O)C(O)[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(-c3ccccn3)cc2)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@]1(O)C(C)=O
Product: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(-c2ccccn2)cc1

Procedure:
5-Methyl-4-{[4-(pyridin-2-yl)phenyl]methyl}-3-(2,3,4,6-tetraacetyl-β-D-glucopyranosyloxy)-1H-pyrazole was prepared in a similar manner to that described in Example 4 using 5-methyl-4-{[4-(pyridin-2-yl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-one instead of 5-methyl-4-[(4-cyclopropylphenyl)methyl]-1,2-dihydro-3H-pyrazol-3-one. Then the title compound was prepared in a similar manner to that described in Example 21 using 5-methyl-4-{[4-(pyridin-2-yl)phenyl]methyl}-3-(2,3,4,6-tetraacetyl-β-D-glucopyranosyloxy)-1H-pyrazole instead of 5-methyl-4-[(4-cyclopropylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17][C:18]([O:20]CC)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[OH-].[K+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24]
Reactant: CCOC(=O)C=CC=CC=CC=Cc1c(C)cc(OC)c(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C)c(C=CC=CC=CC=CC(=O)O)c(C)c1C
Reaction time: 18 h
Yield: 14.1 %

Procedure:
A solution of 6.1 g (0.019 mol) of the ethyl ester of Example 1 was dissolved in 15 mL of ethanol and a solution of KOH (1.6 g, 0.028 mol) in 5 mL of ethanol and 1 mL of water was added. The mixture was stirred under nitrogen for 18 hrs and ethanol was evaporated in vacuo. The residue was dissolved in 100 mL of water and the resulting mixture extracted with three 20 mL-portions of ethyl acetate. The organic layers were discarded. The aqueous layer was cooled in an ice bath and acidified to pH 3 with 10N hydrochloric acid. The yellow precipitate was extracted into ethyl acetate, washed with brine and dried. Evaporation of solvent in vacuo afforded a yellow substance. Crystallization from ether gave 0.8 g of the product as yellow crystals: mp 187°-189° C.; MS-298 (m+); UV(MeOH) λmax 340 nm.
Reaction SMILES: [H-].[Na+].[C:3]1(/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:21][N:20]=1.O>CN(C)C=O>[N:28]1([CH2:27][CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([O:17][CH2:16][C:14]3[N:15]=[C:11](/[CH:10]=[CH:9]/[C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[O:12][CH:13]=3)=[N:20][CH:21]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: OCc1coc(/C=C/c2ccccc2)n1
Reactant: Clc1ccc(CCCn2ccnc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C(=C/c1nc(COc2ccc(CCCn3ccnc3)cn2)co1)\c1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Sodium hydride (oily, 60%, 660 mg) was added to a solution of 2-[(E)-2-phenylethenyl]-4-oxazolylmethanol (3.02 g) in N,N-dimethylformamide (30 ml) and stirred at 90° C. for 30 minutes, to which was added a solution of 2-chloro-5-[3-(1-imidazolyl)propyl]pyridine (1.10 g) in N,N-dimethylformamide (10 ml). The resultant was stirred at 90° C. for 14 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane-methanol (10:1:0.5, v/v), crystals of 5-[3-(1-imidazolyl)propyl]-2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]pyridine (900 mg, 47%) was obtained. Recrystallization ethyl acetate-hexane gave pale brown prisms, mp 120-121° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:31][C:32]1(C)[O:37]C(=O)[CH2:35][C:34](=O)[O:33]1.N1C=CC=CC=1>C(Cl)Cl>[CH2:34]([O:33][C:32](=[O:37])[CH2:31][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=1)[CH3:35]
Reactant: O=C(O)Cc1ccncc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Cc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 19.8 %

Procedure:
A solution of pyridin-4-yl-acetic acid hydrochloride salt (1.73 g 10 mmol) in CH2Cl2 (50 mL) was treated with triethylamine (2.09 mL, 15 mmol), followed by 1,1′-carbonyldiimidazole (2.43 g, 15 mol). After 4 h, the solution was added dropwise to a 0° C. solution of 2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum's acid; 1.73 g, 12 mmol) and pyridine (1.63 mL, 20 mmol) in CH2Cl2 (50 mL). The reaction mixture was allowed to warm slowly to rt and was stirred for 18 h. The mixture was washed with H2O (2×), and the organic layer was dried and concentrated. The crude residue was dissolved in EtOH (100 mL) and heated at reflux for 4 h. The mixture was allowed to cool to rt and was concentrated. The residue was purified by chromatography (EtOAc/hexanes) to give the title compound (411 mg, 15%) as a pale yellow oil. MS (ESI): mass calcd. for C11H13NO3, 207.1; m/z found, 208.1 [M+H]+. 1H NMR (CDCl3): 8.57 (dd, J=4.4, 1.6, 2H), 7.16 (dd, J=4.4, 1.6, 2H), 4.20 (q, J=7.2, 2H), 3.88 (s, 2H), 3.51 (s, 2H), 1.28 (t, J=7.2, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5]2.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5]2
Reactant: CCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of the title compound of Example 3 Step A (1.35 g, 5.73 mmol) in DMF (25 mL) was added NaH (252 mg, 60% suspension if mineral oil, 6.30 mmol). After 20 min, benzyl bromide (0.750 mL, 6.30 mmol) was added, and the mixture was allowed to stir for 15 h, whereupon it was quenched by addition of sat. aq. NH4Cl. The aqueous phase was extracted with EtOAc, and the organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 15%, then 15 to 100% EtOAc in hexanes) provided the title compound: LCMS A, tr=4.36 min, m/z 326.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J=1.0 Hz, 1H), 7.34-7.22 (m, 6 H), 7.04 (d, J=7.0 Hz, 2H), 5.88 (s, 2H), 2.99 (t, J=7.5 Hz, 2H), 1.76-1.70 (m, 2H), 1.44-1.36 (m, 2 H), 0.97 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:13][C:14]([C:16]2([NH:31]C(=O)OC(C)(C)C)[CH2:21][CH2:20][N:19]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1>ClCCl>[NH2:31][C:16]1([C:14]([NH:13][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11][OH:12])=[O:15])[CH2:17][CH2:18][N:19]([C:22]2[C:23]3[CH:30]=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: ClCCl
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 19.4 %

Procedure:
HCl (4M in Dioxane) (3.00 mL, 12.00 mmol) was added to (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 22) (1.27 g, 2.40 mmol) in dichloromethane (20 mL). The resulting suspension was stirred at 20° C. for 16 hours. The reaction mixture was filtered through a PTFE filtercup and the crude solid was purified by preparative HPLC (Waters XTerra C18 column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% TFA) and MeCN as eluents. Fractions containing the desired compound were purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.200 g, 19.4%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ 1.45 (2H, d), 1.86 (1H, d), 1.90-1.93 (1H, m), 2.19 (2H, s), 3.38 (2H, q), 3.51-3.58 (2H, m), 4.35-4.38 (2H, m), 4.53 (1H, t), 4.88 (1H, d), 6.58 (1H, t), 7.16 (1H, t), 7.32-7.38 (4H, m), 8.12 (1H, s), 8.43 (1H, d), 11.63 (1H, s), m/z (ESI+) (M+H)+=429; HPLC tR=1.46 min.