Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([NH2:16])[C:14]#[CH:15].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:16][CH2:13][C:14]#[CH:15]
Reactant: C#CCN
Reactant: COc1ccc(C=O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C#CCNCc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,4-dimethoxybenzaldehyde (2.5 g, 15.06 mmol) in methanol (100 ml) was added prop-2-yn-1-amine (1.0 g, 18.18 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, and then cooled to 0° C. NaBH4 (1.0 g, 26.32 mmol) was then added in portions over 15 minutes. The mixture was warmed up and stirred at room temperature for an additional 2 hours. The reaction was quenched with brine (200 mL), and partitioned between brine and ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound which was used in next step without further purification. 1H NMR (400 MHz, dimethylsulfoxide-d6): δ 2.07 (br s, 1H), 3.04 (s, 1H), 3.27 (s, 2H), 3.63 (s, 2H), 3.74 (s, 3H), 3.76 (s, 3H), 6.46 (d, J=8.0 Hz, 1H), 6.52 (s, 1H), 7.15 (d, J=8.4 Hz, 1H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:47])[C:22]1[CH:27]=[CH:26][C:25](Br)=[C:24]([S:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][Si](C(C)(C)C)(C)C)(=[O:31])=[O:30])[CH:23]=1>C1COCC1>[CH3:19][O:20][C:21]([C:22]1[CH:27]=[CH:26][C:25]2[O:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][S:29](=[O:31])(=[O:30])[C:24]=2[CH:23]=1)=[O:47]
Reactant: COC(=O)c1ccc(Br)c(S(=O)(=O)Cc2ccccc2O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)Cc1ccccc1O2
Reaction time: 1 h

Procedure:
Tetra-n-butylammonium fluoride (0.693 g, 2.2 mol) in THF (15 mL) was added dropwise to a solution of Example 1g (0.55 g, 1.1 mmol) in dry THF (5 mL) at 0° C. The reaction mixture was stirred for 1 h and treated with crushed ice to obtain the title compound as a solid. It was filtered, washed with water and dried. Yield: 0.25 g, (75%); 1H NMR (CDCl3): δ 3.90 (s, 3H, OCH3), 4.60 (s, 2H, CH2), 7.30-7.40 (m, 5H, Ar), 8.20 (d, 1H, Ar), 8.60 (d, 1H, Ar); MS: m/e (EI+) 304 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[C:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])#[CH:16]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:20]([C:19]3[CH:21]=[CH:22][CH:23]=[C:17]([C:15]#[CH:16])[CH:18]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: C#Cc1cccc(N)c1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CC(=O)O
Product: C#Cc1cccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)c1
Yield: 87.9 %

Procedure:
To a solution of 10.7 g (0.10 mole) of 4-nitrophthalic anhydride in 150 ml of glacial acetic acid was added 12.9 g (0.11 mole) of 3-ethynylaniline. A white precipitate formed immediately. The mixture was heated to reflux for 1 hour, then cooled and filtered. The precipitate was washed with water and methanol. Recrystallization from toluene gave 25.7 g (87% yield) of 4-nitro-N-(3-ethynylphenyl)phthalimide, m.p. 257°-259° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].[CH3:7][C:8]1[O:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])[CH:15]=[O:16])[C:10](=[O:19])[C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:7][C:8]1[O:13][CH2:12][N:11]([C:14]([CH3:17])([CH:15]([OH:16])[CH2:5][CH2:4][CH:3]=[CH2:2])[CH3:18])[C:10](=[O:19])[C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Reactant: C=CCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCC(O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: -5 °C
Reaction time: 18 h
Yield: 145.5 %

Procedure:
4-Bromobut-1-ene (approximately 0.2 g) was added to a suspension of magnesium (0.17 g) in tetrahydrofuran, under an inert atmosphere at 20° C. Once the reaction had initiated, further 4-bromobut-1-ene (approximately 0.67 g) in tetrahydrofuran was added over 10 minutes. After refluxing for 1 hour, the mixture was cooled to -5° C. and a solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (1.00 g) in tetrahydrofuran was added over 20 minutes. After stirring for 18 hours, ammonium chloride and ethyl acetate were added and the organic phase washed (brine), dried (magnesium sulphate) and evaporated to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylhept-6-en-3-ol (0.68 g) as a white solid, m.p. 74-75° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:17])[N:13]2[CH3:16])=[CH:8][CH:7]=1.[I-:18].[Na+].C(#N)C>O>[I:18][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:17])[N:13]2[CH3:16])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: Cn1c(=O)ccc2ccc(OCCCCl)cc21
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)ccc2ccc(OCCCI)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
7-(3-Chloropropoxy)-1-methyl-1H-quinolin-2-one(2.5 g) and sodium iodide(3.0 g) were added to 30 ml of acetonitrile. The mixture was stirred for 18 hours while heated under reflux. After cooled to room temperature, water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with sodium sulfate and was condensed under reduced pressure to give the title compound(2.4 g) as a pale brown powder.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5]2=[O:21].[CH2:22]([O:24][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:23].C1(C2C=CC=CC=2)C(O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>C1COCC1.[Cu](I)I>[CH2:22]([O:24][C:25](=[O:32])[CH:26]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5]2=[O:21])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:23]
Reactant: COc1ccc(Cn2cnc3ccc(I)cc3c2=O)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc2ncn(Cc3ccc(OC)cc3)c(=O)c2c1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
A solution of 6-iodo-3-(4-methoxy-benzyl)-3H-quinazolin-4-one (0.69 g, 1.75 mmol), malonic acid diethyl ester (0.56 g, 3.49 mmol), copper iodide (0.016 g, 0.090 mmol), biphenyl-2-ol (0.029 g, 0.175 mmol) and cesium carbonate (0.86 g, 2.63 mmol) in THF (10 mL) was heated to 70° C. in a sealed tube for 24 hours. The solution was then cooled to room temperature, saturated sodium bicarbonate was added and the crude product was extracted from ethyl acetate. The product was purified via silica gel column chromatography in hexane:ethyl acetate (1:1) to give 0.51 g (69%) of 2-[3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazolin-6-yl]-malonic acid diethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.21 (m, 1H), 8.05 (s, 1H), 7.80 (dd, 1H, J=2.0, 8.4 Hz), 7.62 (d, 1H, J=8.4 Hz), 7.22 (d, 2H, J=8.8 Hz), 6.78 (d, 2H, J=8.8 Hz), 5.05 (s, 2H), 4.69 (s, 1H), 4.15 (m, 4H), 3.70 (s, 3H), 1.19 (m, 6H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1)(=O)[CH3:2]>O=P(Cl)(Cl)Cl>[I:13][C:9]1[CH:8]=[C:7]([C:6]2[O:14][C:1]([CH3:2])=[N:4][N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)NNC(=O)c1cccc(I)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2cccc(I)c2)o1

Procedure:
The product obtained in Step A above (2.9 g, 9.54 mmol) is heated at 120° C. for 3 hours in 35 ml of POCl3. After evaporation of POCl3, the residue is taken up in toluene and the mixture is evaporated to dryness again. The residue from evaporation is dissolved in ethyl acetate and the organic phase is washed with, in succession, 10% NaHCO3 solution, water and then brine. The organic phase is dried over MgSO4 to yield, after evaporation, the expected product in the form of a creamy white solid.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]2[C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+]>CO>[C:1]1([C@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@@H:8]2[C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccccc1
Yield: 58.5 %

Procedure:
1-tert-Butyl 3-methyl (3S,4S)-4-phenylpiperidine-1,3-dicarboxylate (1.00 g) was dissolved in methanol (40 ml), and thereto was added sodium methoxide (1.0 M methanol solution, 4.70 ml), and the mixture was refluxed for 9 hours. The reaction mixture was cooled, and concentrated under reduced pressure. To the residue was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=5/1) to give the title compound (585 mg).
Reaction SMILES: C([O:5][C:6](=[O:50])[CH2:7][CH2:8][NH:9][C:10](=[O:49])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[C:39]=2[Cl:48])[CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:13]=1)(C)(C)C.Cl>CCOCC>[ClH:48].[Cl:48][C:39]1[C:40]([C:44]([F:45])([F:46])[F:47])=[CH:41][CH:42]=[CH:43][C:38]=1[CH2:37][N:22]([CH2:23][CH:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:21][CH2:20][CH2:19][O:18][C:14]1[CH:13]=[C:12]([CH2:11][C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:50])=[O:5])=[O:49])[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: CCOCC
Product: O=C(O)CCNC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 3-[2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-ethanoylamino]-propionic acid tert-butyl ester (110 mg, 0.15 mmol) in Et2O (5 mL) was added 1M HCl in Et2O (0.46 ml, 0.46 mmol). The mixture was stirred at room temperature for 18 hours. Purification by preparative HPLC (YMC, 75×30 mm, 25 ml/min, 40–100% CH3CN:H2O) afforded the desired carboxylic acid. Treatment of the tertiary amine/carboxylic acid with 1 N HCl (Et2O) followed by concentration in vacuo afforded the title compound as a yellow solid (84 mg, 79%). MS(ES) m/e 653.4 (M+).
Reaction SMILES: C([O:8][CH2:9][C@H:10]([OH:19])[CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C1C=CC=CC=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>[Pd].CO>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][CH2:11][C@@H:10]([OH:19])[CH2:9][OH:8])[CH:14]=1
Reactant: O[C@H](CCc1cccnc1)COCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CO
Product: OC[C@H](O)CCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
Under argon gas, MeOH (70 mL) was added to 10% palladium-on-carbon (1.0 g). Then, the (2R)-1-O-benzyl-4-(3-pyridyl)-1,2-butanediol produced in Example 3 (28.25 g, 100 mmol) and sulfuric acid (19.6 g, 200 mmol) were added. After degassing under reduced pressure, a hydrogen atmosphere was established. The pressure was increased to 3 atm. and the mixture was stirred at room temperature for 16 hours. The palladium-on-carbon was filtered off and the solvent was distilled off under reduced pressure, whereupon a light-yellow oil was obtained. To this oil was added a saturated aqueous solution of sodium hydrogencarbonate for neutralization, followed by concentration under reduced pressure. The residue was extracted with ethyl acetate twice (200 mL each). The organic layers were combined and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the oily residue was purified by silica gel column chromatography (Merck's Kieselgel 60, MeOH/ethyl acetate=1/9) to give 10.52 g (isolation yield: 63%) of (2R)-4-(3-pyridyl)-1,2-butanediol (yellow oil).
Reaction SMILES: C(C1OC[C@H](C2C=CC=CC=2)N=1)(C1OC[C@H](C2C=CC=CC=2)N=1)(C)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:35][CH2:36][C@H:37]2[O:41][C@@H:40]([N:42]3[CH:49]=[CH:48][C:46](=[O:47])[NH:45][C:43]3=[O:44])[C@H:39]([OH:50])[C@@H:38]2[OH:51])=[CH:30][CH:29]=1.[C:66]1([N:72]=[C:73]=[O:74])[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C=CC(=O)NC3=O)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([C:58]2[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:35][CH2:36][C@H:37]2[O:41][C@@H:40]([N:42]3[CH:49]=[CH:48][C:46](=[O:47])[NH:45][C:43]3=[O:44])[C@H:39]([OH:50])[C@@H:38]2[O:51][C:73](=[O:74])[NH:72][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:32][CH:33]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Cu+2]
Agent: CC(C)(C1=N[C@@H](c2ccccc2)CO1)C1=N[C@@H](c2ccccc2)CO1
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The THF solution (1 ml) containing 2,2′-isopropylidenebis[(4S)-4-phenyl-2-oxazoline] (0.02 mmol, 7.2 mg) and Cu(OTf)2 (II) (0.02 mmol, 6.7 mg) was stirred for 30 minutes at room temperature. After the reaction mixture was cooled to 0° C., THF solution (1 ml) of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]uridine (0.2 mmol, 109.3 mg) and THF solution (1 ml) of phenyl isocyanate (0.2 mmol, 23.8 mg) were added thereto. After the mixture was continuously stirred for 1 hour at 0° C. and for 4 hours at room temperature, the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-2′-O-phenylcarbamoyl-uridine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-3′-O-phenylcarbamoyl-uridine were produced at the ratio of 60:40, and the transformation ratio of the reaction was 96%.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](O)=[O:8].Cl.CN(C)CCCN=C=NCC.O>CN(C=O)C>[O:8]=[C:7]1[C@@H:6]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5][O:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=2[NH:1]1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A mixture of (S)-3-(2-amino-phenoxy)-2-tert-butoxycarbonylamino-propionic acid (3.8 g, 12.8 mmol, 1 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 2.46 g, 12.8 mmol, 1 eq) in DMF (56.4 mL) was stirred for 1 h 45 min. The reaction was poured into H2O (250 mL) and extracted with EtOAc. The combined extracts were washed with H2O, dried over Na2SO4 and concentrated to give the title compound (3.1 g, 87%) as a tan solid which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.C([Li])(CC)C.CC1C=CC(S([C:36]#[N:37])(=O)=O)=CC=1>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:7]([C:36]#[N:37])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(C#N)cnc21
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a solution of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo-[2,3-b]pyridine (1.22 g) in tetrahydrofuran (12.2 mL) was added 0.95M sec-butyl lithium in n-hexane (8.3 mL) dropwise at −78° C. The mixture was stirred at the same temperature for 1 hour. To the solution was added 4-methylbenzenesulfonyl cyanide (1.43 g) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The extract was washed with water and brine, dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane to give 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (444 mg) as a white solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Br[C:7]1[S:8][C:9]([C:13]2[C:14]([CH3:28])=[N:15][N:16]3[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:20][C:19]([CH3:27])=[N:18][C:17]=23)=[C:10]([Br:12])[N:11]=1.ICCCC.[Cl-].N>C1COCC1>[Br:12][C:10]1[N:11]=[C:7]([CH2:1][CH2:2][CH2:3][CH3:4])[S:8][C:9]=1[C:13]1[C:14]([CH3:28])=[N:15][N:16]2[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:20][C:19]([CH3:27])=[N:18][C:17]=12
Reactant: [Li]CCCC
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)nc3Br)c(C)nn12
Agent: N
Agent: [Cl-]
Solvent: CCCCI
Solvent: C1CCOC1
Product: CCCCc1nc(Br)c(-c2c(C)nn3c(C(CC)CC)cc(C)nc23)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
Under a nitrogen atmosphere, add n-butyl lithium (2.5 M in hexane, 0.2 mL, 0.5 mmol) to a solution of 3-(2,4-dibromo-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (230 mg, 0.5 mmol) in THF (3 mL) at −78° C. After 30 min, add 1-iodobutane (138 mg, 0.75 mmol) and continue stirring for 1 hour. Warm up to room temperature and stir for one hour. Quench the reaction by adding saturated ammonia chloride solution and extract with ethyl acetate. Dry the organic portion over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting with hexanes/ethyl acetate (10/1.5) to give the title compound as orange foam (78 mg). ES/MS m/z (81Br) 437.4 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:12][CH2:11][CH2:10][O:7]2)=[CH:4][N:3]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(C2OCCO2)cn1
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
To a solution of 6-bromonicotinaldehyde (10.1 g, 51.6 mmol) in toluene (400 mL) was added ethylene glycol (11.4 mL, 206 mmol) and p-toluenesulfonic acid (0.98 g, 5.16 mmol), and the reaction mixture was heated to reflux with azeotropic removal of the water using a Dean-Stark trap, for 2.5 h. The mixture was cooled down and washed with saturated NaHCO3 solution and brine. The organic phase was dried over anhydrous MgSO4 and concentrated to afford title compound 300 (11.7 g, 98% yield) as a brown solid, which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.46 (d, J=2.7 Hz, 1H), 7.65 (dd, J=8.1, 2.7 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 5.83 (s, 1H), 4.20-4.00 (m, 4H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]([N:7]1[CH2:15][CH2:14][CH:10]([C:11](O)=[O:12])[CH2:9][CH2:8]1)=[O:6].C(OC(=O)C)(=O)C>>[CH:5]([N:7]1[CH2:15][CH2:14][CH:10]([C:11]([Cl:3])=[O:12])[CH2:9][CH2:8]1)=[O:6]
Reactant: O=CN1CCC(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: O=CN1CCC(C(=O)Cl)CC1
Reaction time: 3 h
Yield: 100 %

Procedure:
To 100 ml of freshly distilled thionyl chloride was added 30 g of N-formylisonipecotic acid at 0°. After the addition was complete, 2 ml of acetic anhydride was added and the solution was stirred at 20° for three hrs. The reaction mixture was diluted with 3 400-ml portions of petroleum ether, bp, 60°-80°. The resulting solid was collected, washed with 50 ml of ether and dried under vacuum over phosphorous pentoxide to yield 33.5 g (100%) of N-formylisonipecotic acid chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1[OH:8].[Br:29][CH:30]=[CH:31][CH2:32][CH2:33]Br.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1[O:8][CH2:33][CH:32]=[CH:31][CH2:30][Br:29]
Reactant: BrC=CCCBr
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c(OCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCC=CCBr)c(OCC)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(3-bromo-5-ethoxy-4-hydroxy-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (3.04 g), 1,4-dibromobutene (11.68 g) and potassium carbonate (1.887 g) in dioxane (100 ml) was stirred at 80° C. for 5 h. The mixture was poured into water and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in acetonitrile, washed with petroleum ether and heptane to remove most of the excess of dibromobutene. The acetonitrile layer was concentrated in vacuo and the residue recrystallized from dichloromethane and heptane. Yield: 3.02 g. MS-ESI: [M+H]+=579.2
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].C([O-])(O)=O.[Na+].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([CH:22]([OH:32])[C:23]2[C:24]([C:29]([O-:31])=[O:30])=[N:25][CH:26]=[CH:27][CH:28]=2)[N:15]=1.[Li+]>O>[CH3:21][O:20][C:18]1[CH:19]=[C:14]([O:13][CH3:12])[N:15]=[C:16]([C:22]([C:23]2[C:24]([C:29]([OH:31])=[O:30])=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:32])[N:17]=1
Reactant: COc1cc(OC)nc(C(O)c2cccnc2C(=O)[O-])n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: COc1cc(OC)nc(C(=O)c2cccnc2C(=O)O)n1

Procedure:
30.3 g of KMnO4 and 32.3 g of NaHCO3 are suspended in 700 ml of water and 57 g of lithium 3-[(4,6-dimethoxy-2-pyrimidinyl)hydroxymethyl]-2-pyridine carboxylate is added with stirring. The reaction mixture is refluxed for 4 hrs and suction filtered hot. The filtrate is cooled over ice water and audified with conc. HCl (60 ml). The precipitated solid is filtered and dried in vacuo at 50° to give the title compound m.p. 159°-161° C.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[C:10]([CH3:26])([N:11]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:19]([O:18][C:16]([N:11]1[CH2:12][CH2:13][CH:14]2[CH2:15][NH:8][CH2:9][C:10]12[CH3:26])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCN(C(=O)OCc3ccccc3)C2(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC12CNCC1CCN2C(=O)OCc1ccccc1
Yield: 55.4 %

Procedure:
The product of Example 20F (0.8 g, 2.22 mmol) was treated with TFA (5 mL) in CH2Cl2 (10 mL) at ambient temperature for 1 h. The mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 90: 9: 1 CH2Cl2: MeOH: NH4OH) to give the title compound (0.32 g, 1.23 mmol, 55% yield). 1H NMR (MeOH-d4, 300 MHz) δ 1.42, 1.47 (s, 3H, rotamers), 1.63-1.75 (m, 1H), 1.98-2.13 (m, 1H), 2.37-2.52 (m, 1H), 2.62-2.76 (m, 2H), 3.00-3.12 (m, 1H), 3.26, 3.47 (d, J=12.6 Hz, 1H, rotamers), 3.53-3.62 (m, 2H), 5.08, 5.13 (s, 2H, rotamers), 7.25-7.42 (m, 5H); MS (DCl/NH3) m/z 261 (M+H)+.