Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([OH:11])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[Cl:12]Cl>C(O)(=O)C>[Cl:12][C:3]1[S:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([OH:11])[C:10]=2[C:2]=1[CH3:1]
Reactant: Cc1csc2ncnc(O)c12
Reactant: ClCl
Solvent: CC(=O)O
Product: Cc1c(Cl)sc2ncnc(O)c12
Reaction time: 48 h
Yield: 82 %

Procedure:
To a solution of 5-methylthieno[2,3-d]pyrimidin-4-ol (2 g, 12 mmol) in acetic acid (30 mL) at room temperature, chlorine gas was bubbled for 3 h. The reaction mixture was stirred at same temperature for 2 days. The solvent was evaporated under reduced pressure at 40° C. and the residue was dissolved in ethyl acetate (30 mL) and washed with sat. NaHCO3 solution (3×20 mL). The organic layer was dried over sodium sulfate and evaporated to get the title compound as a pale yellow solid (2 g, 82%). 1H NMR (400 MHz, CDCl3 and CD3OD): δ 7.90 (s, 1H), 2.55 (s, 3H). MS (ESI) m/z: Calculated: 200.65; Observed: 201.3 (M++1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][NH:26]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][N:26]1[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4ccccc4C3)c(F)c(NCCO)c2c1=O
Yield: 42.7 %

Procedure:
205 mg of 1-cyclopropyl-5(2-hydroxyethylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 119 mg of isoindoline, 182 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 113 mg of the target compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12](OC)O)[N:6]=[CH:5]2.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl.CO.CC(O)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:6]=[CH:5]2
Reactant: COC(O)Cn1ncc2cc(I)ccc21
Reactant: C1COCCN1
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Ic1ccc2c(cnn2CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
To a solution of 2-(5-iodo-1H-indazol-1-yl)-1-methoxyethanol (360 mg, 1.13 mmol) in CH2Cl2 (10.0 mL), MeOH (10.0 mL) and AcOH (4.0 mL) was added morpholine (295 mg, 3.39 mmol) and picoline-borane complex (120 mg, 1.13 mmol). The solution was stirred at ambient temperature for 1.5 h. The reaction mixture was concentrated, diluted with 1 N HCl (10.0 mL) and stirred at ambient temperature for 30 minutes. The mixture was made basic with 1N NaOH (10.0 mL) and extracted with EtOAc (3×50 mL). The organics were dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (12 g ISCO column, eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 20 mL/min) gave the title compound (164 mg, 41%) as an off-white powder. 1H NMR (300 MHz, CDCl3) 8.08 (d, J=1.0 1H), 7.90 (s, 1H), 7.7.62-7.56 (dd, J=8.8, 1.6 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.47 (t, J=6.9 Hz, 2H), 3.64 (t, J=4.7 Hz, 4H), 2.85 (t, J=6.9, 2H), 2.48 (d, J=4.7 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[CH2:17][CH2:18][CH3:19])[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[CH2:17][CH2:18][CH3:19])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OCC)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(c1ccc(C(=O)NCCC(=O)OCC)cc1)C(C(=O)O)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of the slower-eluting diastereomer of tert-butyl 2-(4-chlorophenyl)-3-(4-{[(3-ethoxy-3-oxopropyl)amino]carbonyl}phenyl)hexanoate (1.9 g, 3.8 mmol) in DCM (20 mL) at 0° C. was added TFA (20 mL) over 1 min. After being stirred for 30 minutes, the solution was concentrated to afford the title compound. After being dried on high vacuum overnight, the material was used directly for the next step. LC1 2.09 min. (M+H)+ 446.
Reaction SMILES: [Mg].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13][CH2:14]C)=[O:12].Cl.[OH-].[NH4+].S(=O)(=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [Mg]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2N1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Magnesium turnings (6.449 g) are added to a suspension of ethyl indole-2-carboxylate (I, Aldrich, 25.083 g) in methanol (freshly opened, HPLC grade, 350 ml). The mixture is stirred at 24° for 10 minutes, then placed in an ice bath. After stirring for 15 minutes in the ice bath, there is much gas evolution and the temperature rises to 35° but then subsides to 0° within one hour. After stirring for another two hours at 0°, cold hydrochloric acid (3N, 250 ml) is added slowly. The mixture turns to a gel. The gel is then treated with ammonium hydroxide (3N, 250 ml). Upon adding methylene chloride to the gel, it forms an inseparable suspension. The crude mixture is made acidic (pH 1) with aqueous sodium bisulfate (10%) then made alkaline (pH 8-9) with ammonium hydroxide (3N). This mixture is then extracted with methylene chloride. The combined organic layers are dried over magnesium sulfate and concentrated to provide a mixture of an oil with some solid. From this mixture an off white solid is obtained by washing the mixture with ethyl acetate/hexane (25/75). A small sample (620 mg) of the recovered oil is purified by passing it over a silica column (20.5×2.5 cm, 40-63μ). The column is eluted with ethyl acetate/hexane (1/3, 11; 1/1, 0.5 l) collecting 25 ml fractions. The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3, 300 MHz) 7.04, 6.71, 4.46, 4.37, 3.74 and 3.35 δ; CMR (CDCl3, 75.47 MHz) 33.69, 52.42, 59.81, 110.05, 119.48, 124.45, 126.63, 127.67, 150.03 and 174.62 δ; IR (CHCl3) 3480, 3390, 2970, 1730, 1605, 1480, 1460, 1430 and 1200 cm-1 ; MS (m/e) 177, 147, 129, 119, 118, 117, 91, 86, 84 and 49, exact mass calcd for C10H11NO2 (177.0790), found 177.0789; TLC (ethyl acetate/hexane, 1/1) Rf 32 0.55 (UV).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[CH:5]([C:7]1[C:15]2[O:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:11]=2[C:10]([CH3:25])=[C:9]([NH:26][C:27](=[O:33])[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:8]=1[CH3:34])=[O:6]>O>[OH:6][CH:5]([C:7]1[C:15]2[O:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:11]=2[C:10]([CH3:25])=[C:9]([NH:26][C:27](=[O:33])[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:8]=1[CH3:34])[CH2:1][CH3:2]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC[Mg]Cl
Solvent: O
Product: CCC(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Reaction time: 1 h
Yield: 35.1 %

Procedure:
To ethylmagnesium chloride (2.0 M THF solution, 5.0 mL, 10.0 mmol) was added N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (0.7 g, 1.72 mmol) obtained in Example 20 at 0° C. and the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was added to water and the product was extracted with ethyl acetate. The organic layer was washed with water and 1 N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 264 mg (yield: 35%) of the title compound as a low polarity isomer. Melting point: 145-146° C. (ethyl acetate-hexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24]>>[N+:23]([C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:7]([CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)[C:8](=[O:9])[CH2:10][CH2:11]2)([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Agent: O=S(=O)(O)O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(4-Piperidinyl)-3,4-dihydrocarbostyril (0.2 g) is added to conc. sulfuric acid (5 ml) and thereto is added fuming nitric acid (0.1 ml) under ice cooling. The mixture is stirred at room temperature for 30 minutes, and then the reaction mixture is poured into ice-water. The mixture is basified and extracted with dichloromethane. The solvent is concentrated to give 6-nitro-1-(4-piperidinyl)-3,4-dihydrocarbostyril (0.2 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][O-:11].[Na+]>C1(C)C(C)=CC=CC=1>[C:1]([CH2:2][C:10](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Yield: 193.4 %

Procedure:
acetophenone (30.0 grams; 0.25 mol); sodium methoxide (17.3 grames; 0.3 mol) and xylene 28.,0 grams) were added to the resulting mixture (347.0 grams) from the azetropic distillation. The reaction procedure set forth hereinabove was repeated with this reaction mixture giving dibenzoylmethane (54.2 grams; 92% yield) 92% pure by GLC analysis.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([C:7]1[S:8][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:10][CH:11]=1)=[O:6])C.C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:12]([C:9]1[S:8][C:7]([C:5](=[O:6])[C:4]([OH:16])=[O:3])=[CH:11][CH:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(C(=O)C(=O)OCC)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCc1ccc(C(=O)C(=O)O)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
To solution containing (5-butyl-thiophen-2-yl)-oxo-acetic acid ethyl ester (Step a, 1 g, 4.2 mmol) dissolved in ethanol 10 mL) was added K2CO3 2N (10 mL). The reaction was stirred at room temperature 6 h. The ethanol was removed under reduce pressure and the residue taken in water (50 mL) then washed with ether. The aqueous was separated and made acidic with concentrated HCl then extracted with CHCl3 (2×). The organic layers were separated and combined and dried over MgSO4, then filtered and stripped. A white solid (0.6 g, 67% yield) was recovered. MS m/e 211 (M)−; 1HNMR (DMSO-d6 300 MHz) δ 0.9 (t, 3H), 1.3 (m, 2H), 1.6 (m, 2H), 2.8 (t, 2H), 4.3 (b, 1H), 7.1 (s, 1H), 7.9 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([C:35]1([O:38]C(=O)C)[CH2:37][CH2:36]1)=[O:34]>>[OH:38][C:35]1([C:33]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=5[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3][CH2:2]2)=[O:34])[CH2:37][CH2:36]1
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCNCC3)c[nH]c12
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCN(C(=O)C4(O)CC4)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A184) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([OH:20])=[CH:15][CH:16]=2)[O:11][CH:10]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[O-]S([O-])=O.[Na+].[Na+]>O1CCOCC1>[OH:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]3[C:18](=[O:19])[C:17]4[CH:16]=[CH:15][C:14]([OH:20])=[CH:13][C:12]=4[O:11][C:10]=3[O:1][C:2]=2[CH:7]=1
Reactant: O=c1c(-c2ccc(O)cc2O)coc2cc(O)ccc12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1c2ccc(O)cc2oc2oc3cc(O)ccc3c12
Temperature: 90 °C
Yield: 20 %

Procedure:
A mixture of 15 (0.25 g, 0.93 mmol) and DDQ (0.42 g, 1.87 mmol) in dioxane was heated to 90° C. for 45 min. The reaction was allowed to cool and poured into 10% Na2SO3 and extracted with EtOAc. The EtOAc was dried over MgSO4, filtered and concentrated to give a yellow solid that was triturated with MeOH to give 16 as a white solid (0.050 g): Mp>300° C.; 1H NMR (DMSO d6) δ 10.88 (br s, 1H), 9.93 (br s, 1H), 8.05 (d, 1H, J=8.6 Hz), 7.77 (d, 1H, J=8.4 Hz), 7.10 (d, 1H, J=1.9 Hz), 7.05 (d, 1H, J=2.0 Hz), 7.01 (dd, 1H, J=8.6 Hz, 2.1 Hz), 6.92 (dd, 1H, J=8.4 Hz, 1.9 Hz); MS FI (neg) 267 (M−H)−.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].C([Al+]CC(C)C)C(C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)C>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7])([CH3:11])([CH3:12])[CH3:10]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
N-t-Butoxycarbonyl-L-phenylalanine methyl ester (250 g., 0.90 mol) was dried by addition and removal at reduced pressure of 1.0 l dry toluene, and dissolved in dry toluene (3 l.) in a 12 l flask equipped with septum, nitrogen inlet, overhead stirrer, and thermometer. The solution was cooled to -78° C. and a solution of diisobutylaluminum hydride was added via cannula over a period of 0.5 hour so that the temperature was maintained below -70° C. After being stirred an additional 15 minutes, absolute methanol (250 ml.) was added (dropwise at first until vigorous effervescence subsided) at -78° C. followed 20 minutes later by 3.0 l of 50% Rochelle salt solution (also slowly at first). Diethyl ether (2 l) was added to the mixture, and the temperature was raised to 20° C. On standing the layers separated, and the aqueous was extracted with ether (2×1.5 l). The organic phase was washed with brine, dried sodium sulfate and concentrated to give crude N-t-butoxycarbonyl-L-phenylalaninal which was used immediately without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH:14]([OH:16])[CH3:15].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: COc1cc(Br)c(C(C)O)cc1OC(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(Br)c(C(C)=O)cc1OC(C)C
Temperature: 18 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A magnetically stirred solution of alcohol 37 (520 mg, 1.80 mmol) in CH2Cl2 (10 mL), maintained at 0° C. was treated with Dess-Martin periodinane (1.14 g, 2.69 mmol). The resulting mixture was warmed to 18° C., stirred at this temperature for 2 h then concentrated, under reduced pressure, onto TLC-grade silica (ca. 500 mg). The resulting free-flowing solid was subjected to flash chromatography (1:19 v/v ethyl acetate/hexane elution) to afford the title compound 38 (361 mg, 70%) as a pale-yellow solid, m.p. 59.0-59.9° C., Rf 0.6 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO>[Pd]>[Si:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][NH:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cccnc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)NCCC2
Reaction time: 1 h

Procedure:
7-{[tert-Butyl(dimethyl)silyl]oxy}quinoline (0.40 g, 1.5 mmol) in methanol (10 mL, 200 mmol) with 40 mg of 10% Pd on carbon was loaded in a bottle of a Parr Shaker hydrogenator, and shaken for 1 hour under hydrogen atmosphere (50 psi). LC/MS showed that only less than 20% of the reduced product was formed. The reaction mixture continued to be shaken under the same condition for an additional 4 hours. Then LC/MS showed that starting materials were consumed. After filtration, the filtrate was concentrated to yield the desired product. LCMS (M+H)+: m/z=264.3.
Reaction SMILES: Br.[NH2:2][O:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:8][C:9]([O:12][C:13]([NH:15][C@H:16]([C:24](ON1C(=O)CCC1=O)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])([CH3:11])[CH3:10].C(N(CC)CC)C>CN(C=O)C.C(O)C>[C:9]([O:12][C:13]([NH:15][C@H:16]([C:24]([NH:2][O:3][CH2:4][C:5]([OH:7])=[O:6])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])([CH3:10])([CH3:11])[CH3:8]
Reactant: NOCC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NOCC(=O)O

Procedure:
6.97 g (40.5 mmoles) of aminooxy-acetic acid hydrobromide are reacted with 14.68 g (40.5 mmoles) of BOC--Phe--OSu in 100 ml of DMF in the presence of 6.3 ml (45 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo, the oily residue is dissolved in 100 ml of chloroform, and the chloroform solution is washed thrice with 1 n hydrochloric acid. The organic solution is dried, evaporated in vacuo, and the oily residue is solidified with diisopropyl ether. The crude product is purified by precipitation from an ethyl acetate-diisopropyl ether solvent system. 9.70 g (74%) of BOC--Phe--OGly--OH are obtained; m.p.: 136°-137° C., Rf5 : 0.4, [α]D : -17.8° (c: 1.0, in ethanol).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[N:8]=[N:9][NH:10][N:11]=2)=[C:5]([C:12]2[CH:40]=[CH:39][C:15]([C:16]([N:18]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:17])=[CH:14][CH:13]=2)[CH:4]=[N:3]1.Cl.O1CCOCC1>CO>[CH3:25][C:24]1[C:19]([N:18]([C@@H:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[C:16](=[O:17])[C:15]2[CH:39]=[CH:40][C:12]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]=3[C:7]3[N:8]=[N:9][NH:10][N:11]=3)=[CH:13][CH:14]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccnc1N(C(=O)c1ccc(-c2cnn(C)c2-c2nn[nH]n2)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cccnc1N(C(=O)c1ccc(-c2cnn(C)c2-c2nn[nH]n2)cc1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.8 %

Procedure:
Preparation 25, tert-butyl (3R)-3-(4-(1-methyl-5-(2H-tetrazol-5-yl)-1H-pyrazol-4-yl)-N-(3-methylpyridin-2-yl)benzamido)piperidine-1-carboxylate (100 mg, 0.185 mmol) was dissolved in methanol (0.925 mL). To this was added HCl in dioxane (0.694 mL, 4M solution, 2.78 mmol) at room temperature. The reaction was stirred at room temperature. After 2 h, reaction was concentrated under reduced pressure, and then concentrated with toluene (3×10 mL). The crude material was triturated with EtOAc/MeOH (20:1) and filtered to afford N-(3-methylpyridin-2-yl)-4-[1-methyl-5-(2H-tetrazol-5-yl)-1H-pyrazol-4-yl]-N-[(3R)-piperidin-3-yl]benzamide (89.3 mg, 94%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7](=[O:9])[CH3:8])=[CH:3]1.ClS([N:14]=[C:15]=O)(=O)=O.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[C:7]([C:4]1[CH:5]=[C:6]([C:15]#[N:14])[N:2]([CH3:1])[CH:3]=1)(=[O:9])[CH3:8]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(=O)c1ccn(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(C#N)n(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a solution of 1-methyl-3-acetylpyrrole (4.0 g, 32.5 mmol) in dry dichloromethane (40 mL), under nitrogen at −78° C., was added chlorosulfonyl isocyanate (2.8 mL, 32.5 mmol) dropwise. The reaction warmed to room temperature over 2 h, and was then treated with dimethylformamide (8 mL). After 30 min, the reaction was poured into water, treated with a 1 N sodium carbonate solution (10 mL) and extracted with methylene chloride (2×50 mL). The combined organic layers were washed with water, dried (anhydrous sodium sulfate) and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexanes, 3:1 to 1:1) to afford 4-acetyl-1-methyl-1H-pyrrole-2-carbonitrile (2.5 g, 16.87 mmol), which was used without further characterization.
Reaction SMILES: C(=O)CCC1C=CC=CC=1.CC(C(O)CCC1C=CC=CC=1)=C.C([O:26][C:27](=O)[CH2:28][CH2:29]/[C:30](/[CH3:40])=[CH:31]/[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)C>>[CH3:40]/[C:30](=[CH:31]\[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)/[CH2:29][CH2:28][CH:27]=[O:26]
Reactant: CCOC(=O)CC/C(C)=C/CCc1ccccc1
Agent: C=C(C)C(O)CCc1ccccc1
Agent: O=CCCc1ccccc1
Product: C/C(=C\CCc1ccccc1)CCC=O

Procedure:
FIG. 24 depicts the preparation of (E)-9-phenyl-2,6-dimethyl-2,6-nonadienyl]-1-oxy-(tert.-butyl)dimethyl-silane (compound 43). In a coupling reaction hydrocinnamaldehyde (81) was converted to 2-methyl-5-phenyl-1-penten-3-ol (compound 82, CAS-No. 1836-38-0), from which (E)-4-methyl-7-phenyl-4-heptenoic acid ethyl ester (compound 83, CAS-No. 76620-37-6) was obtained. Reduction yielded (4E)-4-methyl-7-phenyl-4-heptenal (compound 84, CAS-No. 238736-71-5), which was transformed to (E)-2,6-dimethyl-9-phenyl-2,6-nonadienoic acid methyl ester (compound 85) in a Wittig-reaction using [1-(methoxycarbonyl)ethylidene]triphenylphosphorane (CAS-No. 2605-68-7). Reduction of compound (85) yielded (2E,6E)-2,6-dimethyl-9-phenyl-2,6-nonadien-1-ol (compound 86, CAS-No. 238736-72-6). Reaction with (tert.-butyl)dimethyl-silylchloride resulted in the formation of compound (43).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[CH3:14][NH2:15]>>[CH3:14][NH:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: CN
Product: CCOC(=S)c1cnc(C)nc1NC
Yield: 88 %

Procedure:
Commercially available ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (9.70 g) was reacted with methylamine in a similar manner to the second stage in Step 1 of Reference Example 1. The reaction mixture was purified by silica gel chromatography (chloroform/methanol) to give ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate (8.37 g, yield 88%). Subsequently, the resulting compound was treated in a similar manner to Steps 1 and 2 of Reference Example 1 to give 4-methylamino-2-methylthiopyrimidine-5-carbohydrazide (5.78 g, yield 74%).
Reaction SMILES: [K].[SH:2][C:3]1[N:4]([CH3:13])[C:5](=[O:12])[C:6]2[CH:11]=[N:10][NH:9][C:7]=2[N:8]=1.[F:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>CN(C=O)C.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][S:2][C:3]3[N:4]([CH3:13])[C:5](=[O:12])[C:6]4[CH:11]=[N:10][NH:9][C:7]=4[N:8]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: Cn1c(S)nc2[nH]ncc2c1=O
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(F)cc3)cc2)nc2[nH]ncc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of 6-mercapto-5-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4(5H)-one potassium (1.0 g) in DMF (20 ml) was added 4-(4-fluorobenzoyl)benzyl bromide (1.745 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol to provide the title compound as colorless solid (1.467 g).