Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][C:10]2=[CH:11][C:12](Br)=[C:13]3[C:17]([C:16]([CH3:18])=[CH:15][CH2:14]3)=[C:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2[C:17]3[CH:16]([CH3:18])[CH2:15][CH2:14][C:13]=3[CH:12]=[CH:11][C:10]=2[CH2:20][CH2:21]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCc2cc(Br)c3c(c2CC1)C(C)=CC3
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)CC3

Procedure:
Into a 500 ml Parr hydrogenation bottle, the product from step (b) (80 mg, 0.23 mmol) dissolved in EtOH (50 ml) was placed. To the argon purged bottle, 10% Pd—C (wet, 100 mg) was added. The bottle was shaken over hydrogen (50 psi) for 3 h. The reaction mixture was filtered through celite and solvent evaporated in vacuo to give the sub-titled compound as colorless oil. MS: ESI (positive): 274 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](OP(N3CCOCC3)(N3CCOCC3)=O)[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1.[SH2:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:34])[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)(N1CCOCC1)N1CCOCC1
Reactant: S
Solvent: C1CCOC1
Product: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1

Procedure:
To a stirred solution of 245 mg. (0.5 mmole) of 7-chloro-2-di-(morpholino)phosphinyloxy-5-phenyl-3H-1,4-benzodiazepine in 10 ml. of tetrahydrofuran containing 0.5 ml. of triethylimine at room temperature was introduced a stream of hydrogen sulfide gas until tlc indicated that all the starting material was consumed (15 minutes). Tetrahydrofuran was evaporated. The residue was partitioned between methylene chloride and water. The methylene chloride layer was dried and evaporated. Crystallization of the residue from methanol yielded, in two crops, a product having a melting point of 243°-245°.
Reaction SMILES: COC([S:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][NH:11][C:10]1=[O:20])=O.O.Cl.[NH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26]>CO>[O:20]=[C:10]1[N:9]([CH2:8][CH2:7][CH2:6][S:5][S:26][CH2:25][C@@H:24]([C:27]([OH:29])=[O:28])[NH2:23])[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][NH:11]1
Reactant: COC(=O)SCCCN1C(=O)NCC1c1ccccc1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Solvent: CO
Solvent: O
Product: N[C@@H](CSSCCCN1C(=O)NCC1c1ccccc1)C(=O)O

Procedure:
A solution of 3.3 g of methyl-[3-(2-oxo-4-phenyl-3-imidazolidinyl)propylthio]formate and 1.8 g of L-cysteine hydrochloride hydrate in 80 ml of methanol is refluxed under nitrogen for three hours. The solvent is removed in vacuo and the residue triturated with ether yielding a hygroscopic solid. The product is further purified by conversion to its 4-methyl benzene sulfonic acid salt, m.p. 172°-178° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:10])=[O:9])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1cccc(-c2ccccc2)c1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
To a solution of 81 (318 mg; 0.85 mmol) in toluene (8.5 mL) was added a solution of phenylboronic acid (152 mg; 1.12 mmol) in ethanol (5.6 mL). Bis(triphenylphosphine)palladium(II) dichloride (32 mg; 0.05 mmol) was then added, followed by the addition of aqueous saturated sodium bicarbonate (3.3 mL). The reaction was placed under a nitrogen atmosphere and then heated at 80° C. for 17 hours. After cooling to room temperature, the reaction was extracted with dichloromethane (70 mL) and washed with aqueous hydrochloric acid (40 mL; 2N), water (40 mL), and aqueous saturated sodium chloride (40 mL). The dichloromethane extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by a silica gel chromatography (9% to 16% ethyl acetate in hexanes gradient) to yield the title compound as a white solid (217 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:41])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])=[CH:24][CH:23]=1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=3[C:6](=[O:12])[NH:7]4)=[CH:27][CH:26]=2)=[O:41])=[C:31]([C:37]([F:38])([F:39])[F:40])[CH:32]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2cc(C(F)(F)F)ccc12
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2C(F)(F)F)cc1
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccc(C(F)(F)F)cc4c23)cc1)c1ccc(F)cc1C(F)(F)F

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 378, method 2 using 1-chloro-9-trifluoromethyl-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-amino-phenyl)-4-fluoro-2-trifluoromethyl-benzamide to provide 404. LC-MS (M+H=561, obsd.=561). 1H NMR (400 MHz, DMSO-d6): δ, 6.96 (d, 1H), 7.18 (d, 2H), 7.54 (m, 2H), 7.76 (m, 2H), 7.78 (d, 1H), 7.97 (d, 1H), 8.10 (d, 1H), 8.27 (s, 1H), 8.99 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7][NH2:8])=[CH:3][CH:2]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([CH3:13])=O>C(Cl)Cl>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]=[C:11]([CH3:13])[C:10]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:2]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)C(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(C)=NNc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
para-Tolylhydrazine (1.2024 g, 9.84 mmol, 1.0 eq.) was combined with ethyl pyruvate (1.08 ml, 9.84 mmol, 1.0 eq.) and 3A sieves (3.6 g, 300% by weight) in methylene chloride (9.8 ml, 1M) at room temperature. After 30 minutes, the reaction was filtered through anhydrous magnesium sulfate and concentrated to give the title A compound (2.095 g) which was used in the next step without purification or characterization.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17]>CC(C)=O>[CH2:16]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH3:17]
Reactant: Oc1cccc(F)c1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(F)c1F
Temperature: 70 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
2,3-difluorophenol 3a (4 g, 30.7 mmol) was dissolved in 60 mL acetone, followed by addition of potassium carbonate (6.36 g, 46.1 mmol) and ethyl iodide (3.19 mL, 39.9 mmol). The reaction mixture was stirred for 5 hours at 70° C. Thereafter, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 100 mL ethyl acetate, and washed with water (100 mL) and saturated sodium chloride solution (100 mL), and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 1-ethoxy-2,3-difluoro-benzene 3b (4.82 g, yellow grease), yield: 99.4%. 1H NMR (400 MHz, CDCl3): δ 6.95-6.89 (m, 1H), 6.78-6.71 (m, 1H), 4.12 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: [Na+].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1>C(O)(C)C.[OH-].[Na+]>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]#[C:15][CH2:14][O:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:10])=[O:11])=[CH:5][CH:4]=2)=[CH:18][CH:19]=1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: Clc1ccc(C#CCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=S(=O)(O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Temperature: 70 °C
Yield: 71.6 %

Procedure:
To a solution of 4-hydroxybenzenesulfonic acid sodium salt (2.81 g, 12.11 mmol) in 50 mL of isopropyl alcohol, 11.8 mL 2N NaOH and 5.56 g (24.2 mmol, 2 eq) of 1-(3-bromo-prop-1-ynyl)-4-chloro-benzene was added. The solution was heated to 70° C. overnight. The reaction was cooled, concentrated in vacuo, filtered and air dried to afford 2.8 g (67%) of 4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-benzenesulfonic acid, sodium salt. Electrospray Mass Spec 321.3 (M−H)−
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=O)=O>CN(C=O)C>[N:1]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Temperature: 90 °C
Yield: 97.1 %

Procedure:
Under a nitrogen atmosphere, sodium azide (29.8 g, 458 mmol) was added to a solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (118 g, 416 mmol) in DMF, and the reaction was heated at 90° C. for six hours. The reaction was allowed to cool to room temperature overnight, and then the solvent was removed under reduced pressure. Water (1 L) was added, and the resulting solution was extracted with diethyl ether (4×500 mL). The combined extracts were washed with water (1×250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 93.0 g of tert-butyl 2-(2-azidoethoxy)ethylcarbamate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:19])=[C:12]3[S:18][CH:17]=[CH:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:29][CH3:30].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:19])[C:12]3[S:18][CH:17]=[CH:16][C:13]=3[N:14]([CH2:29][CH3:30])[CH:15]=2)=[O:9])=[CH:20][CH:21]=1
Reactant: CCI
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccsc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sccc21
Temperature: 100 °C

Procedure:
N-(4-chlorobenzyl)-7-hydroxythieno[3,2-b]pyridine-6-carboxamide (Example 1, 885 mg)was dissolved in DMF (20 mL) and to the solution was added potassium carbonate (1.92 g) and iodoethane (1.1 mL). The mixture was heated to 100° C. for 16 h. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×25 mL) followed by brine (25 mL), dried (MgSO4), and concentrated. The crude product was purified by column chromatography (EtOAc/heptane, 1/1; CH2Cl2/methanol, 100/1) and the resulting solid was recrystallized from ethanol to afford 590 mg of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([N:12]([CH2:20][C:21]2([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:24][CH2:23][CH2:22]2)C(=O)OC(C)(C)C)=[CH:8][CH:7]=1)=[CH2:5])C.Cl/[C:33](=[N:39]/O)/[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O)(C(F)(F)F)=O>C1COCC1>[F:31][C:30]1[C:25]([C:21]2([CH2:20][NH:12][C:9]3[N:10]=[N:11][C:6]([C:4]4[O:3][N:39]=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:5]=4)=[CH:7][CH:8]=3)[CH2:24][CH2:23][CH2:22]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=C(OCC)c1ccc(N(CC2(c3ncccc3F)CCC2)C(=O)OC(C)(C)C)nn1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
To t-butyl 6-(1-ethoxyvinyl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (439 mg, 1.02 mmol) in THF (5.0 mL) was added (E)-ethyl 2-chloro-2-(hydroxyimino)acetate (465 mg, 3.06 mmol) and TEA (1.4 mL, 10.2 mmol). The reaction mixture was stirred at rt for 30 min followed by addition of TFA (5 mL) and then heated to reflux overnight. The mixture was then concentrated and purified by reverse phase chromatography to give 415 mg of the title compound as a colorless oil, LRMS (M+H+) m/z 398.3.
Reaction SMILES: [OH:1][C:2]([C:5]([OH:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[B:27](O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[CH3:3][C:2]1([CH3:4])[C:5]([CH3:7])([CH3:6])[O:8][B:27]([C:18]2[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:1]1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: CC(C)(O)C(C)(C)O
Solvent: CCOCC
Product: CC1(C)OB(c2cc(C(F)(F)F)ccc2OCc2ccccc2)OC1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Pinacol (1.82 g) was added to a solution of the product from example 32 step (ii) (4.54 g) in ether (40 ml) and stirred at RT for 20 h. The reaction was diluted with ether (100 ml), washed with brine, dried (MgSO4) and evaporated. Yield 5.7 g.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[N+:18]([O-])=O>C(O)(=O)C.[Fe]>[NH2:18][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:7][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(C)nc1C(=O)OCC
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(N)c(C)nc1C(=O)OCC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
56.9 g (1.065 mol) of iron powder in 200 ml of glacial acetic acid were initially taken and were heated to 70° C. while stirring, and a solution of 100 g (0.355 mol) of diethyl 6-methyl-5-nitropyridine-2,3-dicarboxylate (EP 227 932) in 700 ml of glacial acetic acid was added in the course of 20 minutes. Stirring was carried out for 2 hours, after which a further 25.2 g (0.45 mol) of iron powder in 200 ml of glacial acetic acid were added and stirring was continued for a further hour at 70° C. The mixture was cooled to 25° C., the precipitate was filtered off with suction and the filtrate was evaporated down under reduced pressure, after which the residue was taken up in methylene chloride, extracted in succession with water, saturated sodium bicarbonate solution and sodium chloride solution, dried over magnesium sulfate and filtered off with suction over a suction filter containing silica gel. 49 g (55% of theory) of the title compound were isolated as a yellow resin from fractions 3 and 4 after they had been evaporated down.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][C:8]([CH3:12])=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[O:5]>C(OCC)(=O)C.[Pd].[Pt]=O>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]([CH3:12])[CH:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[O:5]
Reactant: CC(C)=C(C)CCC(C)CC=O
Agent: O=[Pt]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CC=O)CCC(C)C(C)C
Temperature: 22 °C

Procedure:
11.2 g of 3,6,7-trimethyl-6-octenal is dissolved in 120 ml of ethyl acetate and mixed with 2 g of palladium (10% by wt.) on calcium carbonate and 0.3 of platinum oxide. The mixture is stirred at room temperature (22°C.) under an atmosphere of hydrogen. The course of the hydrogenation is followed by removing samples and subjecting them to gas chromatography. The hydrogenation is terminated when the starting material can no longer be detected by gas chromatography. The product is filtered through Celite diatomaceous earth and concentrated on a rotary evaporator. The resulting oil is purified by chromatography on a 10-fold amount of Kieselgel, using 1% by volume diethyl ether in hexane as the eluant. There is obtained 3,6,7-trimethyl-octan-1-al as a colorless oil; nD25 = 1.4436.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([SH:9])[N:3]=1.[CH2:10](I)[CH2:11][CH3:12]>[OH-].[K+]>[CH2:10]([S:9][C:4]1[N:5]=[C:6]([OH:8])[CH:7]=[C:2]([OH:1])[N:3]=1)[CH2:11][CH3:12]
Reactant: CCCI
Reactant: Oc1cc(O)nc(S)n1
Agent: [K+]
Agent: [OH-]
Product: CCCSc1nc(O)cc(O)n1
Reaction time: 96 h

Procedure:
To a solution of 4,6-dihydroxy-2-mercaptopyrimidine (100 g) in potassium hydroxide (2.5N, 571 ml) was added propyl iodide (76.8 ml) and the whole was stirred for 4 days. The solution was acidified to pH 2-3 and filtered to afford the sub-title compound (15 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][C:6](=[O:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.N#N.FC(F)(F)S(O[Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])(=O)=O>C(Cl)Cl>[O:29]=[C:6]1[CH:5]=[C:4]2[C@:24]([CH3:27])([CH2:25][CH2:26][C@H:2]([O:1][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[CH2:3]2)[C@@H:23]2[C@@H:7]1[C@H:8]1[C@:20]([CH3:28])([CH2:21][CH2:22]2)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#N
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of methyl 313-hydroxy-7-oxochol-5-en-24-oate (2) (5.02 g, 12.5 mmoles) and 2,6-1utidine (3.32 ml, 28.5 mmoles) in CH2Cl2 (23 ml) cooled in an ice bath in a N2 atmosphere was added dropwise with magnetic stirring triisopropylsilyl trifluoromethanesulfonate (4.56 g, 17 mmoles). After 2 hrs, the reaction was diluted with CH2Cl2 (150 ml). It was then washed with cold 2N HCl, washed twice with H2O and then with saturated brine before drying with MgSO4. Evaporation in vacuo and purification of the residue by flash chromatography on silica gel with hexane-EtOAc (10:1 ) gave 5.88 g of 3 as a colorless syrup. NMR (CDCl3): δ0.67 (s, 3H, 18-Me); 0.93 (d, 3H, 20-Me); 1.06 (s, 18H, TIPS Me); 1.19 (s, 3H, 19-Me); 3.66 (s, 3H, CO2Me); 3.68 (m, 1H, 3-H); 5.66 (s, 1H, 6-H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:9]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[C@H:3]1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:9]=1
Reactant: O=Cc1ccccn1
Reactant: CC1CCCNC1c1nc(-c2cccc(C#N)c2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H]1CCCN(Cc2ccccn2)[C@H]1c1nc(-c2cccc(C#N)c2)no1
Yield: 51.5 %

Procedure:
The reaction was carried out as described in Example 43 from 3-[5-(3-methyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile (29 mg, 0.108 mmol) with pyridine-2-carbaldehyde (13.9 mg, 0.13 mmol) and sodium triacetoxyborohydride (34.3 mg, 0.162 mmol) in dichloroethane (2 mL) to give cis-3-[5-(3-Methyl-1-pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile (20 mg, 51.5%); 1H NMR (CDCl3), δ(ppm): 8.55 (d,1H), 8.45 (s, 1H), 8.38 (d, 1H), 7.80 (d,1H), 7.65 (m, 2H), 7.41 (d, 1H), 7.18(m, 1H), 4.40 (d, 1H), 3.76 (d, 1H), 3.53 (d, 1H), 3.03 (m,1H), 2.68 (m,1H), 2.30 (m, 1H), 1.74(m, 4H), 0.82 (d, 3H); and trans-3-[5-(3-methyl-1-pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile (5 mg, 12.9%); 1H NMR (CDCl3), δ(ppm): 8.49+ (d,1H), 8.43 (s, 1H), 8.35 (d, 1H), 7.80 (d,1H), 7.65 (m, 2H), 7.55 (d, 1H), 7.14(m, 1H), 3.59 (m, 3H), 3.03 (m, 1H), 2.25 (m, 2H), 1.92 (m,1H), 1.73 (m, 2H), 1.27(m, 1H), 0.87 (d, 3H).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([CH:17]([CH2:23][C:24]#[CH:25])[C:18](OCC)=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.C1(C)C=CC=CC=1>[CH3:3][C:2]1[NH:5][C:18](=[O:19])[C:17]([CH2:23][C:24]#[CH:25])=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: C#CCC(C(=O)OCC)C(=O)c1ccccc1
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C#CCc1c(-c2ccccc2)nc(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29.2 %

Procedure:
To a stirred suspension of 8.00 g (84.6 mmol) of acetamidine hydrochloride in 100 mL of methanol was added 4.56 g (84.4 mmol) of solid sodium methoxide. The mixture was stirred for 40 min at room temperature and rotovaped to remove the methanol. The residue was suspended in 75 mL of ethanol and a solution of 6.19 g (26.9 mmol) of ethyl 2-benzoyl-pent-4-ynoate in 75 mL of toluene was added. The mixture was heated to reflux with a Dean Stark trap and the first 80 mL of distillate was collected and discarded. An 80 mL portion of toluene was added and the mixture was heated at reflux for two weeks. The mixture was allowed to cool, diluted with 70 mL of ether and extracted with two 50 mL portions of 5% aqueous sodium hydroxide. The aqueous extracts were acidified to pH 1 and washed with two 75 mL portions of ethyl acetate. The pH of the aqueous phase was adjusted to 10 and the white precipitate that formed was collected by filtration. Drying furnished 1.76 g (29%) of 2-methyl-6-phenyl-5-propargyl-4(3H)-pyrimidinone, mp 220°-225° C., 1H-NMR (d6-DMSO) δ 2.3 (3H,s), 2.68(1H,t,J=4), 3.20(2H, d,J=4), 7.45(3H,m), 7.65(2H,m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([N+:19]([O-])=O)=[CH:13][C:12]=1[O:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH2:19])=[CH:13][C:12]=1[O:22][CH3:23])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1CCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCNC(=O)OC(C)(C)C)c(OC)cc1N
Yield: 90.7 %

Procedure:
27 g (83 mmol) N-t-butoxycarbonyl-4-nitro-2,5-dimethoxyphenethylamine J3 was dissolved in 300 ml methanol, and 1.5 g 10% palladium on carbon black was added. This suspension was hydrogenated at 2.2 atm. for 18 hours till no further hydrogen uptake was observed. The catalyst was filtered off and the solvent was evaporated to afford 22.3 g white powder (yield: 98%). 1H-NMR (CDCl3), δ (ppm): 1.40 (s, 9H), 1.55 (s, 2H), 2.65 (t, 2H), 3.25 (t, 2H), 3.70 (s, 3H), 3.80 (s, 31H), 6.30 (s, 1H), 6.58 (s, 1H).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]3[CH2:12][CH2:13][O:14][C:15]([CH2:18][C:19](O)=[O:20])([CH2:16][CH3:17])[C:10]=3[NH:9][C:8]=12.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:16]([C:15]1([CH2:18][CH2:19][OH:20])[C:10]2[NH:9][C:8]3[C:7]([C:11]=2[CH2:12][CH2:13][O:14]1)=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:2][CH3:1])[CH3:17]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A solution of etodolac (2.0 g, 6.97 mmol) in dry THF (5 mL) was added dropwise to 1M LiAlH4 in THF (10.5 mL, 10.5 mmol, 1.5 eq) over five minutes and stirred at room temperature overnight under argon. The resulting mixture was then slowly quenched with EtOAc and poured over water to form an emulsion. The emulsion was filtered, and the aqueous layer was separated and extracted twice with EtOAc. The three organic phases were combined, washed with brine, dried with Na2SO4, concentrated, and purified by column chromatography using 50:50:EtOAc:Hexane to give a yellow oil (1.87 g, 98%): 1HNMR (CDCl3, δ TMS): 0.95 (t, 3H), 1.36 (t, 3H), 1.96 (m, 2H), 2.14 (m, 2H), 2.68 (br, OH), 2.81 (m, 2H), 2.83 (q, 2H), 3.70 (m, 2H), 4.07 (m, 2H), 7.02-7.39 (m, 3H, Ar—H), 7.74 (br, 1H, NH). MS+: m/z 296 (MNa+). MS−: m/z 308 (MCl−), 272 ([M−H]−).