Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:15](=[O:18])([O-])[O-:16].[Na+].[Na+].ClC(OC[CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)=O.Cl>O.O1CCOCC1>[CH:28]1[C:27]2[CH:26]([O:16][C:15]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9]4)=[CH:4][CH:3]=3)=[O:18])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[CH:31]=[CH:30][CH:29]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc2ccc(C(=O)O)cc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc2ccc(C(=O)O)cc2c1)OC1c2ccccc2-c2ccccc21
Reaction time: 0.25 h

Procedure:
To 0.504 g (2.70 mmol) of 7-aminonaphthalene-2-carboxylic acid (106; prepared according to the procedure in Harrison, H. A. and Royle, F. A. J. Chem. Soc., 1926, 84) was added 10 mL of dioxane, 5 mL of 10% sodium carbonate, and 35 mL of water. To this clear solution was added 0.786 g (2.97 mmol) of 9-fluorenylmethyl chloroformate, portionwise, over 15 minutes. After 3 hours, the reaction was acidified with 1N HCl and the resulting white precipitate was collected by vacuum filtration. This solid was suspended in diethyl ether and stirred to give a fine precipitate that was collected by vacuum filtration. This provided 0.948 g of compound 107.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:11])=[CH:3]\[C:4]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[O:5].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[C:21]([O:27][CH3:28])(=[O:26])[CH2:22][C:23]([CH3:25])=O>C(O)C>[CH3:25][C:23]1[NH:1][C:2]([CH3:11])=[C:3]([C:4]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[O:5])[CH:17]([C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[C:22]=1[C:21]([O:27][CH3:28])=[O:26]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)CC(C)=O
Reactant: C/C(N)=C/C(=O)OCCC#N
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)C1c1ccc(F)cc1
Yield: 94.4 %

Procedure:
15.4 g (0.1 mol) of 2-cyanoethyl 3-aminocrotonate, 12.4 g (0.1 mol) of p-fluorobenzaldehyde and 11.6 g of methyl acetoacetate are heated overnight under reflux in 150 ml of ethanol. After removing the solvent on a rotary evaporator, the residue is taken up in ethyl acetate, washed with water, dried and 33.8 g of crude product are obtained after removing the solvent in vacuo.
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][N:11]([CH3:25])[C:12]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[CH:1]1([NH:9][CH:15]2[CH2:14][CH2:13][C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([N:11]([CH3:25])[CH3:10])[CH2:17][CH2:16]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCCCC1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(NC2CCCCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.5 %

Procedure:
254 mg Cyclooctylamine and 434 mg 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in dry tetrahydrofuran (15 ml) and 1,2-dichloroethane (5 ml) under argon. Glacial acetic acid (120 mg) and 600 mg sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for 18 hours at RT. For working up, the reaction mixture was concentrated and the residue was washed with one molar hydrochloric acid (20 ml) and with ether (2×30 ml). The aqueous phase was rendered alkaline with five molar sodium hydroxide solution and extracted with ether (3×30 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product (515 mg) was chromatographed over silica gel with methanol. 108 mg N′-cyclooctyl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a colorless oil, from which the corresponding dihydrochloride was precipitated with 3.3 M ethanolic hydrochloric acid (0.25 ml) in 2-butanone (2 ml) (102 mg; m.p. 247-249° C.).
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[Si:8]([O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:27]=[C:26]([NH:28][C:29]3[C:30]([O:35]C)=[N:31][CH:32]=[CH:33][CH:34]=3)[N:25]=[C:24]([NH:37][C@H:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=3)[CH3:39])[CH:23]=2)[CH2:18][CH2:17]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].O>C(#N)C>[Si:8]([O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[C:24]([NH:37][C@H:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=3)[CH3:39])[N:25]=[C:26]([NH:28][C:29]3[C:30](=[O:35])[NH:31][CH:32]=[CH:33][CH:34]=3)[N:27]=2)[CH2:18][CH2:17]1)([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:10])[CH3:9]
Reactant: COc1ncccc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C[C@H](Nc1cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)nc(Nc2ccc[nH]c2=O)n1)c1ccc(F)cn1
Temperature: 80 °C
Yield: 128.5 %

Procedure:
Trimethylsilyl chloride (0.285 mL, 2.25 mmol) and sodium iodide (337 mg, 2.25 mmol) were added to a stirred solution of 6-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-N4-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N2-(2-methoxypyridin-3-yl)pyrimidine-2,4-diamine (Preparation 10c, 415 mg, 0.75 mmol) in acetonitrile (5 mL) and the reaction mixture was heated at 80° C. for 4.5 hours. After cooling to ambient temperature, water was added and the mixture was extracted with ethyl acetate (×3). The pH was then adjusted to ca. 6 with 2M aqueous sodium hydroxide solution and the aqueous phase was extracted with ethyl acetate (×3). The combined organic extract was washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure to give the title compound (0.52 g, 100%) as a brown oil which was used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[N:27]1[N:36]2[C:30]([CH2:31][NH:32][C:33]3[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=3[CH2:35]2)=[CH:29][CH:28]=1>C(Cl)Cl.C(OCC)(=O)C>[N:27]1[N:36]2[C:30]([CH2:31][N:32]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:33]3[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=3[CH2:35]2)=[CH:29][CH:28]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a mixture of 1.37 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml of triethylamine. To the mixture is added 5 mmol of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine. The reaction mixture is allowed to stir at room temperature for 48 hours and the volatiles are removed in vacuo to give a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO3 and brine. The solution is dried with Na2SO4 and the solvent removed in vacuo. The residue is purified by flash chromatography on silica gel with ethyl acetate-hexane to give the desired product, m.p. 142°-146° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[C:29]([Si:33]([CH3:44])([CH3:43])[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]1)([CH3:32])([CH3:31])[CH3:30].N1C(C)=CC=CC=1C>CN(C)C=O.C(Cl)Cl>[C:29]([Si:33]([CH3:44])([CH3:43])[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][C:39]([NH:42][C:14](=[O:15])[C@@H:13]([C:5]2[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[N:38]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1C#N
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C#N)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
In a round bottom flask was placed (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (75 mg, 0.23 mmol), methylene chloride (2 mL) and N,N-dimethylformamide (3 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 130 μL, 0.26 mmol). Upon addition there was gas evolution. This was stirred for 30 min at 25° C. after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 56 mg, 0.23 mmol), 2,6-lutidine (55 μL, 0.46 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 2 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 40% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (105 mg, 84%) as a white foam: [α]24589=−11.0° (c=0.20, methanol); ES-HRMS m/e calcd for C27H40N4O4SSi (M+H)+ 545.2613, observed 545.2603; 1H NMR (400 MHz, CDCl3) δ −0.05 (s, 6H, 2×SiCH3), 0.84 (s, 9H, 3×CH3), 1.14 (m, 2H, CH2), 1.46-1.94 (m, 8H, 4×CH2), 2.24 (m, 1H, CH), 3.27 (s, 3H, SO2CH3), 3.59 (t, J=7.6 Hz, 1H, ArCH), 3.87 (t, J=5.3 Hz, 2H, OCH2), 4.08 (t, J=5.3 Hz, 2H, NCH2), 6.62 (d, J=2.2 Hz, 1H, Ar), 7.35 (d, J=2.2 Hz, 1H, Ar), 7.84 (dd, Jm=1.8 Hz, Jo=8.3 Hz, 1H, Ar), 7.91 (brs, 1H, NH), 7.97 (d, Jm=1.8 Hz, 1H, Ar), 8.15 (d, Jo=8.3 Hz, 1H, Ar).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[O:5][CH2:6][C:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:11]=2[CH3:12])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH3:24]
Reactant: CCOC(=O)CCc1cc(O)ccc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(OCc2ccccc2OCc2nc(-c3ccccc3)oc2C)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.65 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (0.46 g), anhydrous potassium carbonate (0.30 g) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.89 g, 95%) of 3-[2-ethoxy-5-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 146-147° C.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)(=O)C.[Cl-].[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>C(O)C.O.CCOCC>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[CH2:28]([O:29][C:10]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)=[O:11])[CH3:27]
Reactant: CC(=O)N1CCC(C(=O)Cl)(c2ccccc2Sc2ccccc2)CC1
Agent: O=C(O)C(=O)O
Agent: [Cl-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1(c2ccccc2Sc2ccccc2)CCNCC1

Procedure:
A mixture of 2 g of 1-acetyl-4-(2-phenylthiophenyl)-piperidine-4-carbonyl chloride, Example 16, in 50 ml of absolute ethyl alcohol saturated with anhydrous chloride is stirred at reflux for 64 hours. Thereafter, the excess acid and alcohol is removed under reduced pressure, leaving a clear, glassy residue. The residue is dissolved in 30 ml of water and the aqueous solution is extracted with ethyl acetate. The aqueous solution is basified with potassium carbonate, liberating an oil. The oil is dissolved in ether and the ethereal solution is dried before concentrating to dryness, leaving a brownish oil. The oil, in ether, is converted to its oxalic acid salt which is recrystallized from a methyl alcohol-acetone-ether mixture to provide 4-ethoxycarbonyl-4-(2-phenylthiophenyl)-piperidine oxalate.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Pd]>[C:1]([O:4][CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CC(=O)O
Agent: [Pd]
Product: CC(=O)OCc1ccccc1

Procedure:
Using a catalyst consisting of 0.6% Pd, 0.5% Au and 1.0% Bi, without added promoter, under the following reaction conditions: 150° C.; 1100 psig air pressure, reaction time: 3 hours and 1:1 molar ratio of acetic acid to toluene, 1016 grams of benzyl acetate per gram Pd are obtained.
Reaction SMILES: [NH2-:1].[Na+].N.[CH2:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[H][H]>O.C1(C)C(C)=CC=CC=1>[CH2:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[NH2:1][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[N:10]=1.[CH2:4]([C:9]1[N:10]=[C:11]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[N:1]=2)[CH:12]=[CH:13][CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: [H][H]
Reactant: [NH2-]
Agent: CC(C)CCc1ccccn1
Agent: N
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)CCc1cccc(-c2cccc(CCC(C)C)n2)n1
Product: CC(C)CCc1cccc(N)n1
Reaction time: 6.5 h
Yield: 8.2 %
Yield: 38.9 %

Procedure:
In a 300 cc, three-neck flask, equipped with a stirrer and dropping funnel, was made 0.2 mole of sodamide in liquid ammonia. The ammonia was replaced with 100 cc of xylene. A thermometer and reflux condenser were attached to the reaction flask, and the mixture was heated to reflux. Under reflux, 24.1 g (0.16 mole) of 2-isoamylpyridine was added from the dropping funnel. The reaction mixture turned to a deep purple and hydrogen began evolving. Refluxing was continued for 6.5 hours. The temperature range was 140°-146° C. At the end of the reflux, the reaction mixture was cooled to about 100° C. and hydrolyzed with 50 cc of water. The oil layer was separated at room temperature and the aqueous layer was extracted with 22 cc of xylene. The oil layer and xylene extract were distilled through a Vigreaux column to give 15.3 g of 2-isoamylpyridine (0.10 mole), 0.8 g of 2-amino-6-isoamylpyridine (8.2% yield) and 3.4 g of 6,6'-di-isoamyl-2,2'-bipyridyl (38.9% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17](O)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.53 g (purity 73%, 3.35 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 1.52 g (purity 93%, 83% of theory)
Reaction SMILES: C([Li])CCC.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([CH3:23])[CH2:17]1>CCCCCC.C(OCC)C>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[C:19]1([OH:22])[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]1[CH3:23]
Reactant: c1ccc2occc2c1
Reactant: CC1CN(C)CCC1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1CN(C)CCC1(O)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
50 ml of a bimolar solution of n-butyl lithium in hexane is added dropwise within 30 minutes, at a reaction temperature of -5°, to a solution of 11.8 g of benzofuran in 100 ml of diethyl ether. The solution is then stirred for a further hour at 0°. There is thereupon made within 15 minutes a dropwise addition of a solution of 1,3-dimethyl-4-piperidone in 50 ml of abs. diethyl ether. The reaction temperature is maintained at 0° by external cooling. The reaction solution is subsequently stirred for a further 15 hours at room temperature. It is then poured, with stirring, onto 200 g of ice, and the aqueous phase extracted three times with 500 ml of ethyl acetate each time. The combined organic extracts are dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 500 ml of 2N hydrochloric acid and the acid solution washed with ether. The aqueous solution is thereupon adjusted by addition of 10% sodium hydroxide solution to pH 12, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered off under suction, and concentrated by evaporation to obtain 4-(2-benzofuranyl)-1,3-dimethyl-4-piperidinol, which melts at 128°-130° after recrystallisation from hexane.
Reaction SMILES: Br.Br[CH2:3][CH2:4][CH:5]([NH2:9])[C:6]([OH:8])=[O:7].[CH3:10][S:11](C)=[O:12]>>[NH2:9][C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3][S:11][CH3:10].[NH2:9][C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3][OH:12]
Reactant: CS(C)=O
Reactant: NC(CCBr)C(=O)O
Agent: Br
Product: CSCC[C@H](N)C(=O)O
Product: N[C@@H](CCO)C(=O)O
Yield: 2.6 %
Yield: 82 %

Procedure:
4-Bromo-2-aminobutanoic acid hydrobromide (1 eq.) was treated with sodium methane thiolate (3.2 eq.) in DMSO (25 eq.) at 80° C. for 1 hour. Methionine (82% yield) and homoserine (2.6% yield) were obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[C:18]([O:22][C:23]([N:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35](O)=[O:36])[CH:31]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35]([N:1]3[CH2:2][CH:3]([N:5]4[CH2:6][CH2:7][N:8]([C:11]([C:13]5[S:14][CH:15]=[CH:16][N:17]=5)=[O:12])[CH2:9][CH2:10]4)[CH2:4]3)=[O:36])[CH:31]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)N3CC(N4CCN(C(=O)c5nccs5)CC4)C3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of compound 5e (651 mg, 2 mmol), 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester 17b (555 mg, 2 mmol), and EDC (466 mg, 3 mmol) in CH2Cl2 (20 mL) was added Et3N (0.84 mL, 6 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was extracted with CH2Cl2, and H2O after acidifying the water layer to pH˜6 with 1N aqueous HCl. The organic solution was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave 17c (826 mg). MS m/z (M+H+) 512.1.
Reaction SMILES: [CH2:1]([S:4][CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[S:9][CH:10]=1)[CH2:2][CH3:3].[OH:19]OS([O-])=O.[K+].[OH2:25]>CO>[CH2:1]([S:4]([CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[S:9][CH:10]=1)(=[O:19])=[O:25])[CH2:2][CH3:3]
Reactant: CCCSCc1csc(NC(=O)OC(C)(C)C)n1
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Product: CCCS(=O)(=O)Cc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 4-(propylthiomethyl)thiazol-2-ylcarbamate (16 mmol) in MeOH (175 mL) was added a solution of oxone (3.0 eq, 29.5 g) in H2O (75 mL) and stirred for 3 hours at room temperature. H2O was added to the reaction mixture and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and concentration afforded the title sulfone (4.71 g, 97% yield) as a yellow/orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1.[C:27]1([CH2:33][OH:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+]>CN(C=O)C>[CH2:33]([O:34][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(OCc4ccccc4)ncn3)CC2)CC1
Temperature: 30 °C

Procedure:
The tert-butyl 1′-(6-chloropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (100 mg, 0.26 mmol), phenylmethanol (0.031 mL, 0.29 mmol) were added to DMF (2.6 mL), and then sodium hydride (7 mg, 0.29 mmol) was added to the mixture. The reaction was heated to 30° C. for 30 min. The reaction crude was cooled down to r.t. and quenched with ice ammonia chloride solution (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with brine (10 mL, ×1), dried over magnesium sulfate, filtered and concentrated by rotavapor. The crude mixture was purified by preparative TLC with 30% ethylacetate:hexane to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:18][NH:19][O:20][CH3:21]>>[NH2:1][C:2]1[CH:10]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:19]([O:20][CH3:21])[CH3:18])=[O:5]
Reactant: CNOC
Reactant: Nc1cc(S(F)(F)(F)(F)F)ccc1C(=O)O
Agent: Cl
Product: CON(C)C(=O)c1ccc(S(F)(F)(F)(F)F)cc1N

Procedure:
2-Amino-4-(pentafluorosulfanyl)benzoic acid (2.0 g) was reacted with N,O-dimethylhydroxylamine hydrochloride analogously to example 15a). 2.3 g of the desired product were obtained.