Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:8][C:9]1[N:10]=[N:11][N:12]([CH2:14][C:15]2[NH:19][N:18]=[N:17][N:16]=2)[N:13]=1)C1C=CC=CC=1>[Hg].CN(C=O)C>[NH:16]1[C:15]([CH2:14][N:12]2[N:11]=[N:10][C:9]([SH:8])=[N:13]2)=[N:19][N:18]=[N:17]1
Reactant: c1ccc(CSc2nnn(Cc3nnn[nH]3)n2)cc1
Agent: [Hg]
Solvent: CN(C)C=O
Product: Sc1nnn(Cc2nnn[nH]2)n1
Reaction time: 0.14 h

Procedure:
5-Benzylthio-2-(1H-tetrazole-5-ylmethyl)-2H-tetrazole, 175 mg., prepared as described above under part C, was dissolved in 40 ml. of distilled DMF and reduced at the mercury pool cathode (14 cm2Hg pool) with a platinium wire anode. The electrodes were separated by a glass frit. The electrolyte was tetraethylammonium perchlorate, 0.1 M in the DMF solution of the substrate. The electrolysis was carried out at -2.7 to -2.85 volts for 500 seconds at -2.80 v. for about 630 seconds.
Reaction SMILES: O1CCC(=CC[C@H](C(OC(C)(C)C)=O)[C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])CC1.C([NH:29][NH2:30])C(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>O1CCOCC1>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:10][C:11]([NH:29][NH2:30])=[O:12]
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CC=C1CCOCC1)C(=O)OC(C)(C)C
Reactant: CC(C)CNN
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)CCC(=O)NN

Procedure:
In a manner analogous to that described in Example 2, parts (iii)-(v), starting from 4-tert-butyl hydrogen 3(S)-[(tetrahydro-2H-pyran-4-ylidene)ethyl]-2(R)-isobutylsuccinate and isobutylhydrazine and using trimethylsilyl trifluoromethanesulphonate in 1,4-dioxane instead of trifluoroacetic acid to deprotect the tertiary butyl ester there was obtained 2(R)-[3-(tetrahydro-2H-pyran-4-ylidene)-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-propyl]-2′-isobutyl-2′-methanesulphonyl)-4-methylvalerohydrazide in the form of an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=1.[CH3:16][C:17]1[C:18]([O:20][C:21](=O)[C:22]=1[CH3:23])=[O:19]>C(O)(=O)C>[NH2:15][S:12]([C:4]1[CH:3]=[C:2]([N:1]2[C:18](=[O:19])[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]2=[O:20])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=[O:13])=[O:14]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: COC(=O)c1ccc(N)cc1S(N)(=O)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N2C(=O)C(C)=C(C)C2=O)cc1S(N)(=O)=O
Reaction time: 2 h
Yield: 43 %

Procedure:
In 3 ml of acetic acid, 1 mmol of methyl 4-amino-2-(aminosulfonyl)benzoate and 1.05 mmol of 2,3-dimethylmaleic anhydride were stirred at 80° C. for 40 hours. Acetic acid was then distilled off from the reaction mixture, followed by the addition of 20 ml of ice water to the oily residue. After the mixture thus formed was stirred for 2 hours, the resulting precipitate was collected by filtration and then dried in air. Yield: 43%. Its physiocochemical properties are shown in Table 8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.C=O.[CH3:19]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH3:19])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(=O)O
Reactant: Fc1ccc2nnc([C@H]3CCCNC3)n2c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC[C@H](c2nnc3ccc(F)cn23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a yellow solution of Intermediate 88c (220 mg, 1.00 mmol), formaldehyde (37% in water, 0.811 mL, 10.0 mmol) and AcOH (0.057 mL, 1.00 mmol) in DCM-MeOH (5:1, 12 mL) was added NaBH(OAc)3 (424 mg, 2.00 mmol) (CARE: gas evolution) and the solution stirred at RT for 2 h. The solution was concentrated in vacuo to 5 mL volume, then applied to an SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (50 mL); concentration in vacuo gave the title compound as a pale yellow gum, that became a white solid on standing (234 mg, quant.). LCMS (Method 3): Rt 0.45 min, m/z 235 [MH+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][O:5][C:4](=[O:8])[CH:3]=1.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:9]([S:16][C:2]1[CH:7]=[CH:6][O:5][C:4](=[O:8])[CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: SCc1ccccc1
Reactant: O=c1cc(Cl)cco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(SCc2ccccc2)cco1
Reaction time: 1 h

Procedure:
To a solution of 0.433 g (0.0033 mol) of 4-chloro-2-oxo-2H-pyran and 0.41 g (0.0033 mol) of benzyl mercaptan in 2 ml of dimethyl formamide is added 0.228 g (0.00165 mol) of K2CO3. The reaction mixture is stirred for 1 hour and then the same amount of K2CO3 is once more added. The reaction mixture is then stirred overnight at 25° C., diluted with 30 ml of CH2C2, and extracted with 5×50 ml of a saturated aqueous solution of NaCl. The organic phase is dried over Na2SO4 and concentrated in a water jet vacuum. The distillation residue is chromatographed over silica gel. Yield: 0.36 g (50%). Melting point: 105°-106° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[Cl-].[NH4+]>C(O)C.O1CCCC1.[Fe]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: CN(C)CCSc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)CCSc1ccc(N)cc1
Temperature: 100 °C

Procedure:
To a solution of N,N-dimethyl-N-{2-[(4-nitrophenyl)thio]ethyl}amine (0.58 g, 3.0 mmol) in ethanol (45 mL), tetrahydrofuran (23 mL), and saturated aqueous ammonium chloride solution is added iron powder (1.1 g, 6.4 mmol). The mixture is heated in a 100° C. oil bath for one hour. While still hot, the reaction mixture is filtered through a pad of diatomaceous earth. The concentrated filtrate is partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material is purified by reverse-phase high performance liquid chromatography to give 4-(2-dimethylamino-ethylsulfanyl)-phenylamine.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][F:22])[N:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][CH2:21][C:17]1[N:16]=[C:15]([C:14]#[C:13][CH2:12][CH2:11][C:9]2[N:10]=[C:3]3[C:2]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:7][CH:6]=[CH:5][N:4]3[CH:8]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: FCc1cccc(C#CCCc2cn3cccc(Br)c3n2)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: FCc1cccc(C#CCCc2cn3cccc(-c4ccccc4)c3n2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.9 %

Procedure:
To a solution of 8-bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (compound 171(C), 301 mg, 0.84 mmol) and phenylboronic acid (50 mg, 1.3 mmol) in degazed DME (4.2 mL) was added 1.32 mL of a solution of K3PO4 2M (degazed before use). After stirring at room temperature for 5 min under N2, Pd(PPh3)4 (190 mg, 0.17 mmol) was added in one portion. The resulting mixture was heated at 80° C. for 4 h. The Mixture was cooled down to room temperature and diluted in AcOEt. The organic layer was washed twice with saturated NaCl, dried over magnesium sulfate, filtered and concentrated. The crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 60/40 as eluent) to afford 137 mg of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-8-phenyl-imidazo[1,2-a]pyridine (Yield: 46%) as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][NH2:6].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].S>O>[CH2:16]([O:15][C:13]([NH:6][CH2:5][CH2:4][CH2:3][C@@H:2]([C:7]([OH:9])=[O:8])[NH2:1])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Dissolve ornithine (13.3 g, 0.1 mol) in 1N sodium hydroxide (200 mL, 0.2 mol). Add a solution of CuSO4.5H2O (12.5 g, 0.05 mol) in water (50 mL). Stir the mixture until solution is complete. Treat with benzyl chloroformate (17.1 g, 0.1 mol) and stir at room temperature until reaction is complete. Suction filter, wash the residue with 1:3.5 methanol-water and dry at 60° C. to give the copper complex. Suspend the copper complex in water, treat with excess hydrogen sulfide, heat to boiling, then cool to room temperature. Mix with 1N sodium hydroxide and filter. Stir the filtrate with a slight excess of 1N hydrochloric acid and filter. Wash the residue with water and dry to give N5 -benzyloxycarbonyl-ornithine.
Reaction SMILES: C1O[C:4]2([CH:11]3[CH2:12][C:7]4([S:14]([NH2:17])(=[O:16])=[O:15])[CH2:8][CH:9]([CH2:13][CH:5]2[CH2:6]4)[CH2:10]3)[O:3]C1.Cl>C1COCC1>[NH2:17][S:14]([C:7]12[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:13][CH:5]([C:4]3=[O:3])[CH2:6]1)[CH2:8]2)(=[O:15])=[O:16]
Reactant: NS(=O)(=O)C12CC3CC(C1)C1(OCCO1)C(C3)C2
Agent: Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)C12CC3CC(C1)C(=O)C(C3)C2
Temperature: 60 °C
Yield: 82.9 %

Procedure:
A solution of the product of Example 54G (1.26 g, 4.63 mmol) in THF (15 mL) at room temperature was treated with 1N hydrochloric acid (14 mL). Reaction heated at 60° C. for 16 hours. Reaction quenched with saturated sodium bicarbonate, and product extracted with 20% methanol in chloroform (2×) and 40% THF in DCM (2×). Extracts dried (Na2SO4), filtered, and evaporated under reduced pressure to provide the title compound (0.880 g, 82%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Br)=[C:50]([F:56])[CH:49]=1>CN(C)C=O>[CH3:4][C:1]([O:5][C:6](=[O:44])[N:7]([CH2:52][C:51]1[CH:54]=[CH:55][C:48]([Br:47])=[CH:49][C:50]=1[F:56])[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:23]=3)[CH2:20][CH2:21]2)=[O:15])[CH:13]=1)([CH3:2])[CH3:3]
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(=O)N2CCC(c3cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cncc(N(Cc4ccc(Br)cc4F)C(=O)OC(C)(C)C)c3)CC2)c1)C(=O)OC(C)(C)C
Reaction time: 0.05 h
Yield: 94.2 %

Procedure:
To a solution of {5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)methanoyl]-pyridin-3-yl}carbamic acid tert-butyl ester (0.0745 g, 0.1220 mmol) in dimethylformamide (2.0 mL) was added sodium hydride (61% suspension in mineral oil, 0.0216 g, 0.5499 mmol). Deprotonation was allowed to occur over 3 minutes while stirring under inert atmosphere. 4-Bromo-2-fluorobenzyl bromide (0.1559 g, 0.5819 mmol) was added to the anion solution. The mixture was stirred an additional 10 minutes, then quenched with water (5.0 mL). The reaction solution was extracted with ethyl acetate (15 mL), and the organic phase was washed with brine (2×10 mL), dried over magnesium sulfate, filtered, and evaporated to dryness. Purification of the residue on silica gel eluting first with ethyl acetate/methylene chloride/hexane (1:1:2, v/v/v) and then with ethyl acetate and methylene chloride (1:1, v/v) afforded (4-bromo-2-fluoro-benzyl)-{5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)-methanoyl]-pyridin-3-yl}-carbamic acid dimethyl-ethyl ester as a colorless oil (0.0917 g): TLC, 50:50-methylene chloride:ethyl acetate, Rf=0.59. 1H NMR (300 MHz, CDCl3) δ 8.47-8.51 (m, 2H), 7.61 (br s, 1H), 7.07-7.32 (m, 7H), 4.89 (s, 2H), 4.78 (s, 2H), 4.77-4.92 (m partially obscured, 1H), 3.68-3.83 (br m, 1H), 3.09-3.24 (br, m, 1H), 2.70-2.97 (m, 2H), 1.45 (s, 18H), 1.44 (s, 9H), 1.30-2.04 (m partially obscured, 4H); 13C NMR (75 MHz, CDCl3) δ 167.0, 160.4 (d, 250.8), 154.0, 152.7, 148.5, 144.9, 139.0, 138.7, 132.2, 131.9, 130.7, 129.7, 127.9 (d, 3.4), 125.8, 125.7, 125.3, 123.8 (d, 14.5), 121.8 (d, 9.7), 119.3 (d, 24.8), 82.5, 82.2, 49.5, 46.9, 42.6, 32.8 (br), 28.4, 28.2, 28.0; 19F NMR (282 MHz, CDCl3) δ-114.9; MS (CI) m/z 797 (M+H).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C([O:6][C:7](=O)[NH:8][C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[CH:10][C:11]#[N:12])C.[NH:22]([C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)=O)[NH2:23].O>CN1CCCC1=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:9]1[NH:8][C:7](=[O:6])[N:23]2[N:22]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[N:12]=[C:11]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)[nH]c(=O)n3n2)CC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
In a round-bottom flask fitted with reflux condenser and a drying tube filled with calcium chloride, 5.86 g (20.6 mmol) of ethyl[2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate and 5.00 g (20.6 mmol) of tert-butyl 4-(hydrazinylcarbonyl)piperidine-1-carboxylate were dissolved in 11 ml of 1-methyl-2-pyrrolidone, and the reaction mixture was stirred at 150° C. for 3 h. The reaction solution was cooled to RT, water (150 ml) was added and the mixture was stirred in an ultrasonic bath for another 2 min. The solid was filtered off with suction and dried under high vacuum. This gave 7.23 g (76% of theory) of the product.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12](=[O:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[C:16]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].CC(CC(C)C)=O>[C:16]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([C:10]4[NH:11][C:12](=[O:15])[S:13][CH:14]=4)=[CH:6][CH:5]=3)[CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]c(-c2ccc(CCCl)cc2)cs1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc2)cs1
Yield: 21.6 %

Procedure:
To a 35 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.40 g (5.84 mmol) of 4-(4-(2-chloroethyl)phenyl)thiazol-2-one, 1.24 g (5.84 mmol) of N-(1-naphthyl)piperazine, 0.81 ml (5.84 mmol) of triethylamine, 0.62 g (5.84 mmol) of sodium carbonate, 2 mg of sodium iodide, and 12 ml of methylisobutylketone. The reaction was heated at reflux for 5 days, cooled, and evaporated. The residue was taken up in ethyl acetate/water, the layers separated, and the ethyl acetate layer washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent. The product fractions were evaporated, and the residue taken up in hot methylene chloride/methanol, treated with ethyl acetate saturated with hydrochloride, precipitated with ether, filtered, washed with ether, and dried to give 0.523 g (18%) of a white solid, m.p. 307°-309° C.
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH2:5]([SiH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:6]>[Cu].[Cu](Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:4][CH2:1][CH2:2][CH2:3][Si:7]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:5][CH3:6]
Reactant: C=CCCl
Reactant: CC[SiH](CC)CC
Agent: Cl[Cu]Cl
Agent: [Cu+2]
Agent: [Cu]
Product: CC[Si](CC)(CC)CCCCl
Reaction time: 45 h

Procedure:
Table 1 shows that copper catalysts, especially copper chloride and copper acetate, and copper sulphate, are effective in catalyzing the hydrosilation of allyl chloride with triethylsilane, at 200° C. for 45 hours, yielding quantitatively 3-chloropropyltriethylsilane.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]([C:13]2[S:14][C:15]([C:19](=[O:28])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]([CH3:18])[CH:17]=2)[C:9](=[O:29])[CH:8]=1)(=O)=O.[CH2:32](B(O)O)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:21]([NH:20][C:19]([C:15]1[S:14][C:13]([N:10]2[CH:11]=[CH:12][C:7]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:8][C:9]2=[O:29])=[CH:17][C:16]=1[CH3:18])=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(-n2ccc(OS(=O)(=O)C(F)(F)F)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: OB(O)CCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-n2ccc(CCc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
A mixture of 1-(5-(benzylcarbamoyl)-4-methylthiophen-2-yl)-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (0.15 g, 0.32 mmol), phenethyl boronic acid (0.047 g, 0.31 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1:1 complex with dichloromethane (0.023 g, 0.028 mmol) and potassium carbonate (0.13 g, 0.95 mmol) in tetrahydrofuran (3 mL) and water (0.3 mL) was stirred in a sealed tube at 70° C. for 16 hours under nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature, and was partitioned between ethyl acetate (75 mL) and water (35 mL). The organic layer was washed sequentially with 10% aqueous hydrochloric acid (30 mL), saturated aqueous sodium bicarbonate solution (2×25 mL) and brine (30 mL), then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 20% ethyl acetate in dichloromethane to afford the title compound as a light cream color solid in 40% yield (0.054 g): mp 145-146° C.; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=7.3 Hz, 1H), 7.38-7.15 (m, 10H), 6.89 (s, 1H), 6.48 (s, 1H), 6.19 (t, J=5.8 Hz, 1H), 6.16 (dd, J=7.3, 1.9 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 2.96-2.87 (m, 2H), 2.84-2.75 (m, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.9, 160.7, 154.3, 140.1, 139.54, 139.5, 137.9, 133.2, 128.7, 128.6, 128.3, 127.8, 127.6, 127.2, 126.4, 121.8, 119.2, 109.3, 43.9, 36.9, 35.1, 15.9; MS (ES+) m/z 429.3 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([OH:12])=[O:11].[CH3:13]O>>[NH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C(O)C1CCCN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCCN1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7 mL of thionyl chloride was dissolved in 50 mL of methanol in an ice-water bath, followed by addition of pyrrolidine-2-carboxylic acid 10a (5 g, 43.40 mmol). The mixture was warmed up to room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure to obtain methyl pyrrolidine-2-carboxylate 10b (10 g) crude product as a white solid, which was directly used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2.[H][H]>CO.O=[Pt]=O>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1
Reactant: [H][H]
Reactant: Cc1cc2c([N+](=O)[O-])cccc2cn1
Agent: O=[Pt]=O
Solvent: CO
Product: Cc1cc2c(N)cccc2cn1
Yield: 45 %

Procedure:
3-Methyl-5-nitroisoquinoline (Description 44; 660 mg, 3.51 mmol) was dissolved in MeOH (30 ml) and PtO2 catalyst (120 mg) was added. The mixture was stirred for 1 hour 45 minutes under a balloon of hydrogen, then the catalyst was filtered off, washing with more methanol. The filtrate was evaporated and purified by flash column chromatography using as eluant 5% methanol in dichloromethane to give the title compound (250 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]([NH:17][O:18]C3CCCCO3)=[O:16])[C:8]3[N:9]2[N:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]([NH:17][OH:18])=[O:16])[C:8]3[N:9]2[N:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: O=C(NOC1CCCCO1)c1cc2ccc(Cl)cc2n2nnnc12
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NO)c1cc2ccc(Cl)cc2n2nnnc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of THP oxamate 6 (0.035 g, 0.1 mmol) in THF (1 mL) was added 2N HCl (1 mL) and stirred at room temperature for 6 h. The reaction solvent was removed under a reduced pressure and the resulting aqueous solution was diluted with water. The precipitated solid was filtered, washed with water and dried to give the desired oxamic acid 7. 1H NMR (CDCl3): δ 8.80 (s, 1H), 8.64 (bd, 1H), 8.06 (d, 1H, J=8.1 Hz), 7.70 (dd, 1H, J=2.4 and 8.7 Hz), LCMS (ret. time): 20.47 min.; MS (m/z): 264 (MH+).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][N:73]([C:76](=[O:82])[CH:77]([NH2:81])[CH:78]([F:80])[CH3:79])[CH2:72][CH2:71]1)=[O:69])[CH2:65][CH3:66].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][N:73]([C:76](=[O:82])[CH:77]([NH:81][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:28])[CH:78]([F:80])[CH3:79])[CH2:72][CH2:71]1)=[O:69])[CH2:65][CH3:66]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCOC(=O)N1CCN(C(=O)C(N)C(C)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOC(=O)N1CCN(C(=O)C(NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C(C)F)CC1

Procedure:
To a solution of 150 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 4 ml DMF were added 138 mg HATU, 124 l DIPEA and 100 mg 4-(2-Amino-3-fluoro-butyryl)-piperazine-1-carboxylic acid propyl ester. After stirring for 12 h saturated NaHCO3 solution (1.5 ml) was added and the mixture passed through a Chem Elute® cartridge eluting with DCM. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.