Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]2[O:12][N:11]=[C:10]([CH2:13][CH2:14][CH2:15]O)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:21]1[C:29]2[N:28]=[C:27]([Cl:30])[N:26](CC=C)[C:25]=2[C:24](=[O:34])[NH:23][C:22]1=[O:35])[CH2:18][CH2:19][CH3:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[CH2:17]([N:21]1[C:29]2[N:28]=[C:27]([Cl:30])[NH:26][C:25]=2[C:24](=[O:34])[N:23]([CH2:15][CH2:14][CH2:13][C:10]2[N:9]=[C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)[C:22]1=[O:35])[CH2:18][CH2:19][CH3:20]
Reactant: OCCCc1noc(Cc2ccccc2)n1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCn1c(=O)n(CCCc2noc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Yield: 63.4 %

Procedure:
A solution of 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (594 mg, 2.7 mmol) in THF (25 ml) was treated with 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (700 mg, 2.48 mmol) and PPh3 (779 mg, 2.97 mmol) under nitrogen. DBAD (684 mg, 2.97 mmol) was added in one portion and the reaction left to react for 60 h. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. MeOH was added to the residue and then passed down an aminopropyl column with the product eluting with 2-4% AcOH/MeOH. Product fractions were combined and concentrated. The off-white residue was recrystallised from EtOAc:cyclohexane (1:1), giving the title compound as a white solid (696 mg, 63%).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[F:28][C:29]([F:39])([F:40])[C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(C(F)(F)F)cc1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (1.0 ml), and a solution of 4-trifluoromethylbenzoyl chloride (1.5 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:19]
Reactant: [H][H]
Reactant: O=C(NN1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NN1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 99.4 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 210 (0.255 g, 0.71 mml) in methanol (15 mL) was added 10% Pd/C (0.5 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)-6-hydroxy-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 211 (0.19 g, quantitative yield) as a colorless foam.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=O)(C)(C)C.[CH2:22](N(CC)CC)C.[N:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.FC(F)(F)C(O)=O>ClCCl>[CH:33]1([NH:29][C:34]([NH:14][CH2:13][C@H:11]2[CH2:10][C@@H:9]([C:15]([N:17]3[CH2:21][CH2:20][S:19][CH2:18]3)=[O:16])[NH:8][CH2:12]2)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:22]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)NC1CCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of Example 17D (32.0 mg, 0.1 mmol) and triethylamine (0.03 mL, 0.2 mmol) in anhydrous dichloromethane (2 mL) was added pyrrolidine-1-carbonyl chloride (16.0 mg, 0.12 mmol) and the mixture was allowed to stir for 6 hours at room temperature. The mixture was concentrated under reduced pressure and the residue was chromatographed on a Biotage 40M eluting with 20% hexane/80% ethyl acetate to provide a yellow oil. The oil was dissolved in anhydrous dichloromethane (5 mL) and trifluoroacetic acid (0.075 mL) in dichloromethane (0.075 mL) were added to the mixture via syringe. The mixture was allowed to stir for 5 hours at room temperature and concentrated under reduced pressure to provide the titled compound. MS (ESI) m/e 313 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.72 (m, 1 H) 1.91 (t, 4 H) 2.66 (m, 2 H) 3.08 (m, 1 H) 3.16 (m, 2 H) 3.26 (m, 2 H) 3.30 (t, 4 H) 3.45 (m, 1 H) 3.74 (m, 1 H) 3.87 (m, 1 H) 4.51 (m, 1 H) 4.62 (m, 2 H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.[IH:21].II.S(=O)(=O)(O)O>CO.C(O)(=O)C>[C:1]1([C:7]2[CH:12]=[C:11]([I:21])[CH:10]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Reactant: I
Agent: II
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Ic1cc(-c2ccccc2)cc(-c2ccccc2)c1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A three neck flask was charged with 250 g of m-terphenyl (manufactured by Aldrich Co., Ltd.), 50 g of hydroiodic acid dihydrate, 75 g of iodine, 750 mL of acetic acid and 25 mL of cone, sulfuric acid, and they were reacted at 70° C. for 3 hours. After reaction, the solution was poured into 5 L of methanol and then stirred for one hour. This was separated by filtration, and crystal obtained was refined by means of column chromatography and recrystallized from acetonitrile to obtain 64 g of 5-phenyl-3-iodobiphenyl (intermediate 3) shown, below and 17 g of 3′-phenyl-4-iodobiphenyl (intermediate 4) shown below.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=[O:16])[C:4]#[C:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[CH2:19]1[CH2:23]OC[CH2:20]1.C1([Mg]Br)CC1.[NH4+].[Cl-]>C(Cl)Cl>[CH:20]1([C:3]([OH:16])([C:4]#[C:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:11])[CH3:12])[CH:7]([CH3:8])[CH3:9])[C:2]([F:1])([F:17])[F:18])[CH2:19][CH2:23]1
Reactant: C1CCOC1
Reactant: CC(C)[Si](C#CC(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)[Si](C#CC(O)(C1CC1)C(F)(F)F)(C(C)C)C(C)C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1,1-trifluoro-4-(triisopropylsilyl)but-3-yn-2-one (2.01 g, 7.22 mmol) in CH2Cl2 (50 mL) at 0° C. was added a THF solution of cyclopropylmagnesium bromide (0.5 M, 21.7 mL, 10.8 mmol). After 1.5 h, a saturated solution of NH4Cl was added. The aqueous layer was extracted with CHCl3 (3×), and the combined organic layers were washed with H2O and brine, dried (Na2SO4) and concentrated under vacuum at 30° C. affording the title compound. 1H NMR (500 MHz, acetone-d6): 5.97 (s, 1H), 1.36 (m, 1H), 1.10 (m, 21H), 0.74 (m, 1H), 0.65 (m, 2H), 0.60 (m, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14](O)=O>C(O)(=O)C.O>[CH3:11][C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:14])[CH:1]=2)[CH:6]=1
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2cc(C)ccc2c1

Procedure:
The crude 2,6-naphthalenedicarboxylic acid used for the following Examples was obtained by the liquid phase, air oxidation of 2,6-dimethylnaphthalene in acetic acid/water solvent catalyzed by cobalt II acetate, manganese II acetate and hydrogen bromide as the promoter.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@@H:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.[C:30]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)([OH:32])=[O:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:17]([N:16]([CH2:19][CH3:20])[C:14]([C:13]1[CH:21]=[CH:22][C:10]([C@H:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[N:3]2[C@@H:2]([CH3:1])[CH2:7][N:6]([CH2:36][C:35]3[CH:34]=[C:33]([CH:40]=[CH:39][CH:38]=3)[C:30]([OH:32])=[O:31])[C@H:5]([CH3:8])[CH2:4]2)=[CH:11][CH:12]=1)=[O:15])[CH3:18]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3cccc(C(=O)O)c3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.3 %

Procedure:
The 4-[(R)-((2S,5R)-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (2.50 g, 6.32 mmol) and 3-carboxybenzaldehyde (1.90 g, 12.64 mmol) were placed in a 250 mL flask with 60 mL of tetrahydrofuran and 0.80 mL (13.91 mmol) of acetic acid. The reaction was stirred at room temperature for 20 minutes, and sodium triacetoxyborohydride (2.68 g, 12.64 mmol) was added portionwise. The reaction solution became very turbid and was sealed under mntrogen and stirred overnight. The reaction mixture was evaporated to dryness and partitioned between ethyl acetate (60 mL) and 3M HCl (12 mL). The organic layer was extracted with a further 5×12 mL 3M HCl. The combined aqueous extracts were adjusted to pH 4.5-5 with 0.5 M NaOH solution and solid Na2CO3 The resulting gel was collected by filtration, dissolved in 30 mL of 0.5 M NaOH solution, and extracted with 20 mL of EtOAc/Et2O twice to remove impurities. 1M HCl was added dropwise to the aqueous solution to the precipitation point at pH 4.5-5. The resulting white gel was collected by filtration and washed with a small volume of cold water. The 3-{(2R,5S)-4-[(R)-(4-diethylcarbamoylphenyl)-(3-hydroxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}benzoic acid was dried in a vacuum oven (30 mmHg, 40° C.) to give 1.55 g of white solid. 1 H NMR (300 MHz, d6-DMSO): δ 0.99-1.20 (m, 12H); 1.89-2.05 (m, 2H); 2.48-2.65 (m, 5H); 3.06-3.57 (m, 5H); 3.78-3.83 (d, J=12.5 Hz, 1H); 4.94 (s, 1H); 6.63-6.84 (m, 3H); 7.09-7.91 (m, 9H); 9.36 (s, 1H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)(=O)C.O=[CH:10][C:11]([Cl:14])([Cl:13])[Cl:12].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:11]([Cl:14])([Cl:13])[CH:10]1[NH:4][CH2:3][CH2:1][O:2]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: ClC(Cl)(Cl)C1NCCO1

Procedure:
To a 2 liter 3-necked flask equipped with a stirrer, Dean-Stark trap, a condenser and dropping funnel were added 214 g (3.51 moles) ethanolamine and 450 g. toluene. Then 273 g (4.55 moles) of glacial acetic acid were added slowly to keep the temperature (cooling if necessary) at 30°-45° C. Then 568 g (3.85 moles) of chloral were added at 40°-50° C. The reaction mixture was refluxed to remove water and, when complete, the temperature increased to 115°-120° C. The reaction mixture was cooled in an ice bath and the product precipitated after standing for several hours to give 189.5 g (28.5%) m.p. 72°-74° C. The filtrate was washed with 5.0 moles of 20% sodium hydroxide and more product precipitated. Filtration and drying yielded 228.5 g (34.3%), m.p. 73°-75° C. The toluene layer was washed with water and evaporated to give a solid. Washing with water and filtration yielded upon drying 328 g. (49.2%), m.p. 62°-72° C. for a total yield of 556.0 g (83.5%). The analysis was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH3:23]>[Ni].C(O)C.[H][H]>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][NH2:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: N
Reactant: CCCCCCOc1ccc(C=O)cc1OCCCCCC
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCCCCCOc1ccc(CN)cc1OCCCCCC
Yield: 52.1 %

Procedure:
Raney nickel (500 mg.), 3,4-dihexoxybenzaldehyde (6.12 g., 0.02 M) and ammonia (3.0 g., 0.177 M) in ethanol (100 ml.) are charged into a Paar shaker and hydrogenated at 40° C and an initial pressure of 51 psi. When approximately 20 psi drop in hydrogen pressure is observed, about 24 hours, the contents are removed and filtered. The filtrate is concentrated in vacuo to an amber oil which is dissolved in ethyl acetate (50 ml.). The solution is treated with ethyl acetate saturated with hydrogen chloride (100 ml.) and the resulting white hydrochloride salt collected; 3.7 g., m.p. 205°-206° C. The salt is then partitioned between chloroform (100 ml.) and saturated sodium bicarbonate solution (50 ml.). The chloroform phase is separated, washed with water (50 ml.), dried (Na2SO4) and concentrated to give 3,4-dihexoxybenzylamine as an oil; 3.2 g., 52.1% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(C)CBr

Procedure:
To ethyl 3-methyl-2-butenoate (10.0 g, 78.0 mmol) in 80 ml of carbon tetrachloride heated under gentle reflux is added N-bromosuccinimide (15.0 g, 84.0 mmol) in portions, followed by traces of radical initiator (benzoyl peroxide, ca. 0.2 g, and AIBN, ca. 0.1 g) in portions over one hour. After the final addition, the mixture is heated under reflux for 30 min. The reaction mixture is cooled and filtered and the solvent is removed by rotoevaporation to give ethyl 4-bromo-3-methyl-2-butenoate.
Reaction SMILES: [BH4-].[Li+].[Br:3][CH2:4][CH2:5][N:6]1[C:10]([C:11](OC)=[O:12])=[CH:9][C:8]([N+:15]([O-:17])=[O:16])=[N:7]1.C(OCC)(=O)C.O>O1CCCC1>[Br:3][CH2:4][CH2:5][N:6]1[C:10]([CH2:11][OH:12])=[CH:9][C:8]([N+:15]([O-:17])=[O:16])=[N:7]1
Reactant: COC(=O)c1cc([N+](=O)[O-])nn1CCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a suspension of lithium borohydride (755 mg, 34.7 mmol) in tetrahydrofuran (100 mL) at 0° C. was added a solution of methyl 1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate (4.82 g, 17.3 mmol) in tetrahydrofuran (10 mL) drop wise maintain a temperature below 0° C. The resulting solution was allowed to stir at room temperature for 2 h. To the resulting mixture was slowly added ethyl acetate (20 ml) and water (20 ml). The biphasic mixture was separated and aqueous layer extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate and the resulting mixture was filtered and concentrated in vacuo to give (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (4.24 g, 98%) as a light yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C@H:14]1[C:23]2[C:18](=[C:19]([Cl:25])[CH:20]=[C:21]([Cl:24])[CH:22]=2)[CH2:17][N:16]([CH3:26])[CH2:15]1)=[O:6].CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[ClH:1].[Cl:24][C:21]1[CH:22]=[C:23]2[C:18](=[C:19]([Cl:25])[CH:20]=1)[CH2:17][N:16]([CH3:26])[CH2:15][C@H:14]2[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:7]1[CH2:2][CH2:3][CH2:4][C:5]1=[O:6]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2NC(=O)CCCCl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2CCCC2=O)C1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.6 %

Procedure:
4-Chloro-N-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-butyramide (249 mg) was dissolved in abs. DMSO (10 ml) and finely powdered and dried potassium carbonate (250 mg) was added. With exclusion of moisture, the mixture was stirred vigorously at room temperature for 4 h. After standing overnight, the reaction mixture was diluted with water (50 ml) and then extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with sodium hydrogencarbonate and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was dissolved in water/acetonitrile and adjusted to pH 2 with 0.1 N HCl. After freeze-drying overnight, the desired product (116 mg) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=O)=[C:4]([OH:26])[CH:3]=1)=[O:9].O.[NH2:28][NH2:29]>C(O)C>[N:28](=[CH:24][C:5]1[C:6]2[O:17][C:16]3[C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]([O:21][CH3:22])=[C:12]([CH3:23])[C:11]=3[O:10][C:8](=[O:9])[C:7]=2[C:2]([CH3:1])=[CH:3][C:4]=1[OH:26])[NH2:29]
Reactant: NN
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=NN)c1O2

Procedure:
To a stirring solution of psoromic acid (1 mmol) in ethanol (25 mL) was added hydrazine hydrate (1 mmol). The reaction was stirred for half an hour and monitored by TLC. Upon completion, all of the solvent was removed by rotary evaporation. The residue was redissolved in ethanol and dried over anhydrous magnesium sulfate, filtered, and evaporated by a rotary evaporator to yield a white solid product.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:10]([OH:29])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=1[O:27][CH3:28])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:42]([Si:46]([CH3:49])([CH3:48])Cl)([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:10]([O:29][Si:46]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:49])[CH3:48])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=1[O:27][CH3:28])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Reaction time: 2.5 h

Procedure:
A solution of 1.308 g (2.597 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoic acid, 1.443 g (20.776 mmol) of imidazole and 1.816 g (11.686 mmol) of tert-butyldimethylchlorosilane in 13 ml of abs. DMF is stirred at RT for 17 h under argon. After that, the reaction mixture is poured onto ice-water and this mixture is extracted with ethyl acetate. The organic phase is washed with cold 10% citric acid solution and saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated on a RE at approximately 30° C. The resulting product is dissolved in 34.51 ml of methanol and 11.82 ml of THF, and this solution is treated, at RT, with 2.08 g of potassium carbonate in 11.82 ml of water. After it has been stirred for 2.5 h, the reaction mixture is concentrated down, at approximately 30° C., to half its volume and treated with ethyl acetate and 10% citric acid solution (cold), and the phases are separated. The organic phase is washed a further two times with (cold) saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate, 1:1, and then 1:1.5), and the title compound is obtained. TLC Rf (J)=0.02. FAB-MS (M+H)+ =618 IR(KBr) inter alia: 1712, 1495, 1366, 1101 and 836 cm-1. 1H-NMR(CD3OD) inter alia: 7.30-7.10 (m, 5H); 6.84 and 6.67 (each d, each 1H); 6.23 and 5.55 (each d, in all 1H from NH); 3.86, 3.81 and 3.80 (each s, each 3H); 1.31 and 1.20 (each s, in all 9H from Boc); 0.93 (s, 9H); 0.14 and0.11 (each s, each 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC=CC=1.C(P)=CC=C.[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[C:20]([CH2:22][C:23]([O:25][CH2:26][CH2:27][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24])#[N:21]
Reactant: Ic1ccccc1
Reactant: CCOC(=O)CC#N
Agent: C=CC=CP
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Brc1ccccc1
Product: N#CCC(=O)OCCc1ccccc1

Procedure:
The general procedure (acetonitrile, 82° C., 12 hours with iodobenzene; 30 hours in the case of bromobenzene) was followed using 9.52 mg (0.05 mmol) of copper iodide CuI, 31.4 mg (0.1 mmol) of (Z)-cinnamic butadienylphosphine of example A-1-1, 80 ml (0.75 mmol) of ethyl cyanoacetate, 318 mg (1.5 mmol) of potassium phosphate (K3PO4), 56 μl (0.5 mmol) of iodobenzene (53 μl of bromobenzene) and 500 μl of acetonitrile. The residue obtained after treatment (dichloromethane/water extraction) was purified by chromatography on a silica column (gradient: hexanes/CH2Cl2 100:0 to 75:25).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.ClCCCl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:8][C:6]2[N:7]=[C:2]([NH2:1])[CH:3]=[CH:4][CH:5]=2)[CH2:13][CH2:12]1
Reactant: Nc1cccc(C=O)n1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(Cc2cccc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 1-neck round-bottom flask, 6-Amino-pyridine-2-carbaldehyde (2.85 g, 23.3 mmol), 1-Methylpiperazine (5.00 mL, 45.1 mmol), 1,2-Dichloroethane (100 mL, 1000 mmol) and Acetic acid (2.50 mL, 44.0 mmol) were added and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (14.8 g, 70.0 mmol) was added portion wise over 20 minutes. The reaction mixture was stirred at room temperature over night. The reaction was partitioned with Sat. NaHCO3. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and stripped to give a yellow solid. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 20% methano). The collected fractions afforded 6-(4-Methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine as a yellow solid (1.20, 25%)