Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.O>O1CCOCC1>[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:18][CH:19]=1)=[O:22]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1

Procedure:
At room temperature, 31.60 g (281.48 mmol) of potassium tert-butoxide and 52.70 g (270.22 mmol) of tert-butyl bromoacetate are added to a solution of 27.50 g (225.18 mmol) of 4-hydroxybenzaldehyde in 200 ml of dioxane, and the mixture is heated at the boil overnight. 1 l of water is added, and the mixture is then extracted with diethyl ether, washed with 1 N sodium hydroxide solution, water and saturated sodium chloride solution and dried over magnesium sulphate, and the solvent is distilled off. Flash chromatography on silica gel (cyclohexane→cyclohexane/ethyl acetate 20:1→10:1→5:1) gives, after recrystallization from pentane, the target compound.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Yield: 92.8 %

Procedure:
This compound is prepared according to procedure described in step A) of Preparation 8.3, starting with 2.6 g of magnesium in 15 ml of THF, 15 g of 1-bromo-4-methylbenzene in 100 ml of THF and 16.6 g of 1-benzyl-4-piperidinone in 100 ml of THF. 22.9 g of the expected product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:16][N:17]([CH:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26](O)=[O:27])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC[Al](Cl)CC.C1C=CC2N(O)N=NC=2C=1.C[N+]1([O-])CCOCC1>CN(C)C=O.O.CCOC(C)=O>[C:21]([O:20][C:18](=[O:19])[N:17]([C@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26]([N:11]1[CH2:12][CH2:13][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:14][CH3:15])[CH2:9][CH2:10]1)=[O:27])[CH3:16])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc(F)cc1C1CCNCC1
Reactant: CN(C(=O)OC(C)(C)C)C(Cc1ccccc1)C(=O)O
Agent: CC[Al](Cl)CC
Agent: C[N+]1([O-])CCOCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C1CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above product of 4-(5-fluoro-2-methoxy-phenyl)-piperidine was dissolved in N,N-dimethylformamide (10 mL) at 0° C. To the resulting solution, 0.70 g (2.5 mmole) of 2-[N-methyl-N-(tert-butoxycarbonyl)-amino]-3-phenyl-propionic acid in a minimal amount of DMF was added, followed by DEAC (0.48 g, 2.5 mmole), HOBT (0.41 g, 2.5 mmole) and NMO (0.37 mL, 3.4 mmole) and the mixture was stirred overnight (the reaction temperature was slowly allowed to warm up to room temperature). The reaction mixture was diluted with water (50 mL) and EtOAc (50 mL) and the layers separated. The aqueous layer was washed with HCl (1N), saturated NaHCO3, and the combined aqueous layers were extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. Flash chromatography, gradient elution with 1:4 EtOAc-hexane to 3:7 EtOAc-hexane to afford (R)-{1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-2-oxo-ethyl}-methyl-carbamic acid tert-butyl ester as a yellow oil.
Reaction SMILES: C([N:6]1[CH2:11][CH:10]([CH3:12])[CH:9]([NH:13][CH:14]2[CH2:16][CH2:15]2)[CH:8]([CH3:17])[CH2:7]1)(OCC)=O.[OH-].[Na+]>C(O)C>[CH:14]1([NH:13][CH:9]2[CH:8]([CH3:17])[CH2:7][NH:6][CH2:11][CH:10]2[CH3:12])[CH2:16][CH2:15]1
Reactant: CCOC(=O)N1CC(C)C(NC2CC2)C(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CNCC(C)C1NC1CC1

Procedure:
The Mixture B of isomers of 1-carbethoxy-4-cyclopropylamino-3,5-dimethylpiperidine (2.8 g, 1.16 mmol) was stirred in a mixture 5 N NaOH solution (20 ml) and ethyl alcohol (5 ml) at 100° C. for 120 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to afford Mixture B of isomers of 4-cyclopropylamino-3,5-dimethylpiperidine as an oil. Yield 1.6 g (84%), C10H20N2, m/z 169 (M+1) PMR (CDCl3): 0.82-1.05 (m, 10H), 1.5 (m, H), 1.75 (m, H,), 2.16-2.38 (m, 3H), 2.65 (m, 1H), 2.78 (m, 1H), 3.02 (m, 1H), 3.41 (m, 1H), 3.64 (m, 1H).
Reaction SMILES: [OH-].[Al+3:2].[OH-].[OH-].[P:5](=[O:9])([OH:8])([OH:7])[OH:6]>>[P:5]([O-:9])([OH:8])([OH:7])=[O:6].[P:5]([O-:9])([OH:8])([OH:7])=[O:6].[P:5]([O-:9])([OH:8])([OH:7])=[O:6].[Al+3:2]
Reactant: O=P(O)(O)O
Agent: [Al+3]
Agent: [OH-]
Product: O=P([O-])(O)O

Procedure:
23.4 g (0.3 mol, moist) of aluminum hydroxide are dissolved in 88.2 g (0.9 mol, 85%) phosphoric acid while stirring and heating.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[C:8]([C:18](OCC)=[O:19])[N:7]=1)=O)C.[BH4-].[Na+].[Cl-].[Cl-].[Ca+2]>C1COCC1.[Cl-].[Na+].O>[N:12]1([C:10]2[CH:11]=[C:6]([CH2:4][OH:3])[N:7]=[C:8]([CH2:18][OH:19])[CH:9]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cc(N2CCNCC2)cc(C(=O)OCC)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(N2CCNCC2)cc(CO)n1

Procedure:
Diethyl-4-piperazinyl-2,6-pyridinedicarboxylate is dissolved in THF and treated with NaBH4 and CaCl2. Brine is added and the organic phase is separated. The organic phase is washed with brine, dried (Na2SO4) and the solvent is evaporated. The residue is purified by flash chromatography on a silica gel column to give the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C-:15]#[N:16].[K+].C(O)(=O)C>C1COCC1.O>[C:15]([C:10]1([OH:14])[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(O)(C#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
1-Boc-3-piperidinone (5.0 g, 0.0251 mol) in THF (15 mL) was added dropwise to a solution of potassium cyanide (1.8 g 0.0276 mol) in water (15 mL) at 0-5° C. Acetic acid (1.6 mL, 0.0276 mol) was added and the solution was allowed to warm to room temperature and stir for 1 hr. The mixture was partitioned between water (50 mL) and ethyl acetate (1×150 mL). The organics were washed with 2×50 mL water, 1×50 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to obtain 5.5 g of yellow solid. The material was used without purification. MS (ESI) m/z 265 [M+K]+.
Reaction SMILES: [C-:1]1([C:6]([OH:8])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].C(Cl)(=O)C(Cl)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>>[C-:1]1([C:6]([N:21]=[N+:22]=[N-:23])=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)[c-]1cccc1
Agent: [Fe+2]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Product: [N-]=[N+]=NC(=O)[c-]1cccc1

Procedure:
Ferrocene carbonyl azide was prepared from ferrocenecarboxylic acid by reaction with oxalyl chloride and sodium azide.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[OH:31].C([O-])(O)=O.[Na+].S1C2C=CC=CC=2C(N2CCN(CCCCOC3C=CC(C(=O)C)=CC=3OC)CC2)=N1>O.CC#N>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Agent: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2nsc3ccccc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(OCCCN2CCC(c3nsc4cc(F)ccc34)CC2)c(O)c1
Yield: 97 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (2.4 g, 10.1 mmol), 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (2.5 g, 11.1 mmol), NaHCO3, (0.94 g, 11.1 mmol), KI (100 mg) and CH3CN (1(30 ml) was stirred at reflux under N2 for 65 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed with H2O (1×) and brine (3×) and after drying with MgSO4 the solvent was evaporated to give 4.2 g of a dark solid. Three consecutive recrystallizations from EtOH provided 2.1 g (48%) of glittery beige crystals m.p.=135°-137° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)=[O:7])(=[O:4])=[O:3]>C(O)C.[Pd].O>[CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)=[O:7])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)NC(=O)c1cccc(N)c1
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To a suspension of 1-(methylsulphonylaminocarbonyl)-3-nitrobenzene (4 g, 16 mmol) in ethanol (100 ml) was added 10% palladium on carbon (0.5 g, 12.5% (w/w)) in water (5 ml). The mixture was hydrogenated at 40 psi for 10 min then the catalyst was filtered off and washed with ethanol. The solvent was evaporated in vacuo to give the title compound (2.9 g, 83%) as a tan powder after trituration with diethyl ether, mp 153°-155° C. 1H NMR (360 MHz, D6 -DMSO) δ 3.3 (3H, s), 6.79 (1H, d, J=7.7 Hz), 7.05 (1H, d, J=7.7 Hz), 7.08 (1H, d, J=1.9 Hz), 7.13 (1H, dd, J=7.7 and 7.7 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].C1(C)C=CC=CC=1.[OH-:32].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:32])[CH3:2]
Reactant: [OH-]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a test tube (outside diameter: 21 mm φ×overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (51.2 mg), toluene (0.47 ml), water (0.2 ml), tetra-n-butylammonium bromide (49.9 mg), and sodium hydroxide (54.3 m) were added under a nitrogen atmosphere at room temperature, and stirred at 120° C. for 4 hours. Then, the organic layer was removed. 3.5% by weight of hydrochloric acid (4 ml) was added to the mixture at room temperature, and extracted with tert-butyl methyl ether. Then, the organic layer was concentrated under reduced pressure to give 40.8 mg of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:19]([F:25])([F:24])C(OC)=O.O>CN(C=O)C>[F:24][CH:19]([F:25])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OC(F)F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (6 g), Cs2CO3 (25.7 g) and methyl 2-chloro-2,2-difluoroacetate (5 ml) in DMF (50 ml) was stirred at 90° C. for 1 h. At room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed twice with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1:1 (v/v)] as eluent.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:21][C:22]([CH3:24])=O>>[CH:22]([NH:20][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:24])[CH3:21]
Reactant: NC1CCCC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)NC1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium triacetoxyborohydride (33.76 g, 0.16 mol) was added to a solution of cyclopentylamine (15 ml, 0.15 mol) in acetone (500 ml). The reaction mixture was stirred at room temperature for 24 hr then the solvent was removed and the reaction mixture was partitioned between ethyl acetate (400 ml) and 2M aqueous sodium hydroxide (150 ml). The organic layer was separated, dried (anhydrous magnesium sulphate) and evaporated under reduced pressure to give the title compound (12 g) as a liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (287 g, 1103 mmol) in DMF (150 mL), sodium carbonate (468 g, 4415 mmol) and methyl iodide (626.63 g, 4415 mmol) were added. The reaction mixture was then heated at 60° C. for 8 h. The precipitated solids were filtered and washed with diethyl ether (5 times). The combined organic filtrates were dried, concentrated under reduced pressure giving desired compound methyl 5-bromo-2-methyl-3-nitrobenzoate (302 g, 99%) which was used as is in further reactions
Reaction SMILES: CO.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:17]([OH:18])=[C:16]([C:19]([CH3:21])=[O:20])[CH2:15][S:14]2)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].OO.C1(C)C=CC=CC=1>O.CCCCCCC>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][CH:15]=[C:16]([C:19]([CH3:21])=[O:20])[C:17]=2[OH:18])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)C1=C(O)C(c2ccc(C(C)(C)C)cc2)SC1
Agent: OO
Solvent: CCCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 51 °C
Reaction time: 5 h

Procedure:
A solution having methanol (121.20 g) added to a 11.2 mass % methanol solution (539.0 g, 217.08 mmol) of 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene was heated to 51° C., and a 30 mass % hydrogen peroxide solution (61.6 g, 2.5 equivalent amounts) was dropwise added over a period of 30 minutes, followed by stirring at from 50 to 52° C. for 5 hours. Then, the solution was cooled to 25 to 30° C., and then toluene, heptane and water were added, followed by liquid separation. Then, to the obtained organic layer, a 7 mass % sodium hydrogencarbonate aqueous solution, toluene and heptane were added, followed by liquid separation, and further, the obtained organic layer was washed with a 3 mass % salt solution. The solvent was distilled off under reduced pressure from the obtained organic layer to give a 26.6 mass % solution of the desired product. To the obtained solution, methanol was added to adjust the concentration to 9 mass %, and the solution was heated to from 55 to 60° C. to dissolve the formed solid. To this solution, 24.2 g of water was further dropwise added, followed by stirring for 1 hour. Then, the solution was cooled to −10° C. and stirred for 1 hour. The formed crystals were subjected filtration to give the desired product as yellow crystals (44.2 g, yield: 73.9%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)O1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
A solution of commercial 1-(benzyloxy)-4-bromobenzene (104 g, 395 mmol) and commercial tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (147 g, 474 mmol) in 1100 mL of acetonitrile was purged with nitrogen for 2 min. Water (1100 mL) was added, followed by sodium carbonate (126 g, 1186 mmol) and tetrakis(triphenylphosphine)palladium (27.4 g, 23.7 mmol). The reaction mixture was purged with nitrogen for 5 min, and then heated to 90° C. and stirred for 16 h. The reaction mixture was then allowed to cool to rt and diluted with 1 L of ethyl acetate. The layers were separated, and the aqueous layer was extracted with two additional 250 mL portions of ethyl acetate. The organic layers were combined, washed with 200 mL of brine, dried over sodium sulfate, and evaporated in vacuo to provide an off-white solid. The product was purified by silica gel chromatography eluting with 6% ethyl acetate in petroleum ether to provide 129 g (88%) of the desired product. LC/MS RT (conditions A)=2.732 min, (M−H)+=364.0. 1H NMR (300 MHz, chloroform-d) δ 7.49-7.30 (m, 5H), 7.27 (d, J=10.7 Hz, 2H), 6.99-6.87 (m, 2H), 6.03-5.87 (m, 1H), 5.07 (s, 2H), 4.05 (d, J=2.6 Hz, 2H), 3.62 (t, J=5.7 Hz, 2H), 2.49 (br. s., 2H), 1.49 (s, 9H).
Reaction SMILES: Br[C:2]1(Br)[C:4]2([CH2:8][C@@H:7]([C:9]([OH:11])=[O:10])[N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5]2)[CH2:3]1.OP=O.C(N(CC)CC)C>O.C(#N)C>[C:15]([O:14][C:12]([N:6]1[C@H:7]([C:9]([OH:11])=[O:10])[CH2:8][C:4]2([CH2:3][CH2:2]2)[CH2:5]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC2(C[C@H]1C(=O)O)CC2(Br)Br
Agent: O=PO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1C(=O)O
Temperature: 100 °C
Yield: 69 %

Procedure:
To a mixture of (6S)-1,1-dibromo-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (8.7 g, 21.8 mmol), 50 wt % hypophosphorus acid (25.9 mL, 9 eq) and triethylamine (44.3 mL, 10 eq) in water (104 mL, 12 volumes) was added V-50 (591 mg, 0.1 eq) in 2 mL of 50% aqueous acetonitrile. The mixture was heated at 100° C. During the heating, additional 0.1 eq of V-50 was added to the reaction mixture every 30 minutes. Totally, 0.7 eq of V-50 was added. After heating at 100° C. for 4 hrs, the reaction mixture was evaporated and treated with 2N NaOH. It was extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with 2N HCl, extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated to give the title compound (3.63 g, 69%) as a light yellow solid. 1H NMR (500 MHz, CDCl3): 4.51-4.42 (m, 1H), 3.48-3.11 (m, 2H), 2.27-1.93 (m, 2H), 1.50/1.45 (two overlapping s, 9H), 0.71-0.59 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:10])[C:8]=1[Br:9])[NH2:5].[N:11]([O-])=O.[Na+]>O.Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[C:7]([Br:10])[C:8]=1[Br:9]
Reactant: Nc1cc(Br)c(Br)c(Br)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)c(Br)c(Br)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Tribromoaniline was obtained by the procedure of L. F. Tietze and T. Eicher (L. F. Tietze, T. Eicher. Reaktionen und Synthesen im organisch-chemischen Praktikum und Forschungslaboratorium. (1991) Georg Thieme Verlag, Stuttgart, N.Y.). 7.8 g (24 mmol) of 3,4,5-tribromoaniline were stirred with a solution of 6.5 mL of concentrated hydrochloric acid and 6.5 mL of water. The mixture was cooled to about −10° C. and at this temperature the solution of 2.76 g of NaNO2 in 11 mL of water was added for 20 min with intensive stiffing. The reaction mixture was stirred for 30 min at −10° C. Then the cooled solution of 16.2 g of SnCl2-2H2O in 17 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept at −10° C. for one hour and at 5° C. overnight. The obtained precipitate was filtered off and washed with water. The residue was resuspended in 50 mL of water and concentrated aqueous solution of NaOH was added to get alkaline medium. The 3,4,5-tribromophenylhydrazine was extracted with ether. Organic layer was dried with MgSO4 and ether was evaporated. Yield: 5.5 g (67%). 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.09 (2H, s, arom.), 7.34 (1H, s, NH), 4.19 (2H, d, NH2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
2-(3-Nitrophenyl)ethanol (836 mg, 5.00 mmol) and Pd (10% on charcoal, 200 mg) were suspended in dry methanol (10 mL). After the addition of ammonium formate (1.450 g, 23 mmol) a slightly exothermic and effervescent reaction was observed. After stirring for 1 h at room temperature the mixture was filtered over celite. The filtrate was evaporated and the residue dissolved in ethyl acetate. After washing with saturated aqueous sodium hydrogencarboante solution, water and brine the organic layer was dried (magnesium sulfate) and the solvent removed under reduced pressure affording the title compound in 54% yield (373 mg) as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH2:10]([S:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(SCc2ccccc2)cc1
Temperature: 120 °C
Yield: 30.6 %

Procedure:
Mix under argon atmosphere 4-fluorobenzonitrile (1.21 g, 10 mmol), benzyl mercaptan (1.86 g, 15 mmol), and cesium carbonate (6.5 g, 20 mmol) in anhydrous NMP (20 mL). Degas the flask and fill with argon. Heat at 120° C. for 3 h. Cool to ambient temperature, dilute with EtOAc, filter and wash with 1N aqueous HCl. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate (689 mg, 31%). GC-MS m/z: 225 (M+).