Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:17])[CH3:16].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:17]([CH2:15][CH3:16])[S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(C1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of commercially available 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.58 g, 28 mmol) and ethylamine (2 M in THF, 50 mL, 100 mmol) in THF (100 mL) is stirred at r.t. for 2 h. NaBHAc3 (8.9 g, 42 mmol) is added and the mixture is stirred for 15 h. The mixture is quenched with 1 M aq. NaOH (100 mL) and stirred at r.t. for 6 h. The mixture is extracted with CH2Cl2 (150 mL, then 4×50 mL) and the combined organic extracts are washed with 1 M aq. NaOH (30 mL). The organic phase is dried (Na2SO4), filtered and evaporated. The residue is dissolved in CH2Cl2 (100 mL) and TEA (3 g, 30 mmol) and, subsequently, a solution of 4-methoxy-benzenesulfonylchloride (6.38 g, 30.9 mmol) in CH2Cl2 (10 mL) are added at 0° C. The mixture is warmed to r.t. during 15 h and quenched with 1 M aq. NaOH (30 mL). The phases are separated and the organic phase is washed with 1 M aq. NaOH (30 mL), 1 M aq. KHSO4 (2×30 mL) and sat. aq. NaCl (30 mL). The organic phase is dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, EtOAc-heptane) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]#[N:12].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]2)=[O:8])=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: N#Cc1cc(C(=O)O)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Cl)c(C#N)c2)CC1
Reaction time: 20 h
Yield: 96.2 %

Procedure:
In a 100 mL round-bottom flask under a positive nitrogen pressure of 4-chloro-3-cyanobenzoic acid (4.28 mmol), 1-(tert-butoxycarbonyl)piperazine (1.59 g, 8.56.mmol), EDC (903 mg, 4.71 mmol) and HOBT (694 mg, 5.14 mmol) were dissolved in 17 mL of CH2Cl2. Triethylamine (1.5 mL, 10.7 mmol) was added and the reaction mixture was stirred for 20 h. After this time additional quantities of EDC (411 mg, 2.14 mmol), HOBT (290 mg, 2.14 mmol) and triethylamine (300 □L, 2.14 mmol) were added. After stirring for an additional 20 h the reaction mixture was washed with 6 mL portions of: 10% KHSO4, water, saturated NaHCO3, and saturated NaCl. The organic extracts were dried over Na2SO4, filtered and concentrated to afford 1.44 g of tert-butyl 4-(4-chloro-3-cyanobenzoyl)piperazine-1-carboxylate as a beige solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH2:15]([O:17][C:18]1[C:23]2[CH:24]([NH2:27])[CH2:25][O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1)C.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH3:15][O:17][C:18]1[C:23]2[CH:24]([NH:27][C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)[CH2:25][O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: CCOc1cccc2c1C(N)CO2
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1C(Nc1ccc3cc([N+](=O)[O-])ccc3n1)CO2
Temperature: 140 °C
Reaction time: 2 h
Yield: 18.5 %

Procedure:
A mixture of 2-chloro-6-nitro-quinoline (2.0 g, 9.6 mmol) in 1-methyl-2-pyrrolidone (5 mL) with the above described rac-4-ethoxy-2,3-dihydro-benzofuran-3-ylamine (3.78 g, ca. 10 mmol, max. 50% purity) and N-ethyldiisopropylamine (2.45 mL, 14.4 mmol) was stirred at 140° C. for 2 h. Cooled to 23° C., poured onto water and extracted twice with ethyl acetate, dried over Na2SO4 and evaporated totally to give a crude product which was purified by silica gel column chromatography with heptane/dichloromethane followed by trituration with diethyl ether to give the title compound as a yellow solid (0.60 g, 18%); MS: m/e=352.4 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:4]=2[C@:3]21[CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([C:19]([O:21]C)=[O:20])[CH:16]=1)[CH2:11]2.[ClH:23].[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25].[Li+:31].[OH-].Cl>C1COCC1.CO>[O:1]=[C:2]1[NH:10][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:4]=2[C@:3]21[CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([C:19]([OH:21])=[O:20])[CH:16]=1)[CH2:11]2.[Cl-:23].[Li+:31].[ClH:23].[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25]
Reactant: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Product: [Cl-]
Reaction time: 16 h

Procedure:
To a solution of a mixture of methyl (2R)-6′-oxo-1,3,6′,7′-tetrahydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidine]-5-carboxylate (10 mg, 0.034 mmol) and triethylamine hydrochloride (0.034 mmol from previous step) in 1 mL of 1:1 THF/MeOH was added 1N LiOH (102 μL, 102 mmol). After 16 h, the reaction was neutralized to pH=7 with 3 N HCl and then concentrated in vacuo. The crude material was azeotroped from benzene to afford the title compound as a mixture with 3 equivalents of lithium chloride and 1 equivalent of triethylamine hydrochloride. MS: m/z=282.1 (M+1). 1H NMR (500 MHz, DMSO d6): δ 11.57 (s, 1H); 8.69 (s, 1H); 8.11 (s, 1H); 7.84 (m, 2H); 7.40 (dd, J=8.3 Hz, 1H); 3.34-3.28 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([NH:21][NH2:22])=O.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:19]([C:18]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:17]=3[F:16])=[N:21][N:22]=2)[N:3]=1
Reactant: NNC(=O)c1ccc(F)cc1F
Reactant: CC1(c2cc(Cl)nnc2Cl)CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C)cc1
Product: CC1(c2cc3nnc(-c4ccc(F)cc4F)n3nc2Cl)CCCCC1
Yield: 38.7 %

Procedure:
A mixture of 3,6-dichloro-4-(1-methylcyclohexyl)pyridazine (1.29 g, 5.27 mmol), 2,4-difluorobenzoic hydrazide (1.72 g, 10 mmol) and triethylamine hydrochloride (1.09 g, 7.9 mmol) in p-xylene (5 ml) was stirred and heated at reflux for 24 hours. Upon cooling, the volatiles were removed in vacuo and the residue was partitioned between dichloromethane (100 ml) and water (100 ml) and NaHCO3 (100 ml). Undissolved solid was removed by filtration. The layers were separated and the aqueous was further extracted with dichloromethane (2×100 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica eluting with 0%→25% ethyl acetate in dichloromethane to give the required product (0.74 g): 1H NMR (250 MHz, CDCl3) δ1.34-1.74 (6H, m), 1.50 (3H, s), 1.90-2.15 (4H, m), 7.01-7.14 (2H, m), 7.87-7.98 (1H, m), 8.18 (1H, s); MS (ES+) m/e 365 [MH]+, 363 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH2:11])[CH:5]=1.C(N(CC)CC)C.[CH2:20]([O:27][CH2:28][C:29](Cl)=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH:11][C:29](=[O:30])[CH2:28][O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:5]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(NC(=O)COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
A solution of carbonic acid monobenzyl ester (3.50 g, 21.0 mmol) in the 50 ml of DCM and 0.50 ml of DMF was cooled to −78° C. followed by addition of oxalyl chloride (11.79 ml, 105 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. After the completion of the reaction mixture (TLC monitoring), concentrated it to give 2-benzyloxyacetyl chloride (3.0 g, 96%). To an ice cold solution of 3-amino-4-chloro-benzoic acid methyl ester in 10 ml of DCM was added triethylamine (2.47 ml, 17.78 mmol) followed by addition of 2-benzyloxyacetyl chloride (3.0 g, 17.78 mmol) in 10 ml of DCM. The reaction mixture was stirred at 25° C. for 12 hr. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (1.70 g, 31%).
Reaction SMILES: BrC1C=C2C(=CC=1)C=NC/C/2=C\NCC1C=C[CH:18]=[C:17]([OH:21])C=1.[OH:22][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][C:43]=1[OH:44])[CH2:26][NH:27][CH:28]=[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[NH:31][C:30]1=[O:40].C(N(CC)CC)C.[C:52](Cl)(=[O:54])[CH3:53]>N1C=CC=CC=1>[C:52]([O:44][C:43]1[CH:42]=[CH:41][C:25]([CH2:26][NH:27]/[CH:28]=[C:29]2\[C:30](=[O:40])[NH:31][C:32](=[O:39])[C:33]3[C:38]\2=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:24][C:23]=1[O:22][C:17](=[O:21])[CH3:18])(=[O:54])[CH3:53]
Reactant: Oc1cccc(CN/C=C2\CN=Cc3ccc(Br)cc32)c1
Reactant: CC(=O)Cl
Reactant: O=C1NC(=O)c2ccccc2C1=CNCc1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(CN/C=C2\C(=O)NC(=O)c3ccccc32)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
A solution of 4Z)-4-{[(3,4-dihydroxybenzyl)amino]methylene}-isoquinoline-1,3(2H,4H)-dione, (0.2 g, 0.644 mmol) in 0.27 mL (1.93 mmol) of triethylamine and 5 mL of pyridine is stirred at room temperature for 10 min, then 0.1 mL (1.42 mmol) of acetyl chloride is added. The reaction mixture is stirred at room temperature under N2 for 3 h. After evaporating the solvent, the residue is dissolved in dichloromethane, washed twice with water, dried over Mg2SO4, filtered and concentrated to give yellow solid. Recrystallized in EtOAc/Hex to afford 0.28 g (65.1% yield) of light yellow solid: mp 184-186° C.; MS (ESI) m/z 395.3 (M+H)+1, Analysis for C21H18N2O6. Calcd: C, 63.96; H, 4.60; N, 7.10. Found: C, 63.56; H, 4.69; N, 6.72.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 37.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.029 g (37%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]#[CH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.CC.[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CCOCC.Cl.O1CCCC1>[C:25]([O:24][C:18]1([C:11]#[C:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCCCC1
Reactant: C#CCOCc1ccccc1
Agent: CC
Agent: CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)OC1(C#CCOCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-benzyloxy-1-propyne (1 molar equivalent) in dry ether is added dropwise to a stirred solution of ethylmagnesium bromide (1 molar equivalent) in ether at ambient temperature under a nitrogen atmosphere. Upon completing the addition, the reaction mixture is stirred at ambient temperature until gas evolution (ethane generation) ceases, then is cooled to 0° to 5° C. and treated with cyclohexanone (1 molar equivalent) added dropwise at such a rate as to prevent the reaction mixture from attaining room temperature. After completing the addition, the reaction mixture is allowed to warm to room temperature, then is heated at reflux for 1 hour. In vacuo evaporation of the reaction mixture at 40° C. provides a gelatinous residue which is treated with anhydrous tetrahydrofuran and acetic anhydride (1 molar equivalent) and then heated at reflux under a nitrogen atmosphere for 1/2 hour. After cooling to 0° to 5° C., the reaction mixture is slowly diluted with cold 2 N hydrochloric acid, stirred at 0° to 5° C. for 15 minutes and allowed to warm to room temperature. The resulting turbid reaction mixture is extracted several times with ether. The combined organic extract is washed with water (until washings are neutral to Litmus paper) and saturated aqueous brine, dried over sodium sulfate, and filtered. Evaporation (in vacuo at 40° C.) of the filtrate provides the title compound as an essentially colorless oil.
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[F:1][C:2]([F:12])([C:3]1[CH:4]=[C:5]([NH2:6])[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]=1)[C:8]([F:9])([F:11])[F:10]
Reactant: NNc1ccccc1
Reactant: N#CCC(=O)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1
Temperature: 90 °C
Yield: 43.4 %

Procedure:
A stirred mixture of 4,4,5,5,5-pentafluoro-3-oxopentanenitrile (500 mg, 2.66 mmol) and phenylhydrazine hydrochloride (386 mg, 2.66 mmol) in ethanol (5 mL) was heated at 90° C. for 4 h. The reaction mixture was concentrated under reduced pressure, and the obtained oil purified by silica gel flash column chromatography (eluting with a gradient of 100% petroleum ether to 10% ethyl acetate in petroleum ether) to afford 3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-amine (320 mg, 43%) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.51-7.60 (m, 4H), 7.45 (m, 1H), 5.91 (s, 1H), 3.96 (brs, 2H); LC-MS (ESI) m/z 278 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][OH:5].C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl.O>[OH:5][CH2:4][C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][NH:1][C:26](=[O:27])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCC(CO)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(CO)(c1ccccc1)c1ccccc1)OCc1ccccc1
Temperature: 23 °C
Yield: 47.5 %

Procedure:
A solution of 3-amino-2,2-diphenylpropan-1-ol (18.4 g, 80.95 mmol) in dichloromethane (250 mL) was treated with triethylamine (16.9 mL, 121.4 mmol) and benzyl chloroformate (12.7 mL, 89.0 mmol) was then added dropwise over a period of 15 minutes. The reaction was stirred at 23° C., then diluted with water and stirred for 15 more minutes. The phases were separated and the organic phase was washed with 1N HCl, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude title material as an oil. This was purified on silica gel column (20% ethyl acetate/hexane) to give the title material (13.9 g, 47%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm: 2.29 (1H, br s), 4.08 (2H, d, J=6.57 Hz), 4.20 (2H, s), 4.82 (1H, t, J=6.06 Hz), 5.12 (2H, s), 7.14-7.21 (4H, m), 7.23-7.29 (2H, m), 7.31-7.41 (9H, M). HPLC ret. time (Condition C): 6.098 min. LC/MS (M+H)+: 362.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[CH2:7])[CH2:5][OH:6].Cl[CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14].O>O1CCCC1>[CH3:7][C:4](=[CH2:3])[CH2:5][O:6][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: C=C(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)COCc1cccc(C(=O)O)c1
Yield: 85.9 %

Procedure:
To the suspension of Sodium Hydride (1.516 g, 95%, 60 mmol) in tetrahydrofuran (150 ml), 2-Methyl-prop-2-en-1-ol (4.323 g, 4.1 ml, 60 mmol) was added. After the reaction mixture was refluxed for 30 min, 3-Chloromethyl-benzoic acid (4.10 g, 24 mmol) was added and the reaction was kept to reflux for additional 10 h. After cooling down, water (100 ml) was added and the tetrahydrofuran was removed under vacuum. This resulting aqueous solution was adjusted with 6N HCl to pH 2 at 5° C., and the mixture was extracted with Et2O (50 ml×3). The organic phase was combined and washed with water (10 ml×2) respectively. The ether extract was dried with anhydrous sodium sulfate and then concentrated to give 3-(2-Methyl-allyloxymethyl)-benzoic acid as colorless oil (4.25 g, 85.9%). 1H-NMR (400 MHz, d6-DMSO): 7.90 (m, 1 arom.H); 7.85 (m, 1 arom.H); 7.55 (m, 1 arom.H); 7.45 (m, 1 arom.H); 4.96, 4.88 (2 s-like; C═CH2); 4.50 (s, —OCH2—C6H4); 3.90 (s, CH2O); 1.69 (s, CH3). 13C-NMR (100 MHz, d6-DMSO): 167.22 (—C═O); 142.03; 139.00; 131.72; 130.78; 128.56; 128.31; 128.07; 111.71; 73.41; 70.58; 19.30.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:17][OH:18])[CH2:10][C@@H:11]([C:13]([F:16])([F:15])[F:14])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:31][Cr](O[Cr]([O-])(=O)=O)(=O)=O.CN(C=O)C>C(OCC)(=O)C.O>[C:1]([NH:8][C@@H:9]([C:17]([OH:31])=[O:18])[CH2:10][C@@H:11]([C:13]([F:16])([F:15])[F:14])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@@H](C[C@H](CO)NC(=O)OC(C)(C)C)C(F)(F)F
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A mixture of (2S,4R)-, (2R,4S)-N-Boc-5,5,5-trifluoroleucinol (330 mg, 1.23 mmol), PDC (4.62 g, 12.3 mmol), and dry DMF (2.5 mL) was stirred at room temperature under argon for 4 h, then diluted with 50 mL of ethyl acetate and 50 mL of water. The organic layer was washed with 30 mL of 1N HCl and 2×30 mL of water, dried over MgSO4, and concentrated to give 198 mg of (2S,4R)-, (2R,4S)-N-Boc-5,5,5-trifluoroleucine as a pale-brownish oil (60%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:16]=1[C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:16]=1[C:25](=[CH2:1])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(=O)c1c(OCOC)cccc1OCOC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C(=O)OCC)c1c(OCOC)cccc1OCOC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (3.13 g, 8.75 mmol) in dry tetrahydrofuran (30 ml) at 0° C. KHMDS (1.745 g, 8.75 mmol) was slowly added and the reaction mixture was stirred for 15 minutes at 0° C. and for 45 minutes at room temperature. The reaction mixture was cooled to 0° C. and a solution of ethyl (2,6-bis{[(methyloxy)methyl]oxy}phenyl)(oxo)acetate (Reference Intermediate 209, 1.74 g) in dry tetrahydrofuran (10 mL) was slowly added and the reaction mixture was stirred for 2 hours at 0° C. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (20 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound as a colourless oil (1.37 g).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: NCCN1CCOCC1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Azidobenzoic acid (846 mg, 5.08 mmol), HOBt (416 mg, 3.05 mmol, 0.6 eq.) and N-(2-aminoethyl)morpholine (0.716 ml, 5.34 mmol, 1.05 eq.) were dissolved in acetonitrile (9 ml) and DMF (3 ml), WSC (1.19 g, 6.10 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (40 ml), and washed with 5% aqueous sodium carbonate solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][NH2:15])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(Cl)cc2)CC1
Yield: 71.7 %

Procedure:
To a solution of 4-(4-chlorophenyl)-4-cyanopiperidin-1-carboxylic acid tert-butyl ester (0.355 g, 1.107 mmol) in ethanol (20 ml) at room temperature was added Raney Nickel (Raney Nickel 2800, 1 ml) and the suspension stirred under 1 atmosphere of hydrogen for 20 hours. The suspension was filtered through celite and the filtrate concentrated to give the amine as an oil (0.258 g, 69%). LC/MS: (LCT) Rt 5.02 [M-But-NH2]+ 324.