Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)/[CH:3]=[C:4](\[NH2:15])/[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].FC(F)(F)CO.[H][H]>[B-](F)(F)(F)F.C1C2C=CC1C=C2.C1C2C=CC1C=C2.[Rh].CO>[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][C@H:4]([NH2:15])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]
Reactant: [H][H]
Reactant: N/C(=C\C(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: [Rh]
Agent: C1=CC2C=CC1C2
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: OCC(F)(F)F
Product: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 50 °C
Reaction time: 17 h

Procedure:
Into a flask were charged bis(norbornadiene)rhodium(I) tetrafluoroborate {[Rh(nbd)2]BF4}(41.55 mg, 0.1 mmol), Ligand D (69.73 mg, 0.1 mmol) and the enamine amide 2-4 (45 g, 111.1 mmol) under a nitrogen atmosphere. To this mixture a solvent mixture of 37.5 mL methanol (extra dry and degassed) and 112.5 mL 2,2,2-trifluoroethanol (distilled and degassed) were added. The slurry was then transferred under nitrogen into an stainless steel autoclave and sealed. The autoclave was then heated to 50° C. and pressurized to 500 psig with hydrogen. A sample taken after 17 hours was analyzed using HPLC, which confirmed the end of the reaction giving 94% assay yield and 94% ee.
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].C[N-]C.C[N-]C.[V+4:13].[CH3:14][Si:15]([CH2:18][Li])([CH3:17])[CH3:16]>CCCCC>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:14][Si:15]([CH2:18][V+2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])([CH3:17])[CH3:16]
Reactant: [Li]C[Si](C)(C)C
Reactant: [V+4]
Agent: C[N-]C
Solvent: CCCCC
Product: C[Si](C)(C)C[V+2]C[Si](C)(C)C
Reaction time: 3 h

Procedure:
To a stirred solution of 0.80 g of vanadium tetrakis(dimethylamide) in pentane was added a solution of 0.63 g of trimethylsilylmethyllithium in pentane. Lithium dimethylamide precipitated rapidly. The reaction mixture contained a total of about 50-100 ml of pentane. After stirring for three hours the mixture was filtered, and part of the pentane was evaporated. The solution was kept at -40° C. overnight, following which the remainder of the pentane was evaporated, to give bis(trimethylsilylmethyl)vanadium bis(dimethylamide) as a dark-green oil, which was purified by distillation at 100° C. under high vacuum.
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[C:11]([OH:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([CH2:36][CH2:37]O)=[CH:34][CH:33]=2)=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[C:11]([O:19][CH2:37][CH2:36][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)=[CH:40][CH:39]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1
Reactant: O=C(O)c1cccnc1
Reactant: OCCc1ccc(OCCCCc2ccc(Cl)cc2)cc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(OCCc1ccc(OCCCCc2ccc(Cl)cc2)cc1)c1cccnc1
Yield: 53.7 %

Procedure:
Benzenesulfonyl chloride (7.66 ml, 0.06 mole) is added with stirrin to a 9.2 g (0.075 mole) of nicotinic acid in 30 ml of pyridine, and then 15.2 g (0.05 mole) of 4-(4-chlorophenylbutoxy)phenethyl alcohol is added to the solution. The mixture is stirred as discribed in Example 1. The reaction mixture is poured into water, and extracted with chloroform, the chloroform layer is washed with potassium carbonate solution and water. The chloroform is removed to give a red-syrup. The red-syrup is purified by chromatography on silica gel using a mixture of benzene and chloroform (1:1) as eluent, to give 11 g (53.6%) of a title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[N:3]=1.[OH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][C:13]3[C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:3]=[C:2]([C:36]3[CH:37]=[C:32]([OH:31])[CH:33]=[CH:34][CH:35]=3)[C:10]=12
Reactant: OB(O)c1cccc(O)c1
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1Cn1nc(I)c2c(N)ncnc21
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: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1Cn1nc(-c2cccc(O)c2)c2c(N)ncnc21
Temperature: 100 °C

Procedure:
Prepared according to Procedure J. A mixture of 3-iodo-1-((8-methyl-2-o-tolylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (51 mg, 0.1 mmol), 3-hydroxyphenylboronic acid (15.2 mg, 1.1 eq), sodium carbonate (55 mg, 5 eq), tetrakis(triphenylphosphine)palladium (6 mg, 5% mmol) in DMF (1 mL) and water (0.3 mL) was heated to 100° C. under N2 for 4 h. The reaction mixture was cooled to room temperature, filtered and purified by reverse HPLC (MeCN/H2O/0.1% TFA) on C18 to give a white solid [PI3Kδ IC50=7 nM]. 1H-NMR (DMSO-d6) δ 8.37 (s, 1H), 8.35 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.14-7.17 (m, 4H), 6.87-6.97 (m, 4H), 5.63 (s, br, 2H), 2.63 (s, 3H), 1.91 (s, 3H). Mass Spectrum (ESI) m/e=473 (M+1).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[CH:12][N:11](COCC[Si](C)(C)C)[N:10]=2)[CH:6]=[C:5]([C:22]([F:25])([F:24])[F:23])[N:4]=1.C(OCC)(=O)C.CCCCCC>Cl.O1CCOCC1>[NH:11]1[CH:12]=[N:13][C:9]([C:7]2[CH:6]=[C:5]([C:22]([F:23])([F:24])[F:25])[N:4]=[C:3]([C:2]([F:27])([F:1])[F:26])[CH:8]=2)=[N:10]1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc(C(F)(F)F)nc(C(F)(F)F)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: FC(F)(F)c1cc(-c2nc[nH]n2)cc(C(F)(F)F)n1
Temperature: 60 °C
Yield: 58.5 %

Procedure:
In a 10 mL seal tube, 2,6-bis(trifluoromethyl)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)pyridine (2) (0.15 g, 1 eq.) was dissolved in dioxane HCl (5 mL) and seal tube was heated to 60° C. for 6 h. Reaction completion was monitored on TLC using ethyl acetate:hexane (5:5) as mobile phase. The reaction mixture was quenched into the ice-water NaHCO3 solution (50 mL) and was extracted with ethyl acetate (3×50 mL). Organic layer was washed with brine solution (3×50 mL). The organic layer was dried using anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the 0.3 g of crude compound. The compound was purified by column chromatography using ethyl acetate/hexane as mobile phase. Compound was eluted out at 30% ethyl acetate in hexane to afford 4-(1H-1,2,4-triazol-3-yl)-2,6-bis(trifluoromethyl)pyridine (3) 0.060 g. Yield: 58.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].[CH:35]1[CH:36]=[CH:37]C2N(O)N=[N:41][C:39]=2[CH:40]=1.CCN=C=NCCCN(C)C.Cl.N1([OH:63])CCNCC1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([N:41]2[CH2:37][CH2:36][CH:35]([OH:63])[CH2:40][CH2:39]2)=[O:33])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: On1nnc2ccccc21
Reactant: ON1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (100 mg, 0.19 mmol), HOBt (3 mg, 0.1 eq.), EDAC.HCl (44 mg, 1.2 eq.) and piperazin-1-ol (21 mg, 1.1 eq.) in DMF (2 mL) at rt was added TEA (0.067 mL, 2.5 eq.). After stirring at rt for 7 days, the reaction was concentrated, diluted with DCM (10 mL) and methanol (0.5 mL) and then mixed with solid sodium bicarbonate. After stirring at rt for 15 mins, the suspension was loaded onto a silica gel column to give the titled compound as an orange solid.
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.[C:8]1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:19][C:20]1[CH:21]=[C:22](C(=O)C)[CH:23]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]=1[O:26][CH3:27]>CO>[C:28]([C:24]1[C:25]([O:26][CH3:27])=[C:20]([CH:21]=[C:22]([C:1]([O:4][CH3:5])([O:6][CH3:7])[CH3:8])[CH:23]=1)[NH2:19])([CH3:30])([CH3:29])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(OC)OC
Reactant: COc1c(N)cc(C(C)=O)cc1C(C)(C)C
Solvent: CO
Product: COc1c(N)cc(C(C)(OC)OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Trimethyl orthoformate (20 ml), p-toluenesulfonic acid (0.5 g, 1.9 mmol) and 3A-molecular sieves (4 g) were added to a solution of 1-[3-amino-5-(tert-butyl)-4-methoxyphenyl]-1-ethanone (4 g, 19 mmol) in methanol (20 ml) and the mixture was stirred at room temperature for 13 hours. The reaction mixture was filtered through celite and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, the mixture was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield 5.2 g of 3-(tert-butyl)-5-(1,1-dimethoxyethyl)-2-methoxyaniline as a crude product. Acetone (1.7 ml, 22 mmol), acetic acid (3.2 ml, 56 mmol) and 3A-molecular sieves (2 g) were added to a solution of the compound (5.2 g, 19 mmol) in methanol (6 ml) and the mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (1.1 g, 17 mmol) was added to the reaction mixture prior to stirring at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, washing was performed with saturated sodium hydrogencarbonate water and brine in that order, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.0 g) as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[CH:29]=[O:30])=[N:26][C:25]([O:31][CH3:32])=[CH:24][CH:23]=2.N1CCC[C@H]1C(O)=O.C(OCC)(=O)C>CS(C)=O.O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH:14]([CH:15]=[O:16])[CH:29]([C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[N:26]=3)[N:21]=[CH:20][C:19]=2[Cl:18])[OH:30])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2ncc(Cl)c(C=O)c2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc2ncc(Cl)c(C(O)C(C=O)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1

Procedure:
A solution of [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (3.1 g, 25.1 mmol, 1.0 eq), 3-chloro-6-methoxy-[1,5]naphthyridine-4-carbaldehyde (5.6 g, 25.1 mmol, 1.0 eq) and L-proline (1.16 mg, 10.1 mmol, 0.4 eq) in dimethyl sulfoxide (100 mL) and water (15 mL) is stirred at room temperature for 16 hours. The reaction mixture is then extracted with ethyl acetate (500 mL) and water (500 mL). The organic layer is washed with brine (300 mL), dried over magnesium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:1, v/v) to afford {trans-4-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-1-formyl-2-hydroxy-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a light yellow solid (4.5 g, 39% yield).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]2=[C:11]([C:14](=[S:16])[NH2:15])[N:12]=[CH:13][N:3]12.[I:17][CH3:18]>CC#N>[IH:17].[CH3:18][S:16][C:14]([C:11]1[N:12]=[CH:13][N:3]2[C:2](=[O:1])[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]=12)=[NH:15]
Reactant: C#CCn1nnc2c(C(N)=S)ncn2c1=O
Reactant: CI
Solvent: CC#N
Product: C#CCn1nnc2c(C(=N)SC)ncn2c1=O
Product: I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (0.323 g; 0.86 mmol) was dissolved in dry MeCN (1 mL) and iodomethane (1.220 g; 8.6 mmol) was added and the reaction mixture stirred at room temperature overnight.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.[CH3:28][O:29][C:30](=O)[O:31]C.[H-].[K+].C1C[O:39]CC1>>[O:39]1[CH2:5][CH2:6][CH2:7][CH2:2][CH:1]1[O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[C@H:17]([C:30]([O:29][CH3:28])=[O:31])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: COC(=O)OC
Reactant: C1CCOC1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [H-]
Agent: [K+]
Product: COC(=O)[C@@H]1C[C@H]2[C@@H]3CCc4cc(OC5CCCCO5)ccc4[C@H]3CC[C@]2(C)C1=O
Yield: 90 %

Procedure:
A solution of 3-tetrahydropyranyloxy-1,3,5(10)-estratrien-17-one (2, R=THP) (6.58 g, 18.2 mmol) in dry THF (50 mL) was added over a period of 20 min to a solution of dimethylcarbonate (3.98 mL, 47.23 mmol) and potassium hydride (2.27 g (3.6 g, 70% in oil), 56.68 mmol) in dry THF (40 mL). Then, the mixture was heated to reflux for a period of 3 h. Most of the solvent was then evaporated and the residue was diluted with ethyl acetate (100 mL) and treated with a saturated ammonium chloride solution (50 mL). The organic phase was washed with water (6×40 mL), dried and evaporated to give a yellowish solid. Trituration of the residue with a mixture of acetone:hexanes (1:1) yielded the title compound in 90% yield as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.C(OC(=O)[NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][CH2:40][CH3:41])[N:34]=1)(C)(C)C>>[NH2:32][C:33]1[N:34]=[C:35]([N:39]([CH2:40][CH3:41])[C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=3)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:36]=[CH:37][CH:38]=1
Reactant: CCNc1cccc(NC(=O)OC(C)(C)C)n1
Reactant: O=C(Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cccc(N)n1

Procedure:
The title compound was prepared by procedure analogous to that described in example 325, step 2 using 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl chloride and (6-ethylamino-pyridin-2-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12].[NH2:16][C:17]1[N:22]=[C:21](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:20]([CH2:36][C:37]2[CH:58]=[CH:57][C:40]([O:41][CH2:42][CH2:43][CH2:44][N:45]3[CH2:49][CH2:48][CH2:47][C@@H:46]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:39][C:38]=2[O:59][CH3:60])=[C:19]([CH3:61])[N:18]=1>C(#N)CC.C(OC([O-])=O)(O)=O.[Na+]>[NH2:16][C:17]1[N:22]=[C:21]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12])[C:20]([CH2:36][C:37]2[CH:58]=[CH:57][C:40]([O:41][CH2:42][CH2:43][CH2:44][N:45]3[CH2:49][CH2:48][CH2:47][C@@H:46]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:39][C:38]=2[O:59][CH3:60])=[C:19]([CH3:61])[N:18]=1
Reactant: CCC[C@H](N)CCO
Reactant: COc1cc(OCCCN2CCC[C@@H]2C(=O)OC(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Agent: O=C([O-])OC(=O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCC#N
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(OCCCN2CCC[C@@H]2C(=O)OC(C)(C)C)cc1OC
Temperature: 120 °C
Yield: 76.8 %

Procedure:
Trifluoroacetic acid (0.091 mL) was added to the mixture of (S)-3-aminohexan-1-ol (416 mg) and the product from step (ix) (775 mg) in propionitrile (8 mL). After the mixture was heated at 120° C. for 16 h, the reaction mixture was cooled to RT, diluted with sat. sodium hydrogen dicarbonate and extracted with EtOAc. The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (520 mg) as a white gum; 1H NMR (CDCl3); 6.81 (1H, d), 6.44 (1H, d), 6.38 (1H, dd), 4.80 (2H, br s), 4.13-4.03 (1H, m), 4.03-3.90 (2H, m), 3.84 (3H, s), 3.59 (2H, s), 3.49-3.37 (1H, m), 3.34-3.22 (1H, m), 3.18-3.08 (1H, m), 3.08-3.00 (1H, m), 2.91-2.80 (1H, m), 2.62-2.49 (1H, m), 2.41-2.30 (1H, m), 2.35 (3H, s), 2.10-1.70 (8H, m), 1.44-1.34 (1H, m), 1.42 (9H, s), 1.28-0.89 (4H, m), 0.75 (3H, t); LC-MS: m/z 573.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:15]([N:18]=[C:19]=[O:20])([CH3:17])[CH3:16]>>[CH:15]([NH:18][C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:3][CH2:2]1)=[O:20])([CH3:17])[CH3:16]
Reactant: Nc1ccc(CC2CCNCC2)cc1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of 4-(piperidin-4-ylmethyl)-phenylamine (0.57 g, 3 mmol) in dicholoromethane (20 mL) was cooled in an ice bath under nitrogen atmosphere. Isopropyl isocyanate (0.28 g, 3.3 mmol) was added dropwise to the solution and stirred at ice bath temperature for 30 minutes. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried, and solvents removed in vacua. The crude product was chromatographed on silica gel, eluting with 2% methanol/dichloromethane containing 0.01% ammonium hydroxide, to give 4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenylamine (0.66 g, 80%) as a gum.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([CH2:12][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Reaction time: 1.17 h
Yield: 82.3 %

Procedure:
N-methyl piperazine (1.97 mL, 17.8 mmol) was added dropwise to a solution of 3-fluoro-4-nitrobenzaldehyde (1.50 g, 8.88 mmol) and acetic acid (0.20 mL, 3.54 mmol) in toluene (8.4 mL) at room temperature. The reaction mixture was stirred for 1.5 h at room temperature before the addition of further toluene (3.15 mL) and sodium triacetoxyborohydride (2.97 g, 14.0 mmol). The reaction mixture was stirred for 70 min and then further sodium triacetoxyborohydride (0.40 g, 1.9 mmol) was added. The reaction mixture was stirred for 50 min, and then quenched by the addition of MeOH (2 mL) and saturated aqueous NaHCO3 (10 mL). The reaction mixture was stirred for 30 min. The phases were separated and the aqueous layer was extracted with toluene (2×20 mL, 1×10 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash column chromatography (EtOAc:MeOH:NEt3 19:1:0.1) to give the title compound (1.85 g, 82%) as an orange oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[CH:3]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:20]([C:9]1[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]=1[C:4]1[CH:3]=[C:2]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=2)[CH:7]=[CH:6][N:5]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(F)ccn1
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Into a 30-mL round bottom flask, was placed a solution of 4-fluoro-2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridine (500 mg, 1.66 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), (3-(trifluoromethyl)benzylamine (581 mg, 3.32 mmol, 2.00 equiv), and potassium carbonate (985 mg, 7.14 mmol, 4.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of brine and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/hexane (1:1). The product was obtained as 500 mg (66%) of a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>Cl>[C:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a mixture of 4-hydroxybenzoic acid (16) (20.0 g, 144.8 mmol) and pyridine (60 ml, 742 mmol) at 0° C. was added acetyl chloride (12 ml, 169 mol) over 5 minutes. The resulting mixture was stirred at ice bath temperature for 30 minutes and for 1 hour at room temperature. The mixture was poured into ice water (500 ml) and the pH of the medium was brought to 1-2 by adding conc. HCl (ca. 40 ml). The precipitate was filtered, washed with water (100 ml), and dried (Na2SO4). The obtained solid material was crystallized from methanol-water (1:1) (200 ml) affording the title compound (21.485 g, 82.3%) as white crystals, m.p. 181-183° C. 1H NMR (CDCl3, HMDSO) δ: 2.32 (3H, s); 7.22 (2H, d, J=8.2 Hz); 8.16 (2H, d, J=8.2 Hz); 10.50 (1H, brs).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[C:4]([Cl:11])[CH:3]=1.[CH3:12]I.[H-].[Na+].O.C[N:18]([CH:20]=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:9])[C:20]#[N:18])=[C:4]([Cl:11])[CH:3]=1
Reactant: CI
Reactant: N#CCc1ccc(Br)cc1Cl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C#N)c1ccc(Br)cc1Cl
Temperature: 0 °C
Yield: 63 %

Procedure:
To a stirred solution of 2-(4-bromo-2-chlorophenyl)acetonitrile (1.11 g, 4.82 mmol) in anhydrous DMF (7.6 mL) is added methyl iodide (0.63 mL, 10.1 mmol). The solution is cooled to 0° C. and sodium hydride (60% susp. in oil, 0.63 g, 15.7 mmol) is added in 5 portions over 1 h. The reaction mixture is then left stirring to slowly warm up to room temperature for 18 h. The solution turned to a thick and brown orange paste. Water (20 mL) is then slowly added and the solution extracted with a 3:1 solution of hexane/Et2O (3×25 mL). The organic layer is washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (eluent: Hex/EtOAc 9:1 to 8:2) to provide the expected product 2-(4-bromo-2-chlorophenyl)-2-methylpropanenitrile (0.79 g, 63%). 1H NMR (300 MHz, CHLOROFORM-D): δ 7.61 (1H, d, J=2.1 Hz), 7.43 (1H, dd, J=8.5, 2.1 Hz), 7.34 (1H, d, J=8.6 Hz), 1.85 (6H, s).