Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])=[NH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:28]([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30]>>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[N:10][P:28]([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(C)c1NC(=N)c1ccc(C(C)(C)C)cc1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Product: Cc1cccc(C)c1NC(=NP(C(C)C)C(C)C)c1ccc(C(C)(C)C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.40 g of 4-t-butyl-N1-(2,6-dimethylphenyl)benzamidine (Amidine IV, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a slightly cloudy yellow oil was isolated (2.04 g, 100%).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:30][N:31]1[CH:35]=[C:34]([S:36](Cl)(=[O:38])=[O:37])[C:33]([C:40]([F:43])([F:42])[F:41])=[N:32]1>C(Cl)Cl>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:2]([NH:1][S:36]([C:34]2[C:33]([C:40]([F:43])([F:41])[F:42])=[N:32][N:31]([CH3:30])[CH:35]=2)(=[O:38])=[O:37])[CH2:3][CH2:4]3)[CH:16]=1
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Reactant: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(S(=O)(=O)NC2CCc3cc(Cn4cc(CO)c(C(F)(F)F)n4)ccc32)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.096 mmol, 30 mg) and triethylamine (0.193 mmol, 0.027 mL, 19.50 mg) in DCM (0.9 mL) was added 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride (0.096 mmol, 23.96 mg) and the whole stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to give a clear film (12.0 mg, 0.023 mmol, 23.8%). MS (ESI): m/z [M+H]+ 524.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33]([CH:35]4[CH2:38][NH:37][CH2:36]4)=[O:34])[CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(O[BH-](O[C:49](=[O:51])[CH3:50])OC(=O)C)(=O)C.C[N+](C)(C)C.Cl[CH2:58][CH2:59]Cl>CN(C=O)C>[CH:50]1([C:49]([N:37]2[CH2:38][CH:35]([C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([S:23](=[O:25])(=[O:24])[NH:22][C:13]4[C:12]([NH:11][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=5)=[N:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[CH:27]=3)=[O:34])[CH2:36]2)=[O:51])[CH2:59][CH2:58]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)C3CNC3)c2)cc(OC)c1
Reactant: ClCCCl
Agent: C[N+](C)(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)C3CN(C(=O)C4CC4)C3)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)azetidine-3-carboxamide (110 mg, 0.19 mmol), prepared using procedures similar to those described in Example 372, in 3 mL of DCE and 200 μL of DMF, aldehyde (0.77 mmol, 4.0 eq.)was added slowly followed by tetramethylammonium triacetoxyborohydride (1.16 mmol, 6.0 eq). The reaction was stirred at room temperature overnight. LC/MS indicated the reaction was completed. The solvent was subsequently removed under reduced pressure on a rotary evaporator. The crude material was then redissolved in methanol. Purification of the final product was accomplished by preparatory reverse-phase HPLC with the eluents 25 mM aqueous NH4OAc/CAN. A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C18, OCD 5 μM, 30×70 mm column and running a 5-100% gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:11][C:12]1[CH:23]=[CH:22][C:15]([C:16](N(OC)C)=[O:17])=[CH:14][CH:13]=1>>[CH3:4][OH:8].[Br:11][C:12]1[CH:23]=[CH:22][C:15]([C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH3:10])[CH:3]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Reactant: CCOc1cccc(Br)c1
Product: CCOc1cccc(C(=O)c2ccc(Br)cc2)c1
Product: CO
Yield: 47 %

Procedure:
The title compound was prepared from 3-bromophenetole and 4-bromo-N-methoxy-N-methylbenzamide following the general method of Method 1. The crude product was re-crystallized from methanol affording 0.37 g (47% yield) of the title compound as colorless crystals: mp 68.5-70.1° C.; 1H NMR (400 MHz, CDCl3) δ 7.70-7.60 (m, 4 H), 7.38 (broad t, J=7.6 Hz, 1 H), 7.31-7.27 (m, 2 H), 7.13 (ddd, J=8.2, J=2.3, J=1.2 Hz, 1 H), 4.08 (q, J=7.0 Hz, 2 H), 1.43 (t, J=7.0 Hz, 3 H); 13C NMR (400 MHz, CDCl3) δ 195.5, 159.0, 138.4, 136.4, 131.6, 131.5, 129.3, 127.5, 122.5, 119.5, 114.9, 63.7, 14.7; MS (TSP) m/z 305 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(N(CC)CC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]>[F:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1ccc(F)c(C#N)c1
Temperature: 100 °C

Procedure:
5-Bromo-2-fluorobenzonitrile (5.01 g, 25.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (652 mg, 0.929 mmol), and copper (J) iodide (413 mg, 2.17 mmol) were combined in triethylamine (15 mL) under an atmosphere of nitrogen. Trimethylsilyl acetylene (4.2 mL, 29.7 mmol) was added and the mixture was heated to 100° C. The mixture solidified and was monitored by LC/MS. After completion, the mixture was diluted with methylene chloride and washed with 1 N HCl. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (5-45%) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.09 (dd, J=6.10, 2.03 Hz, 1H) 7.77-7.97 (m, 1H) 7.54 (t, J=9.15 Hz, 1H) 0.15-0.32 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.NC1C=C(C2C(C3C=CC(F)=CC=3)=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1.[CH:55]1([C:58](Cl)=[O:59])[CH2:57][CH2:56]1>>[CH:55]1([C:58]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)=[O:59])[CH2:57][CH2:56]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2F)ccn1
Agent: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Product: O=C(Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2F)ccn1)C1CC1
Yield: 31.7 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 50.0 mg (0.14 mmol) of 4-(2-aminopyridin-4-yl)-3-(2-fluorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 26-5) in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole, and using 31.5 mg (0.30 mmol) of cyclopropylcarbonyl chloride in place of acetic anhydride to obtain 18.5 mg of the title compound as a white powder. (Yield: 31%)
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[C:25](OC)(OC)(OC)[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:25][C:26]1[N:14]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:9]2=[N:10][C:11]([CH3:13])=[CH:12][C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[C:8]2[N:24]=1
Reactant: COC(C)(OC)OC
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)Nc1cc(C)nc2c1nc(C)n2-c1c(C)cc(C)cc1C

Procedure:
A mixture of N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine (250 mg, 0.77 mmol), trimethyl orthoacetate (0.184 g, 1.532 mmol), p-toluenesulfonic acid monohydrate (0.01 g) in toluene was heated at reflux using Dean-Stark apparatus for 3 hours. The mixture was quenched with water, brine, extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After purification, the title compound was obtained as a white crystal, mp 101–103° C. Anal. For C22H30N4 calc. C, 75.39; H, 8.63; N, 15.98; found, C, 75.44; H, 8.95; N, 15.95.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[CH2:9]([Li])CCC.CI.O>O1CCCC1>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:9])[CH3:2]
Reactant: [Li]CCCC
Reactant: CCc1ccccn1
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CC(C)c1ccccn1
Temperature: -20 °C

Procedure:
A solution of 19.4 ml (0.17 mol) of 2-ethylpyridine in 100 ml of tetrahydrofuran was cooled to −20° C. and 125 ml of n-butyllithium (1.6M in hexane, 0.2 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature, stirred for another one hour and subsequently cooled back down to −20° C. A solution of 18 ml (0.25 mol) of methyl iodide in 20 ml of tetrahydrofuran was then added at such a rate that the temperature remained at −20° C. The mixture was allowed to warm to room temperature, stirred for a further 14 hours and hydrolyzed with 60 ml of water. The organic phase was separated off and the aqueous phase was extracted three times with 50 ml each time of diethyl ether. The organic phases were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. The residue obtained in this way was distilled at 81-84° C./60 torr. This gave 10.88 g (53%) of 2-isopropylpyridine.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].C(N(C(C)C)CC)(C)C.[C:17]12(C[C:28]([Cl:30])=[O:29])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.Cl[CH2:32][Cl:33]>CN(C)C=O>[C:17]12([CH2:2][C:3]([OH:5])=[O:4])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.[C:32]([Cl:33])(=[O:4])[C:28]([Cl:30])=[O:29]
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cl)C(=O)Cl
Product: O=C(O)CC12CC3CC(CC(C3)C1)C2
Temperature: -80 °C

Procedure:
One of the 3 parts of the compound of formula (I) in which R1 --(R2)m --(R3)n --(R4)p represents Boc-Arg(benzyloxycarbonyl)2 -Arg(benzyloxycarbonyl)2 -Pro-, R, R5 and R6 represent hydroxyl radicals and R7 represents a hydrogen atom obtained in Example 9 is treated for 90 minutes with 5 ml of a trifluoroacetic acid/distilled water mixture (95/5 by volume). The medium is then brought to dryness on a rotary evaporator (2.6 kPa, 45° C., 45 minutes) and 15 ml of distilled water are then added to the medium. The suspension obtained is frozen to -80° C. and then lyophilized (96 hours). The product is dissolved in 1 ml of dimethylformamide containing 0.0625 ml of diisopropylethylamine (0.36 mmol). 50 μl (50 μmol) of a solution of 1-adamantylacetic acid chloride (obtained by reaction of 38.8 mg (200 μmol) of 1-adamantylacetic acid with 17.2 μl (200 μmol) of oxalyl chloride in 200 μl of dichloromethane in the presence of a drop of dimethylformamide for 15 minutes at a temperature in the region of 20° C.) are then added to the peptide solution and the reaction is carried out at a temperature in the region of 20° C. for 1 hour. The solvent is then removed by virtue of a Speed Vac (Savant) centrifugal evaporator equipped with a vane pump for 18 hours at a temperature in the region of 20° C. The residue is dissolved in 2 ml of a dichloromethane/methanol mixture (1/1 by volume) and then 100 mg of 10% palladium-on-charcoal and 100 mg of ammonium formate are added. The reaction is carried out for 150 minutes with periodic stirring to a vortex. The reaction medium is filtered on a 0.45 μm Millex HV filter (Millipore) and the filter washed with 5 ml of methanol. The solvent is then evaporated under reduced pressure (2.6 kPa, 45° C., 30 minutes). The product is finally purified by high performance liquid chromatography on a 100 Å C18 column (250×10 mm, Bio-Rad), elution being carried out with a gradient from 15 to 40% of acetonitrile containing 0.07% of trifluoroacetic acid (by volume) in water containing 0.07% of trifluoroacetic acid (by volume) at a flow rate of 6 ml/minute, over 30 minutes, and then lyophilized. 2.9 mg of the ditrifluoroacetate of the compound of formula (I) in which R1 --(R2)m --(R3)n --(R4)p represents 1-adamantylacetyl-Arg-Arg-Pro-, R, R5 and R6 represent hydroxyl radicals and R7 represents a hydrogen atom are thus obtained in the form of a white powder [Mass spectrum on Sciex API III, in ESMS (Electrospray Mass Spectrometry): M/z=601.6 (M+2H)2+ ].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([Cl:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>CN(C=O)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:22][C:23]([F:26])([F:25])[F:24])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Oc1cc(Cl)ncc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)COc1cc(Cl)ncc1Cl
Temperature: 90 °C
Yield: 59.1 %

Procedure:
To a solution of 2,5-dichloropyridin-4-ol (CAN 847664-65-7, 1.5 g, 9.15 mmol) in DMF (15 ml) in a microwave vial were added cesium carbonate (4.47 g, 13.7 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.18 g, 13.7 mmol). The vial was sealed and heated at 90° C. overnight. The reaction mixture was diluted with ethylacetate and extracted with water. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. Organic phases were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with a heptane/ethylacetate gradient on silica to yield the titled compound as a colorless oil (1.33 g, 59%). MS (ESI, m/z): 246.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N+:10]([O-])([OH:12])=[O:11]>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cccc(Br)c1
Product: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To ice cold conc. sulphuric acid (400 mL) was added fuming nitric acid (200 mL) dropwise followed by 3-bromobenzaldehyde (i) (100 g, 0.540 mol) dropwise over 15 min. The reaction mixture was stirred for 10 min and then poured carefully over ice-water. The resulting solids were filtered and then purified by flash column chromatography on silica gel, eluting with EtOAc:n-hexane (gradient elution from 1% to 20% v/v) to give (ii) (60 g, 48%).
Reaction SMILES: [N:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([C:11]1[N:12]=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:34])[CH2:23][N:24]3[C:28]([CH3:29])=[CH:27][C:26]([C:30]([F:33])([F:32])[F:31])=[N:25]3)[CH2:18][CH2:17]2)[S:14][CH:15]=1)(=O)[CH3:9]>[Cl-].[NH4+]>[CH3:29][C:28]1[N:24]([CH2:23][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([C:13]3[S:14][CH:15]=[C:11]([C:8](=[N:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH3:9])[N:12]=3)[CH2:17][CH2:18]2)=[O:34])[N:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:27]=1
Reactant: NN1CCCCC1
Reactant: CC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=NN1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reaction time: 2 h

Procedure:
At 80° C., piperidine-1-amine (104 mg) is added to a solution of 1-[4-(4-acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (46 mg). The reaction mixture is stirred at this temperature for a further 2 hours. Aqueous ammonium chloride solution (10 ml) is then added to the reaction mixture. After phase separation, the aqueous phase is extracted three times with methyl tert-butyl ether (20 ml). All the organic phases are dried over Na2SO4. The mixture is then filtered and concentrated under reduced pressure. This gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[N-(piperidin-1-yl)ethanimidoyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (55 mg, 99%), (log P(pH2.7)=3.69).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH:25][OH:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl.O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:25]([CH:17]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O-:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: ONC1CCCCCCC1
Agent: Cl
Solvent: O
Solvent: CO
Product: [O-][N+](=Cc1ccc(OCc2ccccc2)cc1)C1CCCCCCC1
Yield: 47.1 %

Procedure:
A solution of 4-benzyloxybenzaldehyde (12.7 g, 0.060 mol), N-cyclooctylhydroxylamine (10.0 g, 0.070 mol) and a catalytic amount of HCl in methanol (300mL) was refluxed for 56 hours with molecular sieves in a soxhlet for water removal. The reaction mixture was concentrated and dry flash columned on silica with hexanes/ethyl acetate to give the title compound as a pale yellow powder, (9.53 g, 47.0% yield), m.p. 107.5° C. (Rf=0.46 on a silica gel plate using hexanes:EtOAc, 1:1, v:v, as an eluant). The N-cyclooctylhydroxylamine precursor was obtained by sodium cyanoborohydride reduction of cyclooctanone oxime in acetic acid/tetrahydrofuran.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3[CH:23]=[N:24][C:25](C(O)(C)C)=[N:26][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].BrC1C=NC([CH2:39][P:40]([O:45][CH2:46][CH3:47])([O:42][CH2:43][CH3:44])=[O:41])=NC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:43]([O:42][P:40]([CH2:39][C:25]1[N:24]=[CH:23][C:22]([C:13]2[CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:9]3[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=3[CH:12]=2)=[CH:27][N:26]=1)([O:45][CH2:46][CH3:47])=[O:41])[CH3:44]
Reactant: CCOP(=O)(Cc1ncc(Br)cn1)OCC
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(-c3ccccn3)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(CP(=O)(OCC)OCC)nc3)cc(-c3ccccn3)c2s1
Temperature: 100 °C

Procedure:
Intermediate 1 (860 mg, 2.5 mmol), iii (813 mg, 2.63 mmol), Cs2CO3 (2.57 g, 7.90 mmol) and Pd(PPh3)2Cl2 (90 mg, 0.10 mmol) were dissolved in 1-4-dioxane:H2O (10:1; 10 mL) and degassed with a stream of N2 for 10 min. The reaction was sealed under an atmosphere of N2 and heated at 100° C. for 1 h in a microwave reactor. The mixture was concentrated in vacuo, purified over silica (gradient elution: 0-10% DCM-MeOH) and triturated from acetone affording iv (410 mg, 29%). MS: 527.1 [M+H]+.
Reaction SMILES: CO[C:3](=[O:19])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.Cl.[CH3:21][O:22][NH2:23].O.[OH-].[NH4+:26]>CO>[O:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[N:23][O:22][CH3:21])[C:3]([NH2:26])=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C(=O)c1ccccc1Oc1ccccc1
Reactant: [NH4+]
Reactant: CON
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CON=C(C(N)=O)c1ccccc1Oc1ccccc1

Procedure:
To a solution of methyl-(2-phenoxyphenyl)-2-oxoacetate (0.70 g) in methanol (10 ml), 28% aqueous ammonium hydroxide (2.0 ml) was added, and the resultant mixture was stirred overnight, followed by removal of the solvent under reduced pressure. The residue was combined with diethyl ether (150 ml) and water (50 ml) under stirring and, upon dissolution, allowed to stand. The organic layer was separated, washed and dried over anhydrous sodium sulfate. Upon filtration, the filtrate was concentrated under reduced pressure to give residual yellow crystals, which were combined with methanol (10 ml) and O-methylhydroxylamine hydrochloride (1.49 g) while stirring and refluxed for 6 hours. Water (50 ml) was added to the reaction mixture, which was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to give oily residue. The residue was purified by silica gel column chromatography with benzene to give 0.36 g of the objective compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[OH-].[Pd+2].[OH-]>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:19]=[CH:18][N:17]=[N:16]1
Reactant: c1ccc(COc2ccc(-n3ccnn3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc(-n2ccnn2)cc1

Procedure:
1-[4-(benzyloxy)phenyl]-1H-1,2,3-triazole (200 mg, 0.8 mmol) was dissolved in 1.6 mL of a mixture of ethyl acetate and ethanol (1:1). The solution was degassed and purged with nitrogen. Palladium hydroxide (20% w/w on carbon, 55.9 mg, 0.08 mmol) was added and the reaction was degassed and purged with hydrogen three times. The hydrogenation was continued at room temperature under a hydrogen balloon overnight. The catalyst was removed by filtration through a plug of silica gel, which was washed thoroughly with acetone. Concentration afforded the product as white solid. LRMS calc: 161.1; obs: 162.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)[CH2:58][CH2:57]1>CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)[CH2:58][CH2:57]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: C1CCN(CCOC2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCCN2CCCCC2)CC1
Reaction time: 2 h
Yield: 20.9 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1)(0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMA (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 1-(2-(piperidin-4-yloxy)ethyl)piperidine (115) (0.214 g, 1.01 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.069 g, 20.74% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.36-1.45 (2H, m), 1.64-1.94 (8H, m), 2.37-2.50 (4H, m), 2.55 (2H, t), 3.03-3.15 (1H, m), 3.37-3.49 (1H, m), 3.50-3.65 (4H, m), 3.92-4.04 (1H, m), 4.30 (2H, s), 7.00 (1H, t), 7.21-7.32 (2H, m), 7.68-7.79 (3H, m), 8.43-8.49 (1H, m), 10.49 (1H, s); m/z (LC-MS, ESI+), RT=2.01 (M+H 493.5).