Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([O:16][C:17]([C:19]3[CH:30]=[CH:29][C:22]([C:23]([O:25]CC=C)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH3:15])[CH:5]=[CH:4][C:3]1=2.N1CCOCC1.C(O)C>C1COCC1.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>[CH3:31][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([O:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:29][CH:30]=3)=[O:18])[CH3:15])[CH:5]=[CH:4][C:3]1=2
Reactant: C=CCOC(=O)c1ccc(C(=O)OC(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: CCO
Product: CC(OC(=O)c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
A solution of 2.40 g (5.71 mmol) of the ester obtained in Example 59 (b) in 30 ml of THF is treated with mg of tetrakis(triphenylphosphine)palladium(0) and 5 ml of morpholine under the preparation conditions of Example 24(b), to yield 1.94 g (89%) of the expected derivative, melting point 138° C. (αD =-53.2°; c=1, ethanol).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.C(N(CC)CC)C.[Cl:39][CH2:40][C:41](Cl)=[O:42]>O1CCCC1>[Cl:39][CH2:40][C:41]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1)=[O:42]
Reactant: O=C(Cl)CCl
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)CCl)cn5n4)c3)c2)CC1
Yield: 89.5 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (600 mg, 1.46 mmol), triethylamine (305 μL, 2.19 mmol), chloroacetyl chloride (202 μL, 1.75 mmol) and tetrahydrofuran (10 mL) as starting materials and in the same manner as in Example 385, the title compound (636 mg, 89%) was obtained as a gray powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=4[N:23]3[CH3:26])=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 626.8 %

Procedure:
4-(Benzyloxy)pyridin-2(1H)-one (580 mg, 0.28 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (850 mg, 0.23 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (700 mg, 62%) as a green solid: 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J=8.2 Hz, 1H), 7.44-7.39 (m, 4H), 7.38-7.35 (m, 1H), 7.31-7.28 (m, 2H), 7.01 (dd, J=8.3, 1.8 Hz, 1H), 6.09 (d, J=2.6 Hz, 1H), 6.04 (dd, J=7.6, 2.6 Hz, 1H), 5.05 (s, 2H), 4.64 (br m, 2H), 3.74 (br m, 2H), 3.62 (s, 3H), 2.79 (br m, 2H), 1.47 (s, 9H).
Reaction SMILES: Br[C:2]1([F:20])[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH2:3]1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH2:27])=[CH:24][CH:23]=1.Cl>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[F:20][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH:27]=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: O=C(NC1Cc2ccccc2C1)C1=CCC(F)(Br)C=C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(NC1Cc2cccc(C=Cc3ccc(F)cc3)c2C1)c1ccc(F)cc1
Yield: 90 %

Procedure:
150 mg (0.45 mmoles) 4-bromo-N-indan-2-yl-4-fluoro-benzamide, 1 mg palladium-(II)-acetate, 3.4 mg tri-o-tolyl phosphine and 88 mg (0.72 mmoles) para-fluorostyrene were combined in 2 ml triethylamine and stirred under reflux for 9 h. Subsequently, the reaction mixture was poured on a mixture of ice and diluted HCl, the mixture extracted with ethyl acetate and the resulting solution dried and evaporated to dryness. The residual oil was purified using prep. HPLC chromatography. (RP18, acetonitrile/water, 1% trifluoroacetic acid). 152 mg (90%) 4-fluoro-N-{4-[2-(4-fluoro-phenyl)-vinyl]-indan-2-yl}-benzamide were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:23]=1)[N:7]=[C:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10]([C:12](O)=[O:13])=[CH:11]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:46][CH2:47][CH2:48][CH2:49][NH:50][CH2:51][CH2:52][CH3:53].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:23]=1)[N:7]=[C:8]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:9][C:10]([C:12](=[O:13])[N:50]([CH2:49][CH2:48][CH2:47][F:46])[CH2:51][CH2:52][CH3:53])=[CH:11]2
Reactant: CCCNCCCF
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(Br)ccc2C=C(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCN(CCCF)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 148.8 %

Procedure:
(1E,4E)-8-Bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylic acid (0.275 g, 0.721 mmol) was dissolved in 7 mls of dry DMF. To this solution was added HOBT (0.107 g, 0.794 mmol) and EDCI (0.152 mmol, 0.794 mmol), and this mixture was stirred at room temperature for 20 minutes. 3-Fluoro-N-propylpropan-1-amine hydrochloride (0.124 mmol, 0.794 mmol) followed by triethylamine (0.211 mls, 1.515 mmol) were then added and the reaction mixture stirred at room temperature for 16 hours. The mixture was then diluted with EtOAc, washed several times with brine, dried over sodium sulfate and concentrated under reduced pressure. Flash 40 Biotage (40S cartridge, 25% EtOAc/Hexane) afforded 0.089 g (26%) of tert-butyl (1E,4E)-8-bromo-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate. m/z (APCI-pos) M+1=481.8 and 483.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[C:13]([C:34]1[CH:39]=[CH:38][C:37]([O:40]C(=O)C(C)(C)C)=[CH:36][CH:35]=1)=[C:12]2[CH3:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.CC(O)=O.O>O1CCOCC1.CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:21][CH:20]=1)[C:13]([C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1)=[C:12]2[CH3:47])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(OC(=O)C(C)(C)C)cc2)n(Cc2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Agent: [Li]O
Solvent: CO
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A mixture of the substituted indole 23 (61.8 g, 0.098 mol, 1 eq) and LiOH.H2O (8.5 g, 0.202 mol, 2.1 eq) in dioxane/MeOH/H2O (300 mL, 150 mL, 150 mL) was stirred at 60° C. for 2 h. The mixture was cooled to rt and 12.1 mL of AcOH was added in order to adjust the pH to approximately 7. Then water (600 mL) was added and the mixture was extracted with CH2Cl2 (6×150 mL), the organic phase was washed with conc. Aq. Na2CO3, H2O, brine, dried over Na2SO4, and evaporated to give 31 (51.6 g, 97%) as a yellow foam: 1H NMR (CDCl3) δ 7.07 (m, 19 H), 6.10 (s, 2 H), 5.03 (s, 2 H), 4.03 (t, 2 H), 2.8 (t, 2 H), 2.53 (br s, 4 H), 2.21 (s, 3 H), 1.63 (t, 4 H), 1.43 (br s, 2 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O)C.Cl[C:11]1[C:16]([I:17])=[CH:15][N:14]=[C:13]([S:18][CH3:19])[N:12]=1.[CH3:20][NH:21][NH2:22]>O>[I:17][C:16]1[C:11]([N:21]([CH3:20])[NH2:22])=[N:12][C:13]([S:18][CH3:19])=[N:14][CH:15]=1
Reactant: CSc1ncc(I)c(Cl)n1
Reactant: CNN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CSc1ncc(I)c(N(C)N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
603 mg of potassium carbonate was added to ethanol (15 mL) solution of 1.25 g of 4-chloro-5-iodo-2-(methylthio)pyrimidine, and with cooling with ice, 0.28 mL of methylhydrazine was dropwise added thereto. This was stirred overnight at room temperature, then water was added thereto, and the precipitated crystal was taken out through filtration and dried to obtain 851 mg of the entitled compound as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][N:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[C:5]([NH2:13])=[C:4]([N+:14]([O-])=O)[CH:3]=1>CO.[Pd]>[CH3:12][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:2][CH:3]=[C:4]([NH2:14])[C:5]=2[NH2:13])[CH2:10]1
Reactant: CN1CCc2c(N)c([N+](=O)[O-])cc(Br)c2C1
Agent: [Pd]
Solvent: CO
Product: CN1CCc2c(ccc(N)c2N)C1
Reaction time: 24 h
Yield: 48.5 %

Procedure:
A solution of the product from Example 10 (1.50 g, 5.24 mmol) and 20% Pd on carbon (0.30 g) in 100 mL of MeOH was hydrogenated at room temperature and pressure for 24 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was partitioned between CHCl3 and saturated aqueous NaHCO3 solution. The organic phase was separated and the aqueous phase was extracted with additional CHCl3 and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was filtered through a plug of silica gel eluting with 25% EtOH/EtOAc. The eluant was concentrated to give the title compound as an oil (0.45 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:28]([O-])=O)=[C:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[C:18]2=[O:27])[NH:12][CH:13]=1.Cl.O.O.Cl[Sn]Cl.[OH-].[Na+]>O1CCOCC1>[NH2:28][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:13][NH:12][C:11]=1[CH2:14][CH2:15][CH2:16][N:17]1[C:18](=[O:27])[C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]1=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1CCCc1[nH]cc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(-c2ccc(Cl)cc2Cl)c[nH]c1CCCN1C(=O)c2ccccc2C1=O
Reaction time: 12 h

Procedure:
To a round bottom flask containing a stirred solution of 2-{3-[4-(2,4-dichlorophenyl)-3-nitropyrrolyl]propyl}benzo[c]azoline-1,3-dione (4) (1 eq) and con. HCl (7 eq) in dioxane was added solid SnCl2.2H2O (10 eq) in portions. The clear yellow reaction was stirred for 12 hours at which time the reaction was found to be complete by LC/MS. The reaction was neutralized to pH 7 by addition of 6M aq. NaOH, followed by extraction with EtOAc. The organic layers were filtered and concentrated to give a solution of 2-{3-[3-amino-4-(2,4-dichlorophenyl)pyrrolyl]propyl}benzo[c]azoline-1,3-dione (5), which was unstable and used directly in the next step (LC/MS m/z 415.3 MH+). Assumed quantitative yields.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[BH4-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH2:10][OH:11])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1cccc(-c2cnccn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(-c2cnccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
To a stirred solution of 3-(pyrazin-2-yl)benzaldehyde [376637-85-3] (200 mg, 1.09 mmol) in methanol (5 mL), NaBH4 (82 mg, 2.17 mmol) was added at 0° C. and stirred for 10 min. Then the mixture was allowed to warm to rt and stirred for 3 h. The mixture was concentrated under reduced pressure at 45° C., saturated aqueous NH4Cl solution was added and extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the title compound as a liquid (200 mg, 99%). [LCMS RtE=0.20 min, [M+H]+=187.0; TLC Rf=0.26 (ethyl acetate/hexane 50:50)].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C=O)C.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[NH:8][C:7]3=[O:14])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=C1NC(=O)c2cc(O)ccc21
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)c2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a stifling slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0° C. was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright yellow-green mixture was allowed to return to room temp. and was stirred for 1 h, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70° C. overnight, then cooled to room temp. and diluted slowly with water (150 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% hexane) Rf 0.28; 1H NMR (DMSO-d6) δ 7.32 (d, J=12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J=7.8 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 11.43 (br s, 1H); CI-MS m/z 285 ((M+H)+, 100%).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:9]=[C:8]([C:10]([O:12]CC)=O)[O:7][N:6]=1)([CH3:4])[CH3:3].[NH2:15][C@@H:16]([CH3:33])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[C:29]([F:31])[C:26]([C:27]#[N:28])=[C:25]([Cl:32])[CH:24]=2)=[N:19]1>>[Cl:32][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:10]([C:8]3[O:7][N:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:9]=3)=[O:12])[CH3:33])[N:19]=2)[CH:30]=[C:29]([F:31])[C:26]=1[C:27]#[N:28]
Reactant: CCOC(=O)c1nc(C(C)(C)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1nc(C(C)(C)O)no1

Procedure:
The title compound was prepared using the procedure described in Example 52(g) starting from ethyl 3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazole-5-carboxylate (2 mmol, 400 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (2 mmol, 556 mg). Yield 202 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 1.51 (bs, 6H), 4.34-4.37 (m, 2H), 4.43-4.51 (m, 1H), 5.70 (s, 1H), 7.02 (d, 1H), 7.83-7.88 (m, 2H), 7.96 (s, 1H), 9.41 (d, 1H). LC-MS: [M+1]=433.20.
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[F:17][C:18]([C:24]([F:48])([F:47])[C:25]([F:46])([F:45])[C:26]([F:44])([F:43])[C:27]([F:42])([F:41])[C:28]([F:40])([F:39])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])(O)[C:19]([F:22])([F:21])[F:20].C1(C)C=CC=CC=1.S(=O)(=O)(O)O>C(#N)C.O>[C:1]([O:16][C:18]([F:17])([C:24]([F:47])([F:48])[C:25]([F:45])([F:46])[C:26]([F:43])([F:44])[C:27]([F:41])([F:42])[C:28]([F:39])([F:40])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:19]([F:22])([F:21])[F:20])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OC(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCCCCCCCCCCCCC(=O)OC(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 73.1 %

Procedure:
With 500 g of myristic acid were mixed 1,100 g of perfluorooctylethanol and 2,300 ml of toluene, and 20 g of concentrated sulfuric acid was slowly added with stirring. The resulting mixture was vigorously refluxed for about 2 hours and 30 minutes to carry out the reaction until water was removed azeotropically. After completion of the reaction, the reaction mixture was cooled and then treated with decoloring carbon. Acetonitrile was added with stirring and the resulting mixture was ice-cooled to 5° C. to 10° C., followed by crystallization for 1 hour. The crystals precipitated were subjected to washing filtration with acetonitrile and then dried to obtain 1,120 g (yield: 75%) of perfluorooctylethyl myristate.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5])[CH3:2].[C:12](#[N:15])[CH:13]=[CH2:14].CC[O-].[Na+]>>[C:12]([CH2:13][CH2:14][P:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[O:3][CH2:1][CH3:2])#[N:15]
Reactant: CCOP(O)c1ccccc1
Reactant: C=CC#N
Agent: CC[O-]
Agent: [Na+]
Product: CCOP(=O)(CCC#N)c1ccccc1
Reaction time: 1 h

Procedure:
To 42.45 g of phenylphosphonous acid-ethylester and 16.45 ml of acrylonitrile are added with stirring 5 ml of sodium ethylate (1 molar). The reaction is exothermic. After 1 hour stirring at 20° the mixture is fractionally distilled. There is obtained ethyl 2-cyanoethyl(phenyl)phosphinate as a colorless oil, b.p. 134-136°/7 Pa.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:14]([O-])=O)=[C:10]([CH:13]=2)[C:11]#[N:12])[CH:5]=[CH:4][N:3]=[CH:2]1.O.NN.C([OH:22])C>[Ni].CC(N(C)C)=O>[NH2:14][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:13][C:10]=1[C:11]([NH2:12])=[O:22]
Reactant: CCO
Reactant: N#Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CC(=O)N(C)C
Solvent: O
Product: NC(=O)c1cc(-n2ccnc2)ccc1N
Temperature: 40 °C

Procedure:
A mixture of 5-(1-imidazolyl)-2-nitrobenzonitrile (2.14 g), hydrazine hydrate (2 ml), ethanol (25 ml) and DMA (10 ml) was stirred and heated to 40° C. Raney nickel (0.6 g) was added in portions whilst maintaining the temperature at 40-50° C. The mixture was stirred at 40-50° C. for 2 hours. The Raney nickel was filtered off, the mixture was evaporated and the residue was triturated with ethyl acetate (10 ml) to give 2-amino-5-(1-imidazolyl)benzamide (2.03 g); NMR Spectrum: (CD3SOCD3) 6.70 (s, 2H), 6.79 (d, 1H), 7.03 (s, 1H), 7.2 (s, 1H), 7.37 (s, 1H), 7.55 (s, 1H), 7.71 (d, 1H), 7.73 (s, 1H), 8.02 (s, 1H);
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([C:15]2[CH:16]=[N:17][N:18](COCC[Si](C)(C)C)[CH:19]=2)[CH3:14])=[O:11])[N:5]=[CH:4][C:3]=1[NH:28][C@@H:29]1[CH2:34][C@@H:33]2[CH2:35][C@@H:31]([C:32]2([CH3:37])[CH3:36])[C@H:30]1[CH3:38].Cl.O1CCOCC1>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([C:15]2[CH:19]=[N:18][NH:17][CH:16]=2)[CH3:14])=[O:11])[N:5]=[CH:4][C:3]=1[NH:28][C@@H:29]1[CH2:34][C@@H:33]2[CH2:35][C@@H:31]([C:32]2([CH3:36])[CH3:37])[C@H:30]1[CH3:38]
Reactant: CC(NC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O)c1cnn(COCC[Si](C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(NC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O)c1cn[nH]c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 12 %

Procedure:
2-(5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)-N-[1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethyl]acetamide (56.2 mg, 0.10 mmol) was mixed with 4 M hydrogen chloride/1,4-dioxane (2 mL) and stirred at 100° C. for 5 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/MeOH=20/1) to give the desired product (5.2 mg, 12% yield).
Reaction SMILES: [NH2-].[Li+].Br[C:4]1[C:5]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[N:8][CH:9]=1.[Li]CCCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C.Cl.C(OC(=O)C)(C)C.[OH-].[Na+]>C1COCC1.CCCCCC.CC(O)C.O>[C:11]([NH:10][C:7]1[N:8]=[CH:9][C:4]([B:27]([OH:28])[OH:26])=[C:5]([C:14]([F:17])([F:16])[F:15])[CH:6]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(=O)Nc1cc(C(F)(F)F)c(B(O)O)cn1
Temperature: 2 °C
Reaction time: 1.5 h
Yield: 116 %

Procedure:
To a suspension of Lithium amide (5.6 g, 233.2 mmol) in 140 ml THF was added at room temperature 2-propanol (1.3 g, 21.2 mmol). The reaction mixture was cooled to IT=2° C. A solution of B2 (60.0 g, 212 mmol) in 280 ml THF was added while keeping the temperature at IT 2° C. The reaction mixture was stirred at IT=2° C. for 90 min. THF (240 ml) was added and solvent (˜380 ml) was removed by distillation. THF (360 ml) was added and solvent (˜380 ml) was removed by distillation. THF (200 ml) was added and the reaction mixture was cooled to IT=−85° C. A solution (76 ml, 190 mmol) nBuLi, 2.5 M in hexane was added at −85° C. followed by addition of a solution of triisopropylborate (31.9 g, 170 mmol) in THF (17 ml). A solution (17.3 ml, 43.3 mmol) n BuLi, 2.5 M in hexane was added at −85° C. followed by addition of a solution of triisopropylborate (23.9 g, 127 mmol) in THF (13 ml). The reaction mixture was allowed to warm to RT and was stirred over night at RT. Water (15.3 g) and HCl in 2-propanol, 5-6 M (36.7 g) was added at RT. Isopropylacetate (480 ml) was added and solvent was removed by distillation until a volume of ˜360 ml was obtained. Isopropylacetate (480 ml) was added and solvent was removed by distillation until a volume of ˜360 ml was obtained. Isopropylacetate (480 ml) was added and the mixture was cooled to IT=0° C. Water (480 g) was added and by addition of 1N NaOH the pH was adjusted at IT=0° C. to pH 11. The precipitate was removed by filtration. The aquoeus layer was separated at IT=0° C. Water was added and the aquoeus layer was separated at IT=0° C. The combined aquoues layers were cooled to IT=0° C. and the pH was adjusted by addition of 1 N HCl to pH 3. The precipitate was collected and the dried at 30° C./40-45 mbar until constant weight was obtained. 48.9 g (93%) 6-acetamido-4-(trifluoromethyl)pyridin-3-ylboronic acid B3 were obtained.
Reaction SMILES: [OH:1][CH:2]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1)=[O:6].[N:18]1([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[OH:1][CH:2]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:21]2[CH2:22][CH2:23][N:18]([C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])[CH2:19][CH2:20]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: CC(C)(C)C(O)CNC(=O)c1ccc(Cl)nn1
Product: CC(C)(C)C(O)CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a brown solid (75% yield). m.p. 236-240° C. 1H NMR (300 MHZ, CDCl3) δ 7.90, 7.83-7.79, 7.75-7.73, 7.69-7.65, 7.54-7.52, 7.30, 4.29, 3.91-3.73, 3.43-3.32, 3.20-3.11, 2.81, 2.77, 0.95. MS (ES+) m/z 480 (M+1).