Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:15])=[CH:4][C:5]2[C:6](=[CH:8][N:9]([CH2:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.Cl[CH2:17]C(=O)C.C(=O)([O-])[O-].[K+].[K+].[Br:27][C:28]1[N:33]=[C:32]2[CH:34]=[N:35][NH:36][C:31]2=[CH:30][C:29]=1[Br:37].[NH2:38][C:39]1[C:40]([CH3:47])=[N:41][C:42]([Br:46])=[C:43]([Br:45])[CH:44]=1.NC1C(C)=NC=C(Br)C=1.BrN1C(=O)CCC1=O>C(#N)C.C1(C)C=CC=CC=1>[NH2:7][C:6]([CH3:17])([CH2:5][N:35]1[CH:34]=[C:32]2[N:33]=[C:28]([Br:27])[C:29]([Br:37])=[CH:30][C:31]2=[N:36]1)[C:8]#[N:9].[Br:1][C:2]1[C:3]([Br:15])=[CH:4][C:5]2[C:6](=[CH:8][N:9]([CH2:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.[Br:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][NH:10][C:5]2=[CH:4][C:3]=1[Br:15].[NH2:38][C:39]1[C:40]([CH3:47])=[N:41][C:42]([Br:46])=[C:43]([Br:45])[CH:44]=1
Reactant: CC(=O)CCl
Agent: Brc1cc2[nH]ncc2nc1Br
Agent: CC(=O)Cn1cc2nc(Br)c(Br)cc2n1
Agent: Cc1nc(Br)c(Br)cc1N
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(N)(C#N)Cn1cc2nc(Br)c(Br)cc2n1
Yield: 86 %

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5,6-dibromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (60 mg), the title compound was isolated as a white solid (51 mg, 56%). MS (ES): M/Z [M+H]=546. 1H NMR: (400 MHz, DMSO-d6): 1.68 (s, 3H), 5.15 (d, J=13.6 Hz, 1H), 5.16 (d, J=13.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H), 8.74 (s, 1H), 8.78 (s, 1H) and 8.96 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F). 2-Amino-3-(5,6-dibromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (260 mg, 86%; MS (ES): M/Z [M+H]=360) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(5,6-dibromo-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (280 mg). 1-(5,6-Dibromo-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (300 mg) was prepared using a procedure similar to that described in Example 182 part g using chloroacetone and potassium carbonate except starting from 5,6-dibromo-1H-pyrazolo[4,3-b]pyridine (1.18 g). 5,6-Dibromo-1H-pyrazolo[4,3-b]pyridine (1.18 g, 75%) was prepared using a procedure similar to that described in Example 182 part f except starting from 3-amino-5,6-dibromo-2-methylpyridine (1.5 g) and using toluene instead of chloroform. 3-Amino-5,6-dibromo-2-methylpyridine (2.53 g, 89%) was prepared by bromination of 3-amino-5-bromo-2-methylpyridine (2 g, described in Example 182) with N-bromosuccinimide (2.1 g) in acetonitrile (80 mL) at 50° C.
Reaction SMILES: [N:1]([C@H:4]([C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1)[C@@H:5]([NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[CH3:6])=[N+]=[N-]>C1COCC1.O=[Pt]=O>[F:37][C:36]([F:38])([F:39])[C:34]1[CH:35]=[C:30]([C@@H:4]([NH2:1])[C@@H:5]([NH:7][CH2:8][C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=2[O:28][CH3:29])[CH3:6])[CH:31]=[C:32]([C:40]([F:41])([F:43])[F:42])[CH:33]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1R,2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)bi phenyl-2-yl]methyl}propan-2-amine (17.8 mg, 0.0288 mmol) in THF (3 mL) was added PtO2 (12 mg, 0.053 mmol). The reaction was placed under hydrogen balloon atmosphere and stirred at room temperature for 3 h. The catalyst was removed by filtration and the filtrate was concentrated. The residue was put through a short plug of silica gel with 0-10% MeOH/CH2Cl2 to give (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine. LCMS=619.2 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2].[F:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.CO>C(Cl)Cl.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:1]([C:3]1[C:4]([C:29]2[CH:30]=[CH:31][C:32]([O:35][C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)=[CH:33][CH:34]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1NC(=O)OCc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: N#Cc1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of benzyl 2-(3-cyano-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate (370 mg, 0.8 mmol) in 20 mL of DCM was added 4-fluorophenylboronic acid (167 mg, 1.2 mmol), TEA (162 mg, 1.6 mmol) and Cu(OAc)2 (216 mg, 1.2 mmol). After stirring at RT for 16 hr, 100 mL of DCM, 10 mL of CH3OH and 100 mL of brine were added to the mixture. Organic layers were separated from aqueous layers, washed with brine (100 mL×2), dried over Na2SO4 and purified by chromatography column on silica gel eluting with DCM/CH3OH to afford 334 mg (75%) of benzyl 2-(3-cyano-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.76-7.74 (m, 3H), 7.45-7.10 (m, 12H), 7.02 (d, J=8.4 Hz, 2H), 6.59 (d, J=8.0 Hz, 1H), 5.85-5.80 (m, 1H), 5.17 (s, 2H), 3.25-3.18 (m, 1H), 2.97-2.87 (m, 1H), 2.36-2.24 (m, 1H), 2.08-2.00 (m, 1H).
Reaction SMILES: ClC1N=CN=C([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)C=1.O[CH2:28][CH2:29][NH:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1C1(C2CCNCC2)CCN(C([O-])=O)CC1)=[O:32].C(N=C=NC(C)C)(C)C>O1CCOCC1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:36]3[CH:37]=[CH:38][C:33]([C:31]4[O:32][CH2:28][CH2:29][N:30]=4)=[CH:34][CH:35]=3)[CH2:9][CH2:10]2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Reactant: O=C(NCCO)c1ccccc1C1(C2CCNCC2)CCN(C(=O)[O-])CC1
Agent: [Cu+2]
Agent: CC(C)N=C=NC(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(C4=NCCO4)cc3)CC2)CC1

Procedure:
A solution of tert-butyl 1′-(4-{([(2-hydroxyethyl)amino]carbonyl}phenyl)-4,4′-bipiperidine-1-carboxylate (234 mg; 0.542 mmol) in dioxane (5 mL) was treated with N,N′-diisopropylcarbodiimide (68 mg; 0.084 mmol) and Cu(OTf)2 (10 mg; 0.027 mmol). The mixture was refluxed for 5 hr. The reaction was evaporated and chromatographed (PTLC; 40:1 CH2Cl2/MeOH), giving the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][CH:23]=[C:22](I)[C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1[CH:32]=[C:31]2[CH:33]=[CH:34][CH:35]=[C:36]([SH:37])[C:30]2=[CH:29][CH:28]=1.C(O)CO.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.CO.C(Cl)Cl.[Cu]I>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][CH:23]=[C:22]([S:37][C:36]4[C:30]5[C:31](=[CH:32][CH:27]=[CH:28][CH:29]=5)[CH:33]=[CH:34][CH:35]=4)[C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc3c(I)cccc3o2)CC1
Reactant: Sc1cccc2ccccc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CCN(c2nc3c(Sc4cccc5ccccc45)cccc3o2)CC1
Temperature: 90 °C
Yield: 99.8 %

Procedure:
A mixture of 4-(4-iodobenzoxazol-2-yl)piperazine-1-carboxylic acid benzyl ester (0.80 g, 1.73 mmol), 1-naphthylthiol (0.276 g, 1.73 mmol), CuI (0.066 g, 0.35 mmol), ethylene glycol (0.214 g, 3.45 mmol), and K2CO3(0.477 g, 3.45 mmol) in isopropanol was heated at 90° C. overnight, cooled, diluted with 20% MeOH in CH2Cl2 and filtered through a pad of silica gel. The filtrated was concentrated and purified by chromatography with 1-3% MeOH in CH2Cl2 to provide the title compound (0.856 g, 93%), characterized by NMR and mass spectral analyses.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].C(=O)C1C=CC=CC=1>C1COCC1>[CH2:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH:10]=[CH2:11]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1
Product: C=CCc1ccc(C#N)cc1
Yield: 81 %

Procedure:
Highly substituted chloro and methoxy aryl bromides can readily be converted into the desired Grignard reagents 3i, j. After the reaction with ClPPh2 and oxidative work-up, the phosphine oxides 2ia, ja are obtained in good yields (entry 15, 16). This type of compound is of interest in relation with P-ligands for asymmetric catalysis.[5] Also functions like a cyano group are tolerated. Thus, the reaction of 4-bromobenzonitrile in THF at −7° C. leads to the desired arylmagnesium reagent (3d) in only 50% conversion using i-PrMgCl whereas over 90% is observed with i-PrMgCl•LiCl (Scheme 3). The addition of benzaldehyde provides the alcohol 2da in 81% yield whereas allylation of arylmagnesium reagent (3d) with allyl bromide leads to the corresponding 4-allylbenzonitrile in 92% yield (entry 5,6 of Table 1). See FIG. 3 for additional information.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[C:24]([CH:25]=4)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(=[O:28])C>O>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:17]1[C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: Fc1cc(-c2ccc3c(-c4cc5ccccc5[nH]4)n[nH]c3c2)ccn1
Reactant: CC(=O)O
Solvent: O
Product: O=c1cc(-c2ccc3c(-c4cc5ccccc5[nH]4)n[nH]c3c2)cc[nH]1

Procedure:
A solution of the fluoropyridine (3-3, 38 mg, 0.116 mmol) in 80% acetic acid in water (13 mL) was heated at 110° C. for 10 h. The reaction mixture was concentrated in vacuo, partitioned between ethyl acetate and 0.5N-NaOH. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Trituation of the crude solid with ethyl acetate afforded the desired intermediate (3-4); 1H NMR (500 MHz, DMSO-d6) δ 13.5 (s, 1H), 11.7 (bs, 1H), 11.6 (s, 1H), 8.28 (d, 1H, J=8.6 Hz), 7.85 (s, 1H), 7.60 (d, 1H, J=7.8 Hz), 7.55 (dd, 1H, J=8.5, 1.5 Hz), 7.50 (d, 1H, J=6.8 Hz), 7.45 (d, 1H, J=8.1 Hz), 7.16 (d, 1H, J=1.9 Hz), 7.12 (dt, 1H, J=8.1, 0.98 Hz), 7.02 (t, 1H, J=1.9 Hz), 6.69 (d, 1H, J=1.9 Hz), 6.62 (dd, 1H, J=6.8, 1.7 Hz).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]2([C:23]([O:25]C(C)(C)C)=[O:24])[CH2:22][CH2:21]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C>C(O)=O>[C:23]([C:20]1([CH2:19][CH2:18][CH2:17][CH2:16][C:15](=[O:30])[CH2:14][CH2:13][CH2:12][CH2:11][C:8]2([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]2)[CH2:22][CH2:21]1)([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)C1(CCCCC(=O)CCCCC2(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=CO
Product: O=C(CCCCC1(C(=O)O)CC1)CCCCC1(C(=O)O)CC1
Yield: 99.5 %

Procedure:
A solution of tert-butyl 1-[9-[1-(tert-butoxycarbonyl)cyclopropyl]-5-oxononyl]-1-cyclopropanecarboxylate (5.31 g, 12.6 mmol) in HCO2H (50 mL) was stirred for 3 h, evaporated in vacuo and coevaporated from toluene (3×25 mL) to give 1-[9-(1-carboxycyclopropyl)-5-oxononyl]-1-cyclopropanecarboxylic acid (3.89 g, 99%) as a white solid. An analytical sample was obtained after recrystallization from iPr2O/heptane. mp: 132-134° C. 1H NMR (CD3OD): δ=2.45 (t, J=6.9 Hz, 4H), 1.58-1.39 (m, 12H), 1.14 (dd, J=6.6, 3.7 Hz, 4H), 0.70 (dd, J=6.8, 3.9 Hz, 4H). 13C NMR (CD3OD): δ=214.4, 179.4 (2×), 43.5 (2×), 34.9 (2×), 28.5 (2×), 25.1 (2×), 24.2 (2×), 16.2 (4×). Anal. calcd for C17H26O5: C, 65.78; H, 8.44. found: C, 65.40; H, 8.37.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:18])[C:9]=1[O:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1)[CH:5]=O.[NH2:19][C:20]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:21]=1[C:22]([NH2:24])=[O:23].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:24][C:22](=[O:23])[C:21]3[C:20](=[CH:28][C:27]([O:29][CH3:30])=[CH:26][C:25]=3[O:31][CH3:32])[N:19]=2)[CH:7]=[C:8]([CH3:18])[C:9]=1[O:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)c1OC[C@@H]1CCC(=O)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OC[C@@H]4CCC(=O)N4)c(C)c3)nc2c1
Temperature: 150 °C
Yield: 31.5 %

Procedure:
A mixture of (S)-3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)benzaldehyde (0.200 g, 0.81 mmol), 2-amino-4,6-dimethoxybenzamide (0.159 g, 0.81 mmol), NaHSO3 (0.093 g, 0.89 mmol), and p-TsOH (0.015 g, 0.08 mmol) in DMA (10 mL) was heated at 150° C. for 48 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with water (2×200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH to 6:3:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound as an off-white solid (0.108 g, 31%). 1H NMR (300 MHz, DMSO-d6): δ 11.85 (s, 1H), 7.79-7.91 (m, 3H), 6.74 (d, J=2.2 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 3.88-3.94 (m, 4H), 3.84 (s, 3H), 3.63-3.75 (m, 2H), 2.30 (s, 6H), 2.09-2.27 (m, 3H), 1.91-2.00 (m, 1H). APCI MS m/z 424 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[CH2:7]2)([O-])=O.C(Cl)Cl>CO.[Pd]>[N:13]1([CH:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=3)[CH2:9]2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(N1CCOCC1)C2
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc2c(c1)CC(N1CCOCC1)C2
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 4-(5-nitro-indan-2-yl)-morpholine (210 mg, 0.85 mmol) in 20 mL of methanol was added Pd/C 10% (20 mg). The mixture was placed under a H2 atmosphere with stirring for 2 h. TLC showed 2 spots. CH2Cl2 was added to dissolve the ppt. that had formed and the hydrogenation continued further 2 h. The catalyst was removed by filtering, and the filtrate evaporated to give 188 mg of 2-morpholin-4-yl-indan-5-ylamine. The crude amine was used in the next step without purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH2:36][CH:37]([Cl:39])[Cl:38])[CH:31]([NH:40][C:41](=[O:71])[C:42](=[N:68][O:69][CH3:70])[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[S:46][CH:47]=1)[C:30]2=[O:72])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)(=O)C>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[CH2:36][CH:37]([Cl:39])[Cl:38])[CH:31]([NH:40][C:41](=[O:71])[C:42](=[N:68][O:69][CH3:70])[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[S:46][CH:47]=1)[C:30]2=[O:72])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(Cl)Cl)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(Cl)Cl)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A solution of 85% pure meta-chloroperbenzoic acid (0.05 g) in methylene chloride (1 cc) is added all at once to a solution, cooled to -10° C., of product (13d) (0.2 g) in methylene chloride (5 cc). After 30 minutes at -10° C., the reaction mixture is diluted with ethyl acetate (20 cc) and washed with a saturated solution of sodium bicarbonate (2×10 cc) and a saturated solution of sodium chloride (2×10 cc). After the organic phase has been dried over sodium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C., a crude product (13a) (0.15 g) is obtained in the form of a hard orange foam.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([OH:20])([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:16]([F:19])([F:18])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:12]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: Cc1ccccc1C(=O)O
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.C(ON=O)CC(C)C.[I:28]CI>>[I:28][C:2]1[N:3]=[CH:4][C:5]([CH3:19])=[C:6]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:7]=1
Reactant: ICI
Reactant: Cc1cnc(N)nc1Oc1cc(C(F)(F)F)nn1C
Agent: CC(C)CCON=O
Product: Cc1cnc(I)nc1Oc1cc(C(F)(F)F)nn1C
Temperature: 90 °C

Procedure:
To a suspension of 2-amino-4-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-5-methylpyrimidine (5 g) in diiodomethane (25 ml) is added isopentylnitrite (48 ml) and the mixture is heated to 90° C. for 30 min. After cooling, the brownish reaction mixture is evaporated in vacuo and the residue is purified by silica-gel flash chromatography. One obtains the title compound as crystals of mp. 94° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:15]=[C:16]([F:18])[CH:17]=2)[O:9][N:8]=1
Reactant: Fc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: c1cncc(B2OCCCO2)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: ClC(Cl)Cl
Solvent: COCCOC
Product: Fc1cc(-c2cccnc2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 19.1 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (100 mg, 0.312 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (102 mg, 0.624 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 35.8 mg, 0.031 mmol), in a solution of ethylene glycol dimethyl ether (3 mL) and 2M sodium carbonate (3 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with chloroform, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate afforded 19 mg (19%) 3-(2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): 8.92 (s, 1H), 8.84 (d, 1H), 8.70 (d, 1H), 8.39 (s, 1H), 8.25 (d, 1H), 8.00 (m, 2H), 7.90 (td, 1H), 7.65 (m, 1H), 7.55 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1.[OH-].[NH4+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)C.CCOCC>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH3:26][C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[N:9]2)=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(C(=O)n2nc(C3CCN(C)CC3)c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of 4-toluoyl chloride was heated at 100° C. on a steam bath for 4 hrs. Ether was added to the cooled mixture and the salt was coolected. The salt was converted to its free base by means of ammonium hydroxide solution. The base was dissolved in ethanol (90 ml)-ether (175 ml) and 1.5 g of fumaric acid was added. The mixture was stirred at ambient temperature for 16 hrs, and the resultant fumarate salt was collected. Recrystallization twice from methanol-ether yielded 3.8 g (60%) of product, mp 205°-207° C.