Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[O:26][N:25]=[C:24]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][CH:37]3[C:49]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:43]4[C:38]3=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:34])[CH2:29][CH2:28]2)[N:23]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[OH:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[O:26][N:25]=[C:24]([CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][CH2:36][CH:37]3[C:49]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:43]4[C:38]3=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:34])[CH2:31][CH2:32]2)[N:23]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2noc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)n2)CC1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2noc([C@@H]3CC[C@@H]4CN3C(=O)N4O)n2)CC1
Temperature: -78 °C
Reaction time: 6 h
Yield: 110.7 %

Procedure:
BCl3 (8.5 ml, 8.5 mmol; 1 M in CH2Cl2) was added dropwise to a solution of (9H-fluoren-9-yl)methyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (1.0 g, 1.7 mmol, 1.0 eq.) in dried CH2Cl2 (20 mL) at −78° C. The mixture was stiffed under N2 atmosphere at 0° C. for 6 hrs. Then, the reaction mixture was cooled to −78° C. and MeOH (2 mL) was added dropwise. The solvents were evaporated under vacuum at 0° C. to give ((9H-fluoren-9-yl)methyl 4-(5-((2S,5R)-6-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (970 mg) as a yellow solid, which was used directly in the next step. ESI-MS (EI−, m/z): 516.3 [M+H]−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc(OCCN2CCCCC2)c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.42 g, 44.38 mmol), K2CO3 (13.5 g) and acetonitrile was added N-(2-chloroethyl)piperidine hydrochloride (9.8 g). The reaction mixture was refluxed overnight, cooled to room temperature and filtered. The filtrate was stripped to give an oil which was partitioned between CHCl3 (350 ml) and 1M NaOH (200 ml). The organic layer was separated, washed with 1M NaOH (2×200 ml), treated with DARCO®, then MgSO4, filtered, and stripped to afford, as a dark oily liquid, 6.28 g of 3-[2-(1-piperdinyl)ethoxy]benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[I:23]I>C1COCC1>[I:23][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][C:5]=1[CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9]
Reactant: II
Reactant: Cc1ccc(C(C)NC(=O)OC(C)(C)C)cn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(I)c(C(C)NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
Add a solution of tert-butyl 1-(6-methylpyridin-3-yl)ethylcarbamate (6.85 g, 29 mmol) to a solution of tert-butyllithium (51.1 mL, 87 mmol) in THF (70 mL) at −78° C. in THF (20 mL) under N2 using a double-tipped needle. After 30 min, add iodine (11.0 g, 43.5 mmol) in THF (25 mL) over 30 min at −78° C. Stir for 1 h and then warm up to RT. Quench with water, extract in ethyl acetate, wash with saturated aqueous sodium chloride, and dry over Na2SO4. Purify on column chromatography 5% to 50% ethyl acetate in hexanes to obtain the title compound (620 mg). MS (ES) m/z 363 [M+1]+.
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[NH2:12].[N:24]([Si](C)(C)C)=[N+:25]=[N-]>CCOC(C)=O>[N:12]([C:11]1[CH:13]=[CH:14][C:15]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[C:9]([F:8])[CH:10]=1)=[N+:24]=[N-:25]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Nc1ccc(C(=O)N2CCOCC2)c(F)c1
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1ccc(C(=O)N2CCOCC2)c(F)c1
Temperature: -10 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Tert-butyl nitrite (0.16 mL; 1.34 mmol; 1.5 eq.) was added to a solution of 3-fluoro-4-(morpholin-4-ylcarbonyl)aniline (200 mg; 0.89 mmol; 1.0 eq.) in AcOEt (6 mL) maintained at −10° C. The reaction mixture was stirred at −10° C. for 10 minutes before the addition of azidotrimethylsilane (0.14 mL; 1.07 mmol; 1.2 eq.). Reaction mixture was stirred at RT for 2 hours and concentrated under reduced pressure to give the title compound as a pale orange oil (220 mg, 99%). 1H NMR (300 MHz, DMSO-d6): δ: 7.45 (t, J=8.0 Hz, 1H), 7.15 (dd, J=11.0 Hz, 2.1 Hz, 1H), 7.06 (dd, J=8.0 Hz, 2.1 Hz, 1H), 3.64-3.63 (m, 4H), 3.52 (t, J=4.6 Hz, 2H), 3.23 (t, J=4.6 Hz, 2H). MS (ES+): 2521.1; Rt 1.02 min (purity=92%).
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:30]1([CH:35]([CH3:39])[C:36]([OH:38])=O)[CH2:34][CH2:33][CH2:32][CH2:31]1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:48]=[CH:49][C:50]([C:53]#[C:54][C:55]3[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=3)=[N:51][CH:52]=2)=[CH:43][CH:42]=1>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:48]=[CH:49][C:50]([C:53]#[C:54][C:55]3[CH:56]=[CH:57][C:58]([NH:61][C:36](=[O:38])[CH:35]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)[CH3:39])=[CH:59][CH:60]=3)=[N:51][CH:52]=2)=[CH:43][CH:42]=1
Reactant: Nc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Reactant: CC(C(=O)O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C(=O)Nc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.18 mL (1.31 mmol) triethylamine and 269 mg (0.84 mmol) TBTU are added successively to a solution of 100 mg (0.70 mmol) 2-pyrrolidin-1-yl-propionic acid in 10 mL THF. The solution is stirred for 1 h at RT and then 200 mg (0.66 mmol) 4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenylamine are added. The reaction solution is stirred overnight at RT. The reaction is incomplete. Therefore 100 mg (0.70 mmol) 2-pyrrolidin-1-yl-propionic acid in 10 mL THF is added to the reaction mixture (activated for 1 h by stirring with 0.18 mL (1.31 mmol) triethylamine and 269 mg (0.84 mmol) TBTU). The reaction solution is stirred for a further 16 h and diluted with NaHCO3 solution. The aqueous phase is extracted with EtOAc and the organic phase is dried over MgSO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][CH:15]=2)=[N:6]1.[CH3:26][CH:27]([CH3:35])[C:28](=O)[C:29](OCC)=[O:30].S(=O)(=O)(O)O>C(O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[CH:15]=[CH:16][C:17]3[N:21]=[C:28]([CH:27]([CH3:35])[CH3:26])[C:29](=[O:30])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: Nc1ccc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: CCOC(=O)C(=O)C(C)C
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC(C)c1nc2ccc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2[nH]c1=O
Temperature: 25 °C

Procedure:
146 mg (0.435 mmol) of the compound from example 43A were initially charged in ethanol (8 ml), then 69 mg (0.48 mmol) of ethyl 3-methyl-2-oxobutanoate were added and the reaction mixture was heated to reflux overnight. Thereafter, a catalytic amount of conc. sulfuric acid was added and the mixture was again heated to reflux overnight. Subsequently, the mixture was cooled to RT, and the solid formed was filtered off, washed with methanol and dried under high vacuum. This gave 26 mg (14% of theory) of the title compound in solid form.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[C:9]=1[NH:16]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[C:9]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nccc(Cc2ccccc2)c1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: COc1nccc(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To a solution of tert-butyl (4-benzyl-2-methoxypyridin-3-yl)carbamate (25.4 g) in ethyl acetate (202 mL) was added 4N hydrogen chloride/ethyl acetate solution (202 mL) at room temperature, and the mixture was stirred overnight at room temperature, and then at 50° C. for 1 hr. To the reaction mixture was added diisopropyl ether at room temperature, and the obtained precipitate was collected by filtration, and washed with diisopropyl ether. Saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane) to give the title compound (8.8 g).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH3:13][CH:14]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][C:16](OC(CC)C)=[O:17].C(O)(=O)C>CCCCCC.O1CCCC1>[O:17]=[C:16]([CH2:15][CH:14]([CH3:13])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)CC(=O)OC(C)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCCCC(C)CC(=O)CP(=O)(OC)OC
Temperature: -70 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Under an atmosphere of nitrogen, 375 ml of a 1.33 M solution of n-butyllithium in n-hexane were added dropwise to a solution of 61.9 g of dimethyl methylphosphonate in 587 ml of tetrahydrofuran at -70° C. After stirring the mixture for one hour at -70° C., a solution of 40 g of sec-butyl 3-methylheptanoate (prepared as described in Reference Example 1) in 70 ml of tetrahydrofuran was added dropwise at -70° C., and the mixture was stirred at the same temperature for 4 hours and then stirred overnight at room temperature. The reaction mixture was then acidified with acetic acid and filtered to remove the precipitated solid, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to give 42 g of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:15]=2[C:16]#[N:17])[CH2:7]1)=[O:5]>C(O)(=O)C.[Fe]>[NH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH2:12][C@H:8]2[CH2:9][CH2:10][CH2:11][N:6]([C:4](=[O:5])[CH2:3][CH:2]([CH3:1])[CH3:25])[CH2:7]2)[C:15]=1[C:16]#[N:17]
Reactant: CC(C)CC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)-6-nitrobenzonitrile (Example 5c, 43.26 g, ˜18.0 mmol) in glacial acetic acid (35 mL) cooled to 0° C. in an ice bath was added iron powder (2.02 g, 36.1 mmol). The solution was stirred under a N2 balloon at 0° C. for 10 minutes then at room temperature overnight and filtered through a bed of Celite, rinsing well with EtOAc. The EtOAc solution was then washed successively with 2N Na2CO3, water, and brine, dried over Na2SO4, filtered and concentrated to give the crude product as an orange oil. The residue was purified by silica gel chromatography using a 0-60% EtOAc/Hexanes gradient followed by crystalization from EOAc/Hexane to afford the title compound a pale yellow solid (27.01 g, 85.63 mmol, 71% over two steps). 1H NMR (400 MHz, DMSO-d6) 20° C.) δ 0.79-0.92 (3×d, J=6.4 Hz, 6H), 1.19-1.46 (m, 2H), 1.51-2.01 (m, 4H), 2.03-2.25 (m, 2H), 2.57 (dd, J=10.4, 12.8 Hz, 0.3H), 2.75-2.88 (m, 0.6H), 2.92-3.10 (m, 1H), 3.65-4.08 (m, 3.6H), 4.27-4.40 (dm, 0.3H), 5.98 & 6.00 (s & s, 2H), 6.18 (pseudo t, J=8.4 & 9.2 Hz, 1H), 6.32 (pseudo d, J=8.4 Hz, 1H), 7.11-7.21 (m, 1H). MS 316 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].C([Li])(CC)C.[CH2:24]([CH:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[CH2:25][CH3:26].Cl>C1COCC1.CCCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:30]3([OH:33])[CH2:31][CH2:32][CH:27]([CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29]3)=[C:14]([F:18])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCC1CCC(=O)CC1
Reactant: CCCOc1ccc(-c2cccc(F)c2)cc1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2ccc(C3(O)CCC(CCC)CC3)c(F)c2)cc1F
Temperature: -60 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 15.0 g (60.4 mmol) of the 3,3′-difluoro-4-propoxybiphenyl obtained in the first step of Example 1 in 85 ml of THF was added by drops 70 ml (1.04M, cyclohexane solution, corresponding to 72.5 mmol) of sec-butyllithium while being maintained at a temperature lower than −60° C. After finishing of the dropping, it was stirred at the same temperature for 1 hour. Subsequently, a solution of 11.0 g (78.5 mmol) of 4-propylcyclohexanone in 55 ml of THF was added by drops thereto while being maintained at a temperature of −60° C., stirred at the same temperature for 3 hours, and then further stirred at room temperature for 2 hours. After 200 ml of a diluted hydrochloric acid was added by drops to the reaction liquid, it was extracted with 200 ml of toluene. The organic layer thus obtained was washed with a diluted aqueous sodium bicarbonate solution twice and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (eluent: heptane/ethyl acetate=8/2) to obtain 21.2 g of a crude 3,3′-difluoro-4′-(1-hydroxy-4-propylcyclohexyl)-4-propoxybiphenyl. (Yield: 90.6%)
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[N:5][C:6]([Cl:19])=[CH:7][CH:8]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[N:26]=[CH:27][N:28]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:6]1[N:5]=[C:4]2[CH:3]=[C:2]([C:25]3[N:26]=[CH:27][N:28]([C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:29]=3)[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]2=[CH:8][CH:7]=1
Reactant: Clc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1cccc(Cn2c(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc3nc(Cl)ccc32)c1
Temperature: 110 °C

Procedure:
A mixture of 2-bromo-5-chloro-1-(3-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine (0.59 g, 1.7 mmol, prepared as in Example 103, Step 2) and 4-(tributylstannyl)-1-trityl-1H-imidazole (1.0 g, 1.7 mmol, Synthonix) in toluene (32 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (0.19 g, 0.17 mmol, Strem) was added, and the mixture was heated at 110° C. for 17 hours. Solvent was removed in vacuo, and the product was purified by flash chromatography, eluting with a gradient from 0-35% EtOAc in hexanes. Yield: (0.61 g, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.CI.[C:14](=O)([O-])[O-].[Cs+].[Cs+].CCOCC>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:14])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1cccc(Br)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CI
Product: CC(=O)C(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-bromophenylacetone (4.7 g, 22 mmol) in acetonitrile (100 mL) was added methyl iodide (1.4 mL, 22 mmol) and cesium carbonate (14 g, 44 mmol). After stirring at room temperature for 17 h, the reaction mixture was poured into ether (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with ether. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (400 MHz, CD3OD): δ 7.45-7.40 (m, 2H), 7.3-7.2 (m, 2H), 3.87 (q, 1H), 2.06 (s, 3H), 1.34 (d, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2OC)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
1-isopropyl-4-(2-methoxy-4-nitrophenoxy)piperidine (167 mg, 0.57 mmol) was dissolved in 20 mL of methanol and placed under a nitrogen atmosphere. A catalytic amount of 20% palladium hydroxide on carbon was added and a hydrogen balloon was connected to the reaction flask. The flask was flushed five times with hydrogen and stirred at room temperature under hydrogen atmosphere for 16 hours. The reaction mixture was filtered and washed with methanol. The filtrate was evaporated under reduced pressure. Acetonitrile (10 mL) was added to the residue, swirled for 10 min, and decanted away from white film. The acetonitrile layer was evaporated under reduced pressure yielding 4-(1-isopropylpiperidin-4-yloxy)aniline as a brown oil (131 mg, 87%). LC/MS (m/z): 265.2 (MH+), Rt 0.33 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[C:23]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[C:29]3[S:30][C:26]([C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=3)[CH:8]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Reactant: CC(=O)c1ccc(B(O)O)s1
Product: COc1cc(-c2cc3nccc(-c4ccc(C(C)=O)s4)c3o2)cc(OC)c1OC

Procedure:
The title compound was prepared by procedure C using 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (45.00 mg; 0.14 mmol; 1.00 eq.) instead of 7-chloro-2-iodo-furo[3,2-b]pyridine, and 5-acetyl-2-thiopheneboronic acid (26.32 mg; 0.15 mmol; 1.10 eq.) instead of 4-fluorophenylboronic acid and was obtained as a yellow solid (15 mg, 26%). (HPLC (method F): 88%, RT: 3.84 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.56 (d, J=5.1, 1H), 8.22 (d, J=4.0, 1H), 8.12 (d, J=3.8, 1H), 7.79 (d, J=1.0, 1H), 7.78 (d, J=5.1, 1H), 7.40 (s, 2H), 3.94 (s, 6H), 3.76 (d, J=0.9, 3H), 2.63 (s, 3H); MS (m/z) 410 [M+H]+, RT: 2.5 min.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[O:16]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:29]2[CH2:30][CH2:31][N:26]([C:19]3[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])[CH2:27][CH2:28]2)=[O:13])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: Cc1cc(C)c(N2CCNCC2)c(C)c1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 23 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (253 mg) described in Preparation Example 16 and 1-(2,4,6-trimethylphenyl)piperazine (215 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (103 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[F:17])[CH2:4][CH:3]1[CH3:18]>[Pd].C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH:3]([CH3:18])[CH2:4]2)=[C:9]([F:17])[CH:10]=1
Reactant: CC1CN(c2ccc([N+](=O)[O-])cc2F)CCN1C
Agent: [Pd]
Solvent: CCO
Product: CC1CN(c2ccc(N)cc2F)CCN1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Absolute ethanol (2 mL) was added to a two-necked round-bottomed flask containing palladium on carbon (0.09 g, 0.42 mmol). The reaction vessel was evacuated and purged with nitrogen three times. 1,2-Dimethyl-4-(2-fluoro-4-nitrophenyl)piperazine (1.06 g, 4.2 mmol) in absolute ethanol (10 mL) was added and the vessel purged thrice more with nitrogen. After purging thrice with hydrogen, the reaction was left to stir under a hydrogen atmosphere at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite washing with additional ethanol. Excess ethanol was removed under reduced pressure to afford the title compound as an off-white oil. LC-MS (UV 215nm): 93%; m/z 224.35; 0.58 min.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:33])[C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:18][C:19]1[CH:20]=[C:21]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:22]=[C:23]([F:33])[C:24]=1[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OB(O)c1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1cc(-n2ncc3c(OCc4ccccc4)cccc32)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 4-[(phenylmethyl)oxy]-1H-indazole (D1) (280 mg, 1.25 mmol) in dichloromethane (20 mL) was added {3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid {DE patent application 4236105} (660 mg, 2.50 mmol), pyridine (0.202 mL, 2.50 mmol), copper acetate (340 mg, 1.88 mmol) and powdered 4A molecular sieves (500 mg). The reaction mixture was stirred at room temperature in the presence of air for 6 days. Celite was added to the mixture then the mixture was filtered through a pad of celite and then the filtrate was washed with water. After separation of the layers, the aqueous phase was re-extracted with dichloromethane. The combined organic layers were dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 5-100% ethyl acetate in hexane to yield the title compound (D35 (257 mg).