Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=1)[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[NH:26][CH:25]=[C:24]([C:27](O)=[O:28])[CH:23]=2)[CH:17]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:66]1[CH2:70][CH2:69][C@H:68]([OH:71])[CH2:67]1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[C:12]1[CH:32]=[CH:31][CH:30]=[C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[NH:26][CH:25]=[C:24]([C:27]([N:66]4[CH2:70][CH2:69][CH:68]([OH:71])[CH2:67]4)=[O:28])[CH:23]=3)[CH:17]=2)[CH:13]=1
Reactant: O[C@H]1CCNC1
Reactant: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc(-c4cc(C(=O)N5CCC(O)C5)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (50 mg, 0.12 mmol), HATU (55 mg, 0.14 mmol) and N,N-diisopropylethylamine (34 mg, 0.26 mmol) in anhydrous DMF (8 ml) was stirred at room temperature for 10 minutes, followed by addition of (S)-3-pyrrolidinol (16 mg, 0.18 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamide as white solid. Yield: 40 mg, 69%.
Reaction SMILES: C(Cl)Cl.ClC(Cl)(Cl)C(=N)O[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:18][C@@H:19]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH3:24])=[O:22].FC(F)(F)S(O)(=O)=O>C1CCCCC1>[CH2:8]([O:18][C@@H:19]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCCC[C@H](O)CC(=O)OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCCC[C@@H](CC(=O)OC)OCc1ccccc1
Temperature: 22.5 °C
Yield: 84.5 %

Procedure:
In a 2 flask were charged 275 ml of methylene chloride, 550 ml of cyclohexane, 140 g of benzyl trichloroacetoimidate, and 75 g of methyl (S)-3-hydroxyheptanoate (compound (37), R1 =ethyl), and 6 ml of trifluoromethanesulfonic acid was added thereto over 5 minutes while maintaining at 20 to 25° C., followed by allowing the mixture to react at 35 to 40° C. for 5 hours. The by-produced salt was removed by filtration, and the filtrate was washed with a sodium hydrogencarbonate aqueous solution. The solvent was removed by distillation under reduced pressure, and the residue was distilled under reduced pressure to obtain 99.0 g (78.7%) of the titled compound (b.p.: 105-108° C./0.1 mmHg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of ethyl 4-piperidinecarboxylate (14.71 g) and triethylamine (12.04 g) in chloroform (200 mL) was cooled to 0° C. and treated dropwise with benzyl chloroformate (17.91 g). The resulting mixture was stirred at 0° C. for 1 hour, then was warmed to room temperature and was stirred for 12 hours. The mixture was then washed (1N hydrochloric acid, brine), dried, filtered and evaporated to yield a pale yellow oil (26.4 g). The oil was purified by chromatography, with dichloromethane:methanol (95.5) as the eluent, to afford the urethane as a colorless syrup (22.15 g); NMR: 7.35 (m, 5), 5.07 (s, 2), 4.06 (q,2, J=7.0), 3.91 (broad d, 2, J=13.3), 2.95 (broad, 2), 2.53 (m, 1), 1.82 (broad d, 2, J=13.3), 1.41 (m, 2), 1.18 (t, 3, J=7.0).
Reaction SMILES: C[C:2]1[S:9][C:8]2[CH:7]=[CH:6][N:5]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[C:4]=2[C:3]=1[C:21](O)=[O:22].C[O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[Li+].[OH-]>CN(C=O)C.C1COCC1.O.CO>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[CH:6]=[CH:7][C:8]3[S:9][CH:2]=[C:3]([C:21]([NH:35][C@H:33]([C:30]4[CH:31]=[CH:32][C:27]([C:26]([OH:25])=[O:36])=[CH:28][CH:29]=4)[CH3:34])=[O:22])[C:4]2=3)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: Cc1sc2ccn(Cc3ccc(C(F)(F)F)cc3)c2c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)c1csc2ccn(Cc3ccc(C(F)(F)F)cc3)c12)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
A mixture of 0.107 g of 2-methyl-4-(4-trifluoromethyl-benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid, 0.150 g of (S)-4-(1-amino-ethyl)-benzoic acid methyl ester, 0.100 g of HOBT-hydrate, 0.133 g of ethyl-dimethylaminopropyl-carbodiimide hydrochloride (EDCI) and 0.150 ml of N-methylmorpholine in 4 ml of DMF was stirred at room temperature for 18 h. The reaction was then quenched with 2 ml of water and 5 ml of sat. NaHCO3 solution. The resulting mixture extracted with 20 ml of EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude methyl ester which was dissolved in 4 ml THF, 4 mL MeOH and 1 mL water and treated with 1 mL of 1N LiOH solution. After stirring for 24 h at room temperature, the reaction mixture was concentrated under reduced pressure to remove THF and MeOH. The residue was diluted with 4 mL of water and treated with 0.7 mL of AcOH with vigorous stirring. After stirring for 2 h, the solid was collected by filtration and air-dried to give 0.110 g of the title compound as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:21]=[C:14]3[CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[N:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:21]=[C:14]3[CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CCN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CCN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-bromo-3-(5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methylpyridin-2(1H)-one 208c (300 mg, 0.85 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (1.21 g, 3.16 mmol), PdCl2(dppf) (35 mg, 0.043 mmol), K3PO4 (361 mg, 1.70 mmol), sodium acetate (140 mg, 1.70 mmol), acetonitrile (10 mL), and water (0.5 mL). The system was evacuated and refilled with N2. The reaction mixture was stirred at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 177a (365 mg, 60%) as a brown oil. MS-ESI: [M+H]+ 611
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)[CH3:5].[OH-].[Na+].Cl>O1CCCC1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH:4]([CH3:5])[C:3]([OH:19])=[O:2])=[O:18])=[CH:9][CH:10]=1)([CH3:16])([CH3:15])[CH3:17]
Reactant: COC(=O)C(C)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(NC(=O)c1ccc(C(C)(C)C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-(4-tert-Butyl-benzoylamino)-propionic acid methyl ester (26.3 g, 95.6 mmol), 200 mL 1M sodium hydroxide, and 100 mL tetrahydrofuran is stirred at room temperature 20 hr. The resulting clear solution is cooled on an ice/water bath and the pH is adjusted to 2 with concentrated hydrochloric acid. The product is extracted with three 250 mL portions of ethyl acetate. The combined extracts are washed with 100 mL each of water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 2-(4-tert-Butyl-benzoylamino)-propionic acid as a white solid, 24.6 g, 95%. MS M++1 260.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.CS(C)=O.[C:26]([NH:33][CH2:34][CH2:35][NH2:36])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.O>[C:29]([O:28][C:26]([NH:33][CH2:34][CH2:35][NH:36][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ccc(C(=O)C(F)(F)F)c(NC(=O)OC(C)(C)C)n1

Procedure:
5 g (15.4 mmol) of tert-butyl [6-chloro-3-(trifluoroacetyl)pyridin-2-yl]carbamate (Example 113A) are introduced into 37.5 ml of DMSO, and 3.2 g (20 mmol) of N-Boc-ethylenediamine and 4 ml (23 mmol) of N,N-diisopropylethylamine are added. The reaction mixture is irradiated in a microwave reactor at 90° C. for 0.5 h. The reaction mixture is taken up in a mixture of ethyl acetate and water. The organic phase is washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated in a rotary evaporator. The reaction mixture is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 5:1→1:1). 2.5 g (34% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:12]2=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=[C:11]2[N:10]=1.ClC1N=C2N([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)C(=O)NC2=CC=1.C1C2CC(Br)C(C2)C1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:37]12[CH2:43][CH:40]([CH2:39][CH2:38]1)[CH2:41][CH:42]2[N:10]1[C:11]2[C:12](=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:9]1=[O:8].[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[C:12]2=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=[C:11]2[N:10]=1
Reactant: Cc1ccc(-n2c(=O)[nH]c3ccc(Cl)nc32)cc1
Agent: BrC1CC2CCC1C2
Agent: Cc1ccc(-n2c(OC3CC4CCC3C4)nc3ccc(Cl)nc32)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2c(=O)n(C3CC4CCC3C4)c3ccc(Cl)nc32)cc1
Temperature: 200 °C
Yield: 30 %

Procedure:
1-Bicyclo[2.2.1]hept-2-yl-5-chloro-3-p-tolyl-13-dihydro-imidazo[4,5-b]pyridine-2-one (38) and 2-(Bicyclo[2.2.1]hept-2-yloxy)-5-chloro-3-p-tolyl-3H-imidazo[4,5-b]pyridine (39). A mixture of 5-Chloro-3-p-tolyl-1,3-dihydro-imidazo[4,5-b]pyridine-2-one (52 mg, 0.2 mmol), exo-2-bromonorbornane (103 μL, 0.8 mmol) and Cs2CO3 (195 mg, 0.6 mmol) in 1.5 mL DMF was heated in microwave at 200° C. for 20 min. After filtration, the filtrate was diluted with EtOAc, washed with water. The organic phase was concentrated, the residue was dissolved in a minimum amount of DCM, and subjected to silica gel column purification to give 21.2 mg (yield: 30%) 1-Bicyclo[2.2.1]hept-2-yl-5-chloro-3-p-tolyl-1,3-dihydro-imidazo[4,5-b]pyridine-2-one (Rf=0.60 in DCM) and 6.2 mg (yield: 9%) 2-(Bicyclo[2.2.1]hept-2-yloxy)-5-chloro-3-p-tolyl-3H-imidazo[4,5-b]pyridine (Rf=0.49 in DCM). Calculated mass=353. Observed mass=354.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:9]([C:27]([O:29]C)=[O:28])=[C:8]1[CH3:31].[OH-].[K+]>O.CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:8]([CH3:31])=[C:9]([C:27]([OH:29])=[O:28])[CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:12]1[CH3:13]
Reactant: COCCOCN1C(C)=C(C(=O)OC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOCN1C(C)=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C

Procedure:
The N-protected diester is then mono-saponified, e.g., by heating with an alkali metal hydroxide or alkoxide (for example, NaOH, KOH, t-BuOK) or an alkali metal carbonate (for example K2CO3) in a water miscible solvent containing 10-45% water (preferably MeOH containing 15-40% water) at reflux temperature (or between 50° C. and reflux temperature for solvents other than MeOH) for 10 to 24 hours to yield an N-protected mono-ester. For example, 1-(2-methoxyethoxy)methyl-2,6-dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine in 20% H2O/MeOH is heated at reflux with aqueous KOH for 16 hours to yield racemic (RS)-1-(2-methoxyethoxy)methyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine ((RS)-18). (Scheme VI, Step 2)
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].I[C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40]>O1CCOCC1>[CH3:42][O:41][C:39](=[O:40])[C:38]1[CH:43]=[CH:44][CH:45]=[CH:46][C:37]=1[C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[CH:14]([N:13]1[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]1[CH2:1][CH3:2])[CH2:15][CH2:16]2
Reactant: COC(=O)c1ccccc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CCC2n1c(CC)nc2c(C)cc(C)nc21
Solvent: C1COCCO1
Product: CCc1nc2c(C)cc(C)nc2n1C1CCc2cc(-c3ccccc3C(=O)OC)ccc21
Temperature: 25 °C
Yield: 28.7 %

Procedure:
A mixture of 2-ethyl-5,7-dimethyl-3-(5-tributylstannyl-indan-1-yl)-3H-imidazol[4,5-b]pyridine (224 mg, 0.41 mmol), methyl 2-iodobenzoate (131 mg, 0.5 mmol) and PdCl2 (PPh3)2 (28 mg, 0.04 mmol) was heated in anhydrous 1,4-dioxane for 20 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and chromatographed on SiO2 -gel using a gradient of 30% EtOAc/hexanes to 50% EtOAc/hexanes to give 50 mg of a colorless oil. 1H NMR (250 MHz, CDCl3): d 7.80 (1 H, d), 7.55 (t, 1 H), 7.43 (t, 2 H), 7.30 (s, 1 H), 7.10 (d, 2 H), 6.90 (m, 2 H), 6.52 (m, 1H), 3.30 (m, 1 H), 3.15 (m, 1 H), 2.85 (q, 2 H), 2.65 (s, 3 H), 2.57 (s, 3 H), 0.90 (t, 3H.
Reaction SMILES: C([NH:4][C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]2[CH2:14][CH2:15][CH2:16][N:17]=[C:6]12)(=O)C>Cl.O>[NH2:4][C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]2[CH2:14][CH2:15][CH2:16][N:17]=[C:6]12
Reactant: CC(=O)NC1(c2cccc(Cl)c2)C2=NCCCN2c2ccccc21
Agent: Cl
Solvent: O
Product: NC1(c2cccc(Cl)c2)C2=NCCCN2c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A solution of the product of Example 1 (2.48 g) in hydrochloric acid 36% w/w (10 ml) was heated at 120° with stirring for 21/2 hours, cooled to room temperature, diluted with H2O (50 ml), washed with ethyl acetate (3×50 ml), basified with 33% aqueous ammonia and extracted with chloroform (3×100 ml). The extracts were washed with brine (100 ml), dried (MgSO4) and evaporated in vacuo. The oil was dissolved in methanol (10 ml), acidified with ethereal HCl, and evaporated in vacuo to give a solid which was triturated with ether (3×10 ml) to give the title compound as the hydrochloride (1.83 g) as colourless crystals, m.p. 274°-276° (dec.).
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][C:12]1[C:13]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)C(=O)[O:19][N:18]=2)=[N:14][O:15][N:16]=1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl.CN(C1C=CN=CC=1)C.CO>[CH2:1]([NH:10][CH2:11][C:12]1[C:13]([C:17](=[N:18][OH:19])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)=[N:14][O:15][N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 9.1 %

Procedure:
Benzoic acid (4.3 mg, 0.035 mmol) and 3-[4-(aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (10 mg, 0.032 mmol) was dissolved in ACN (0.2 mL) and DCM (0.2 mL). To the mixture was added DMAP (2.4 mg, 0.02 mmol) and DIPEA (17 μL, 0.096 mmol). After the mixture became a clear solution, bromotris(pyrrolydino)phophonium hexafluorophosphate (16 mg, 0.035 mmol) was added, followed by additional DIPEA (17 μL, 0.0962 mmol). The reaction mixture was stirred at rt for 6 hrs. LCMS indicated ˜70% ratio of product to starting amine. The reaction was then diluted with MeOH and crude residue was purified by preparative LCMS. The intermediate was stripped to dryness, redissolved in EtOH (1 mL) and 1 M of sodium hydroxide in water (0.06 mL). The reaction was stirred for 1 hr at rt. The reaction was quenched with acetic acid and then diluted with MeOH and crude residue was purified by preparative LCMS to afford the desired product (1.1 mg). MF═C17H13ClFN5O3; LCMS calculated for C17H14ClFN5O3(M+H)+: m/z=390.077.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C#N)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-cyanophenylboronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.78 min; Mass spectrum (ESI+): m/z=406 [M+H]+.
Reaction SMILES: COC1C=CC(CCC2C=CC(OC)=CC=2)=C(C2C=CC=C(O)C=2)C=1.Cl.ClCCN1CCCCC1.C[O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([O:67]C)=[CH:63][CH:62]=2)=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[CH:45]=2)[CH:43]=1>>[OH:67][C:64]1[CH:63]=[CH:62][C:61]([CH2:60][CH2:59][C:41]2[C:42]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][N:53]4[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]4)[CH:45]=3)=[CH:43][C:38]([OH:37])=[CH:39][CH:40]=2)=[CH:66][CH:65]=1
Reactant: COc1ccc(CCc2ccc(OC)cc2-c2cccc(OCCN3CCCCC3)c2)cc1
Agent: COc1ccc(CCc2ccc(OC)cc2-c2cccc(O)c2)cc1
Agent: Cl
Agent: ClCCN1CCCCC1
Product: Oc1ccc(CCc2ccc(O)cc2-c2cccc(OCCN3CCCCC3)c2)cc1
Yield: 65.1 %

Procedure:
Synthesized from 5′-methoxy-2′-[2-(4-methoxyphenyl)ethyl]biphenyl-3-ol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{5′-methoxy-2′-[2-(4-methoxyphenyl)ethyl]biphenyl-3-yloxy}ethyl}piperidine (200 mg) was used according to an analogous synthetic method to Example 779 to provide the title compound (122 mg).
Reaction SMILES: [CH2:1]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([CH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2coc3ccccc23)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CC2COc3ccccc32)cc1
Yield: 20.3 %

Procedure:
To a solution of 19.5 g (91.4 mmole) 3-benzylbenzofuran in 75 ml trifluoroacetic acid was added 31.8 g (273 mmole) triethylsilane and the mixture was heated at reflux for six hours. The mixture was concentrated in vacuo, the residue diluted with water and extracted with ethyl ether. The ether extracts were carbon treated, the filtrate dried (Na2SO4) and the solvent evaporated to provide a dark oil. The oil was purified by silica gel column chromatography eluting with hexane, then its mixtures with ethyl ether. The combined product fractions were evaporated to provide 3.9 g (20%) of the title compound as a yellow oil. 1H-NMR(CDCl3)ppm(delta): 3.2 (m, 2H), 4.0 (m, 2H), 4.6 (t, 1H), 6.7-7.5 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Br)ccc2[N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol) in DMF (6 mL) was added (4-methoxyphenyl)methanamine (342 mg, 2.5 mmol) and TEA (345 mg, 3.4 mmol). The reaction mixture was then stirred at 120° C. for 30 min under microwave heating. After cooling, the mixture was diluted with water (40 mL) and the resulting precipitate collected by filtration, washed with water and dried in vacuo to give the desired product (750 mg, crude, 97% yield) which was used in next step without further purification. LCMS (m/z): 338.1 [M+H]+
Reaction SMILES: [CH3:1][NH:2][NH2:3].O[CH:5]=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=O>CO.O>[CH3:1][N:2]1[CH:5]=[CH:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:3]1
Reactant: O=C(C=CO)c1ccccc1O
Reactant: CNN
Solvent: O
Solvent: CO
Product: Cn1ccc(-c2ccccc2O)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Methyl hydrazine (23.2 mmol, 1.23 ml) is added to a solution of 2-(3-hydroxy-2-propen-1-on-1yl)phenol (J. Am. Chem. Soc., 72:3396, 1950), 15.4 mmol, 2.54 g) in methanol (7 ml) and the mixture is heated at 100° C. for one hour. After cooling, the reaction mixture is diluted with water (100 ml) and stirred for one hour. The precipitate is collected via filtration and purified on silica gel (30% ethyl acetate/hexane) to give 811 mg of 2-(1-methylpyrazol-3-yl)phenol.