Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([O:12][C@H:13]3[C@H:17]4[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]4[O:15][CH2:14]3)[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]2=[N:6][C:7]=1I.[CH3:30][N:31]([CH3:51])[S:32]([CH3:50])(=[N:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)=[O:33]>O1CCOCC1>[OH:21][C@H:20]1[C@H:16]2[O:15][CH2:14][C@@H:13]([O:12][C:10]3[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]4=[N:6][C:7]([C:38]5[CH:37]=[CH:36][C:35]([N:34]=[S:32]([CH3:50])([N:31]([CH3:30])[CH3:51])=[O:33])=[CH:40][CH:39]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:11]=3)[C@H:17]2[O:18][CH2:19]1
Reactant: CN(C)S(C)(=O)=Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(I)nc21
Solvent: C1COCCO1
Product: CN(C)S(C)(=O)=Nc1ccc(-c2nc3c(cc2Cl)nc(O[C@@H]2CO[C@H]4[C@@H]2OC[C@H]4O)n3COCC[Si](C)(C)C)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-iodo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N,N-dimethyl-N′-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3) using 1,4-dioxane as a solvent. LC (method 2): tR=1.00 min; Mass spectrum (ESI+): m/z=624 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].[OH:27][CH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[NH2:35]>>[OH:27][CH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[NH:35][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:25]
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: N[C@@H]1CCCC[C@@H]1CO
Product: N#Cc1ccc2c(c1)cc(C(=O)N[C@@H]1CCCC[C@@H]1CO)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxy-benzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and cis-2-hydroxymethyl-1-cyclohexylamine in a manner similar to that described in Example 11.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]P(=O)(OCC)OCC)[CH:2]=1.C([Li])CCC.[CH:21](=O)[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:21][C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)[CH:2]=1
Reactant: CCOP(=O)(Cc1cccnc1)OCC
Reactant: O=Cc1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=Cc1ccco1)c1cccnc1
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a stirred -78° C. solution of diethyl 3-pyridylmethylphosphonate (3.0 g, 13 mmol), prepared as in step 3, in THF (50 mL) was added n-butyllithium (25 mL, 55 mmol, 2.5M in hexanes). The cold reaction mixture was stirred 0.5 hours followed by the slow addition of furfuraldehyde (1.24 g, 13 mmol). The reaction was stirred 2 hours at -78° C. and the ice bath removed and allowed to stir at ambient temperature overnight. Saturated NH4Cl was added and the mixture was diluted with ether. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel eluting with 40% ethyl acetate-hexanes to afford 1.1 g of 2-[2-{3-pyridyl}ethenyl]furan.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[CH:27][N:26]=2)=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: Nc1ccc(-c2cnccn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Br)c(C(F)(F)F)c1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-bromo-3-(trifluoromethyl)phenyl)acetic acid 46-6 (128 mg, 0.5 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (95 mg, 0.55 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 214 mg, 0.55 mmol) in DMF (2 mL) was added diispropylethyl amine (DIEA, 250 μL, 1.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and concentrated by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give 2-(4-bromo-3-(trifluoromethyl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 118-1 as pale orange solid. MS m/z 438.2 (M+1)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:27][NH:28][CH2:29][CH2:30][CH3:31]>C(#N)C>[CH3:27][N:28]([CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:19]=2)[O:14]1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCNC
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCN(C)CC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-methylpropan-1-amine (N—,N—) (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 297 (M+, 2), 131 (5), 87 (6), 86 (bp), 77 (5), 58 (7).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzoyloxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless, amorphous solid; Rf : 0.61 (SiO2, hexane:acetone=95:5).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([NH:23][C:24]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1)=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCCNc1nc2ccccc2[nH]1
Product: O=C(NC(=S)NCCCNc1nc2ccccc2[nH]1)c1ccccc1

Procedure:
Reacting 2-(3-aminopropylamino)benzimidazole with benzoyl isothiocyanate by the procedure of Example 46 gives N-benzoyl-N'-[3-(2-benzimidazolylamino)propyl]thiourea.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH2:11][F:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO.Cl>[CH3:21][O:22][N:23]=[C:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][F:12]
Reactant: O=C(CF)CCc1ccc(Cl)cc1
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(CF)CCc1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a stirred suspension of 4-(4-chloro-phenyl)-1-fluoro-butan-2-one (0.13 g; 0.62 mmol) in methanol (1.3 ml) was added pyridine (80 μl; 0.99 mmol) followed by a portion wise addition of methoxyamine hydrochloride (78 mg; 0.93 mmol). The reaction mixture was stirred for 16 h at 23° C. The mixture was poured in 1 N hydrochloric acid (5 ml), extracted with dichloromethane (3×3 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 0.13 g (94% of theory) of 4-(4-chloro-phenyl)-1-fluoro-butan-2-one O-methyl-oxime (mixture of E/Z-isomers) as a yellow oil.
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:12]12[CH2:17][CH:16]1[C:15](=[O:18])[O:14][C:13]2=[O:19]>C(O)C>[CH2:1]([N:6]1[CH2:7][CH2:8][N:9]([C:15]([CH:16]2[CH2:17][CH:12]2[C:13]([OH:19])=[O:14])=[O:18])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C1OC(=O)C2CC12
Reactant: CCCCCN1CCNCC1
Solvent: CCO
Product: CCCCCN1CCN(C(=O)C2CC2C(=O)O)CC1

Procedure:
To 100 mL of ethanol is added 1-pentylpiperazine (15.6 g, 0.1 mol) and 11.2 g (0.1 mol) of 3-oxabicyclo[3.1.0]-hexane-2,4-dione. Reflux the reaction and monitor by thin-layer chromatography. Upon completion remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25](=[O:27])[CH3:26])=[CH:14][CH:13]=2)(C)(C)C.[ClH:34]>C(OCC)(=O)C>[ClH:34].[C:25]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:28])[N:10]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:9]([CH2:8][NH2:7])=[C:18]2[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(=O)n(CC(C)C)c(CN)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98 %

Procedure:
Tert-butyl(6-acetyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.10 g, 0.22 mmol) was dissolved in ethyl acetate (4 mL) and a solution (1 mL) of 4N hydrogen chloride in ethyl acetate was added thereto. The mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated under reduced pressure and the residue was precipitated from ethyl acetate-diisopropyl ether (1:10) to give the title compound (0.084 g, 98%) as a pale-yellow powder.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.C([Li])CCC.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CCCCCC.CCOCC.[Cl-].[Cl-].[Zn+2]>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[NH:5][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: COC(=O)CBr
Reactant: COc1ccc2[nH]c(C3CC3)cc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)Cc1c(C2CC2)[nH]c2ccc(OC)cc12

Procedure:
As in Example 1, Part C, 4.46 g (0.024 mole) of 2-cyclopropyl-5-methoxy-1H-indole was treated with 15 mL (0.024 mol) of a 1.6M solution of n-butyl lithum in hexane, 24 ml (0.024 mol) of a 1M solution of ZnCl2 in ether, and 12.27 mL (0.024 mol) of methyl 2-bromoacetate to give after chromatography on silica gel (5% EtOAc/toluene→15% EtOAc/toluene) 3.81 g (61%) of 2-cyclopropyl-5-methoxy-1H-indole-3-acetic acid methyl ester as an oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18])[CH:4]=[CH2:5].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>CN(C)C=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][C:6]1([CH2:3][CH:4]=[CH2:5])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18])[CH3:25]
Reactant: C=CCC1C(=O)CCc2ccc(OC)cc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC1(CC(=O)OCC)C(=O)CCc2ccc(OC)cc21
Reaction time: 1 h

Procedure:
Into a flame-dry 500 ml 3-neck flask provided with mechanical stirrer, dropping funnel and a nitrogen inlet tube was placed 4.21 g sodium hydride (55% dispersion in oil, 100 mmol) with the apparatus placed under nitrogen. The oil was washed out with benzene (3×30 ml), 40 ml dry dimethylformamide was added and the suspension was stirred and cooled in an ice-bath. A solution of 21.6 g (100 mmol) 1-allyl-3,4-dihydro-7-methoxy-2(1H)naphthalenone (VIIIa) in 10 ml dimethylformamide was added dropwise (10 min), then the cooling bath was removed and stirring at room temperature continued until the evolution of gas ceased (2 hr). The brown-colored reaction mixture was cooled (ice-bath) and a solution of 16.7 g (100 mmol) ethyl bromoacetate in 40 ml dimethylformamide was added dropwise keeping the reaction temperature below 25° C. After the addition (15-20 min) stirring in cold was continued for 1 hr and then overnight at room temperature. Water (300 ml) was added and extracted with ether (3×100 ml). The combined ether extracts were washed with water (2×100 ml) dried (MgSO4), the solvent removed by evaporation and the residue was distilled to give 26.0 g (86%) IXa, b.p. 145°-150°/0.05-0.01 mm Hg; IR (neat) 1740, 1715 cm-1 ; NMR δ, 1.05 and 3.92 (triplet and quartet for OCH2CH3), 3.75 (s, 3, OCH3), 4.65-6.0 (m, 3, CH=CH2), 6.55-7.15 (m, 3, ArH).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1COCC1>[CH:5]1[C:4]2[C:9](=[CH:10][C:11]3[C:16]([C:3]=2[CH2:2][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: C1CNCCN1
Reactant: ClCc1c2ccccc2cc2ccccc12
Solvent: C1CCOC1
Product: c1ccc2c(CN3CCNCC3)c3ccccc3cc2c1

Procedure:
Synthesized according to General Procedure A: 9-(chloromethyl)anthracene (4{21}, 5 g, 18.7 mmol, 1 equiv.), piperazine (9.4 g, 109.0 mmol, 6 equiv.), THF (40.0 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5 {21} (4.75 g, 93%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.50 (dd, 2H, J=0.5, 9.0 Hz), 8.41 (s, 1H), 8.00 (td, 2H, J=1.0, 8.5 Hz), 7.52 (ddd, 2H, J=1.5, 6.5, 8.0 Hz), 7.47 (ddd, 2H, J=1.5, 6.5, 8.5 Hz), 4.42 (s, 2H), 2.81 (t, 4H, J=5.0 Hz), 2.59 (br s, 4H), 1.87 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 131.4, 131.3, 129.6, 128.9, 127.3, 125.5, 125.1, 124.8, 54.8, 54.5, 46.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20](N)[CH:21]=1>C(O)(=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)[CH:17]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(Br)ccc1Sc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc(Br)ccc3Sc3ccccc3)ncnc2n1
Temperature: 130 °C
Yield: 65.2 %

Procedure:
A mixture of the product from Example 10B (0.188 g, 1.0 mmol) and 5-bromo-2-(phenylthio)benzenamine (0.280 g, 1.0 mmol) in glacial acetic acid (2 mL) was heated in a 130° C. oil bath for 30 min. The reaction mixture was then cooled to room temperature and the solvent evaporated under reduced pressure. The residue was triturated with methanol, and the resulting solid isolated by vacuum filtration and dried to provide the title compound (0.276 g, 65% yield) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:10][C:6]=2[CH:5]=[C:4]([C:29]#N)[CH:3]=1.CC(C[AlH]CC(C)C)C.CC[O:42]C(C)=O.O>C1COCC1>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:10][C:6]=2[CH:5]=[C:4]([CH:29]=[O:42])[CH:3]=1
Reactant: N#Cc1cc(Br)c2nc(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)[nH]c2c1
Reactant: CCOC(C)=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Br)c2nc(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)[nH]c2c1
Temperature: -40 °C
Reaction time: 10 h
Yield: 43 %

Procedure:
To a solution of (S)-7-Bromo-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzimidazole-5-carbonitrile (150 mg, 0.31 mmol) in THF (50 mL) was added DIBAL-H (1 M toluene solution, 1.55 mL, 1.55 mmol) at −78° C. The reaction mixture was stirred at −40° C. for 10 h and cooled to −78° C. EtOAc (0.5 mL) was added. The reaction mixture was stirred for 30 min at −78° C. before water (1 mL) was added. The reaction mixture was warmed to room temperature and concentrated. The residue was passed through a small pad of celite. The filtrate was concentrated and purified by prep. HPLC to give the titled compound (67 mg, 43%). 1H NMR (400 MHz, CD3OD) δ 9.45 (1H, s), 7.62 (1H, s), 7.56 (1H, narrow d, J=1.6 Hz), 7.44 (1H, narrow d, J=1.0 Hz), 7.32–7.42(2H, m), 7.24–7.30 (3H, m), 6.24 (1H, d, J=7.6 Hz), 5.01 (1H, m), 3.65–3.76 (2H, m). LCMS (M+H)+ m/z 487 (t=1.76 min.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[N:13][C:14]([NH2:29])=[C:15]([O:17][CH:18]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[Cl:28])[CH3:19])[CH:16]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[C:15]([O:17][CH:18]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[Cl:28])[CH3:19])[C:14]([NH2:29])=[N:13][CH:12]=1
Reactant: CC(Oc1cc(C#CCNC(=O)OC(C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Oc1cc(C#CCN)cnc1N)c1c(Cl)ccc(F)c1Cl
Yield: 93 %

Procedure:
The solution of (3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester in 25% TFA in dichloromethane was stirred for 2 hr, then washed by 2N NaOH, water twice, brine, dried over Na2SO4. After filtration and evaporation, 5-(3-amino-prop-1-ynyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine was obtained in 93% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][NH:18][C:17](=[O:20])[NH:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>CC#N>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][NH:18][C:17](=[O:20])[NH:16][CH2:15]2)=[CH:12][C:13]=1[Br:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CNC(=O)NC2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(C2CNC(=O)NC2)cc1Br
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of [4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step, 29 mg, 0.10 mmol) in CH3CN (1 mL), NBS (19.5 mg, 0.100 mmol) was added. The resulting mixture was stirred overnight and concentrated to half the volume. The resulting precipitate was collected by filtration to obtain the title compound (12 mg, 32%): Mass spectrum (ESI, m/z): Calcd. for C15H20BrN3O3, 370.0 and 372.0 (M+H). found 370.1 and 372.1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:34])[CH:27]=1.O>CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10][O:11][CH2:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:34])[CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: N#Cc1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COCc1ccc(C#N)c(F)c1
Reaction time: 0.25 h
Yield: 18.7 %

Procedure:
To a solution of 2.255 g of [4-butyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol in 25 ml of dimethylformamide was added 0.286 g of a 60% dispersion of sodium hydride in mineral oil. After stirring for 15 minutes, 3 g of 4-bromomethyl-2-fluoro-benzonitrile was added. The resulting mixture was stirred at room temperature overnight, then poured into water, extracted with diisopropyl ether. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 95/ethyl acetate 5) to give 0.6 g of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-2-fluoro-benzonitrile, which was transformed into 3-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-2-fluoro-phenyl}-4H-[1,2,4]oxadiazol-5-one according to the method described in example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:30])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[O:17])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>Cl.CC(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:30])[C:16](=[O:17])[C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[CH:22][CH:23]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 243.3 %

Procedure:
To the compound (1.86 g) obtained in step 2 was added 2N hydrogen chloride/2-propanol (10 mL), and the mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give N-[(3R,4R)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methyl-4-morpholin-4-ylbenzamide monohydrochloride (2.00 g, 100%) as a white powder.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[C:5]#[C:4][C:2]([CH3:3])([OH:6])[CH3:1])=[CH:11][CH:10]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C#CC(C)(C)O
Solvent: C1CCOC1
Product: COc1ccc(C(O)C#CC(C)(C)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a pre-cooled, −78° C. stirred solution of 2-methylbut-3-yn-2-ol (4.3 g, 0.04 mol) in dry THF (150 mL) n-BuLi (39.9 mL, 0.03 mol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The mixture was stirred for 30 min at −78° C., and then a solution of 4-methoxy-benzaldehyde (5 g, 0.037 mol) in dry THF (30 mL) was added to reaction mixture and stirring was continued for an additional 40 min at −78° C. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain crude material. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc in hexanes to afford 1-(4-methoxyphenyl)-4-methylpent-2-yne-1,4-diol (6.3 g, 78%) as an oil.