Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:5][C:4]=1[CH3:18].C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[C:30](#[N:32])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:18][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[S:7][C:3]=1[CH2:2][C:30]#[N:32]
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CCl
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
Tetrabutylammonium cyanide (1.44 g, 5.4 mmol) was added to a solution of 5-chloromethyl-4-methyl-2-(3-trifluoromethyl-phenyl)-thiazole (1.2 g, 4.1 mmol) in acetonitrile (27 ml). The solution was stirred at ambient temperature for 16 h, saturated aqueous sodium bicarbonate solution/ice water 1/1 and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give brown oil which was purified by column chromatography (silica gel, pentane/ethyl acetate) to yield 700 mg (2.5 mmol, 60%) of the title compound as orange oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][N:11]1[CH2:18][C@@H:17]2[C@@H:13]([CH2:14][NH:15][CH2:16]2)[CH2:12]1>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([N:15]2[CH2:16][C@@H:17]3[C@@H:13]([CH2:12][N:11]([CH3:10])[CH2:18]3)[CH2:14]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: CN1C[C@H]2CNC[C@H]2C1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Product: CN1C[C@@H]2CN(c3cc(Cl)nc(N)n3)C[C@@H]2C1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
2-Amino-4,6-dichloropyrimidine (1.64 g, 10 mmol) was added portionwise to a stirred solution (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (1.6 g, 12.5 mmol) in absolute EtOH (10 mL) followed by TEA (1.8 mL, 12.5 mmol) dropwise at ambient temperature. The resulting suspension was warmed to reflux (initially a clear solution was observed on warming) and resulted in the gradual formation of a tan coloured precipitate. The mixture was refluxed for a total of 3 hours. The mixture was allowed to cool, EtOH (30 mL) was added to the mixture and heated to give a solution and was left to cool to ambient temperature. The resulting solid was collected by filtration, washed with cold EtOH (50 mL) and dried under suction to yield the title compound as a solid (2.07 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[F:23])=[S:38])=[O:35])=[CH:30][CH:29]=1
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[I:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:32]=[C:31]([NH:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([I:23])[CH:25]=4)[N:33]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: N=C(N)Nc1cccc(I)c1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Solvent: O=[N+]([O-])O
Product: O=C1Cc2cnc(Nc3cccc(I)c3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3-iodo-phenyl)-guanidine nitrate were converted to I-58 (50%): HRMS Calcd. for C18H12ClIN4O: 462.9822, Found 462.9838.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Br[CH2:32][CH2:33][OH:34].C([O-])(O)=O.[Na+]>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:32][CH2:33][OH:34])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 70.2 %

Procedure:
To a solution of COMPOUND 249 (0.1189 g, 0.38 mmol) in CH3CN (4 mL) was added Et3N (0.08 mL, 0.57 mmol), KI (0.0063 g, 0.04 mmol), and 2-bromoethanol (0.03 mL, 0.46 mmol), and stirred at room temperature for 23 hours. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (25:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0946 g (66%) of COMPOUND 339 as a pale yellow oil. 1H NMR (CDCl3) δ 1.71-1.98 (m, 6H), 2.09 (s, 6H), 2.46 (t, 3H, J=5.1 Hz), 2.94 (d, 3H, J=10.8 Hz), 3.56 (t, 2H, J=5.1 Hz), 3.82 (s, 4H), 7.04-7.08 (m, 2H), 7.34 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 18.35, 27.34, 53.93, 55.13, 57.82, 58.52, 59.74, 122.63, 133.76, 138.29, 146.15, 157.80. ES-MS m/z 355.5 (M+H). Anal. Calcd. for C21H30N4O.0.3CH2Cl2: C, 67.33; H, 8.12; N, 14.74. Found: C, 67.46; H, 8.43; N, 14.93.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1)[C:28]([C:41](O)=[O:42])=[CH:27]2.[NH2:44][C:45]1[CH:46]=[N:47][C:48]([N:51]2[CH2:54][CH2:53][CH2:52]2)=[CH:49][CH:50]=1>CN(C=O)C.C(OCC)(=O)C.O>[N:51]1([C:48]2[N:47]=[CH:46][C:45]([NH:44][C:41]([C:28]3[N:29]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=4)[C:30]4[C:26]([CH:27]=3)=[CH:25][C:24]([Br:23])=[CH:32][CH:31]=4)=[O:42])=[CH:50][CH:49]=2)[CH2:54][CH2:53][CH2:52]1
Reactant: O=C(O)c1cc2cc(Br)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(N2CCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(Br)ccc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 594.7 %

Procedure:
0.77 g (4.02 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and 0.54 g (4.02 mmol) of 1-hydroxybenzotriazole (HOBT) are added to a solution, stirred at 20° C. under an inert atmosphere, of 1.4 g (4.02 mmol) of 5-bromo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in stage 17.2, in 20 ml of DMF. The reaction mixture is stirred at ambient temperature for 20 minutes. 0.66 g (4.42 mmol) of 3-amino-6-(azetidin-1-yl)pyridine, prepared according to the protocol described in stage 1.6, is subsequently added to the reaction mixture. After stirring at 20° C. for 18 hours, the reaction mixture is poured into a mixture of 50 ml of water and 50 ml of ethyl acetate. The resulting mixture is separated by settling out and the aqueous phase is extracted with 20 ml of ethyl acetate. The combined organic phases are washed three times with 30 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The isolated product is subsequently precipitated, then washed with isopropyl ether at reflux, filtered under hot conditions, and then dried under reduced pressure. 11.46 g of the expected product are thus isolated.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.C[C:13]1[CH:20]=[CH:19][C:16](C=O)=C[N:14]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[CH3:4][C:3]1[CH:2]=[CH:1][C:20]([CH:19]=[CH2:16])=[CH:13][N:14]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (62.54 g, 0.175 mol) in THF (150 mL) at −78° C. under nitrogen was added 2.5 M of n-butyllithium in hexane (69 mL, 0.17 mol) over a period of 1 hr. The mixture was warmed to room temperature to give a deep yellow ylide solution. To the ylide solution, cooled in ice, was introduced a solution of 6-methylnicotinaldehyde (18.63 g, 0.146 mol) in THF (50 mL). The reaction mixture was warmed to room temperature and stirred for 2 hours. The resulting suspension was heated to 60° C. over 30 minutes and stirred at 60° C. for 1 hour. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated and washed with brine, dried (MgSO4), and concentrated. The residue was purified by silica gel column (0-10% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:28][CH2:29][CH2:30][CH3:31])[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(Cl)(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[CH:4]=[C:3]5[O:2][CH2:1][O:13][C:12]5=[CH:11][C:10]4=[N:9][CH:8]=3)[N:14]([CH2:28][CH2:29][CH2:30][CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: CCCCN(C(=O)c1cc(OC)c(OC)cc1I)c1ccnc2cc3c(cc12)OCO3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCn1c(=O)c2cc(OC)c(OC)cc2c2cnc3cc4c(cc3c21)OCO4
Temperature: 25 °C
Yield: 24 %

Procedure:
A mixture of the N-(6,7-Methylenedioxyquinolin-4-yl)-N-(butyl)-2-iodo-4,5-dimethoxybenzamide (1.0 mmol equiv.), Pd(OAc)2 (0.2 mmol equiv.), P(o-tolyl)3 (0.4 mmol equiv.), and Ag2CO3 (2.0 mmol equiv) was heated to reflux in DMF (30 mL per mmol equiv.) with stirring. The reaction mixture was allowed to cool to room temperature, diluted with CHCl3, and filtered through Celite. The sicciate was extensively washed with 10% CH3OH in CHCl3. The filtrate was concentrated in vacuo and the residue chromatographed on silica gel using chloroform:methanol to provide the title compound; (24% yield); reaction time 45 min; mp 224° C. (dec.); IR (KBr) 1654; 1H NMR (CDCl3); δ 0.99 (t, 3H, J=7.4), 1.62 (m, 2H), 2.09 (m, 2H), 4.07 (s, 3H), 4.14 (s, 3H), 4.49 (m, 2H), 6.19 (s, 2H), 7.50 (s, 1H), 7.61 (s, 1H), 7.70 (s, 1H), 7.92 (s, 1H), 9.40 (s, 1H); 13C NMR (CDCl3) δ 13.7, 20.2, 31.2, 50.6, 56.3, 56.4, 100.7, 102.0, 102.2, 107.4, 108.8, 111.7, 114.9, 119.5, 127.4, 141.1, 143.7, 147.1, 147.5, 149.8, 150.3, 154.1, 164.0; HRMS calcd for C23H22N2O5H: 406.1529. Found 406.1534.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7]1)(=[O:5])[CH3:4]>C(O)C.CCCCCC>[CH2:13]([NH:12][C:10]([C:6]1([C:3](=[O:5])[CH2:4][Br:1])[CH2:9][CH2:8][CH2:7]1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrBr
Reactant: CC(=O)C1(C(=O)NCc2ccccc2)CCC1
Solvent: CCCCCC
Solvent: CCO
Product: O=C(CBr)C1(C(=O)NCc2ccccc2)CCC1
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
Bromine (0.593 mL, 11.51 mmol) was added dropwise to a 0° C. stirred solution of 1-acetyl-N-benzylcyclobutanecarboxamide (2.22 g, 9.60 mmol) in ethanol (35.5 mL). After 15 minutes, the ice bath was removed. The flask was sealed, and stirring was continued for 6.5 hrs. HPLC and LC/MS after 5 hrs indicated a complete or nearly complete reaction. The reaction was quenched by the addition of 25 mL of sat. aq NaHSO3 soluition. EtOAc was added (50 mL), the layers were separated, the aq layer was extracted with EtOAc (20 mL), the combined EtOAc layers were washed with water, brine, dried over Na2SO4, and concentrated under vacuum to give the crude product (2.80 g) as an oily yellow solid. The crude product was sonicated briefly in hexane. The ppt was collected by filtration, rinsed with hexane, and dried under vacuum to yield 2.33 g of the title compound as a pale yellow solid. LC/MS: m/e 312.08 (one of 2 Br-pattern peaks, M+H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[N:19]([CH3:28])[S:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)(=[O:22])=[O:21])=[N:7][CH:6]=1)#[N:2].C([Sn](=O)CCCC)CCC.C[Si]([N:43]=[N+:44]=[N-:45])(C)C>O1CCCC1>[CH3:28][N:19]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][C:10]([C:8]1[S:9][C:5]([CH2:4][CH2:3][C:1]3[N:43]=[N:44][NH:45][N:2]=3)=[CH:6][N:7]=1)=[CH:18]2)[S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CN(c1cccc2cc(-c3ncc(CCC#N)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCCC[Sn](=O)CCCC
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3ncc(CCc4nn[nH]n4)s3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 67 %

Procedure:
A mixture of N-{2-[5-(2-cyanoethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.30 g), dibutyltin oxide (35 mg), trimethylsilylazide (0.74 mL) and tetrahydrofuran (10 mL) was heated under reflux for 3 days. The reaction mixture was concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.22 g, yield 67%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-methanol (9:1, volume ratio). The crystals were recrystallized from ethyl acetate. melting point 211-212° C.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2cccn2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(1H-pyrazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 392.16 g/mol.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH:4]([C:6]1[N:7]=[CH:8][CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:3]
Reactant: CCOC(=O)c1cccnc1C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccnc1C=O
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
In flame-dried glassware under N2 atmosphere, to a solution of 2,3-pyridinedicarboxylic acid diethyl ester (0.254 g, 1.14 mmol) in anhydrous toluene (5 mL) at -78° C. was added diisobutylaluminum hydride (DiBal) (1.48 mL, 1.48 mmol, 1M in toluene). After 30 minutes, additional DiBal (0.4 mL, 0.4 mmol, 1M in toluene) was added. After 15 minutes, the reaction mixture was quenched with methanol (2 mL)/saturated Na/K tartrate (40 mL) and extracted into EtOAc (3×50 mL). The combined organic extracts were washed with saturated NaHCO3 (2×50 mL), saturated brine (1×75 mL), dried over MgSO4, filtered, concentrated, and flash chromatographed (5 to 10% EtOAc/CH2Cl2 gradient) to provide 0.075 g of the title compound as a colorless oil (36.8%). 1H NMR (CDCl3, 300 MHz): δ 10.34 (s, 1H, RCHO), 8.84 (d, 1H, Arom), 8.10 (d, 1H, Arom), 7.56 (dd, 1H, Arom), 4.45 (q, 2H, OCH2), 1.40 (t, 3H, CH2CH3)
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.[NH:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[O:24]2)[CH2:20][CH2:19]1>CC(N(C)C)=O>[F:15][C:14]([F:17])([F:16])[S:11]([C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([N:18]3[CH2:23][CH2:22][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25](=[O:32])[O:24]4)[CH2:20][CH2:19]3)=[N:3][C:4]=2[CH:10]=1)(=[O:13])=[O:12]
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: O=S(=O)(c1ccc2[nH]c(Cl)nc2c1)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: O=C1OC2(CCN(c3nc4cc(S(=O)(=O)C(F)(F)F)ccc4[nH]3)CC2)c2ccccc21

Procedure:
Stir 2-chloro-5-trifluoromethylsulfonyl-1H-benzimidazole (185 mg) and spiro[isobenzofuran-1,4′-piperidin]-3-one (263 mg) in dimethylacetamide (6 mL) at 195° C. for 1 hour. Cool the mixture and partition between EtOAc and half-saturated NaHCO3, wash several times with water, dry and concentrate in vacuo. Purify the residue by chromatography (1:1 hexanes/EtOAc) to obtain 1′-(5-trifluoromethylsulfonyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one.
Reaction SMILES: O[N:2]1[C:23](=[O:24])[NH:22][C@H:21]2[C@@H:3]1[CH2:4][S:5][C@H:6]2[CH2:7][CH2:8][CH2:9][CH:10](N1C(=O)CCC1=O)[C:11](=[O:13])[OH:12]>OP([O-])(O)=O.OP([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-].[Cl-].[K+].[K+].CN(C)C=O>[OH:13][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C@@H:21]2[C@@H:3]([NH:2][C:23]([NH:22]2)=[O:24])[CH2:4][S:5]1)=[O:12]
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 2 h

Procedure:
Synthesis of biotinylated rabbit IgG was carried out as follows: rabbit IgG (2 mg, 12.5 nmoles) was dissolved in 2 mls of pH=7.4 phosphate buffered saline. N-hydroxysuccinimidobiotin was dissolved in N,N-dimethylformamide and 0.3 mg (880 nmoles) of N-hydroxysuccinimidobiotin was added and incubated at room temperature for two hours. The biotinylation mixture was purified by chromotography on Sephadex G-25 (1×25 cm), using the same buffer as eluent resulting in separation of biotinylated antibody from free biotin. The biotin: antibody ratio was 16, as determined by measuring antibody concentration by absorbance at 280 nm and measuring biotin concentration by the method of Green, N. M., Methods in Enzymology, McCormack D. B. and L. B. Wright (ed.) 18A:418 (1970).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12](N)[CH2:13][NH2:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:14][CH2:13][CH2:12][N:10]=2)[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)c1cccc(Br)c1
Reactant: NCCN
Product: CC(C1=NCCN1)c1cccc(Br)c1

Procedure:
rac-2-[1-(3-Bromo-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(3-bromo-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): light yellow solid; MS (ISP): 252.9; 254.9 ((M+H)+.).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[N:18]([CH3:32])[N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:32][N:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:33])=[O:3])=[CH:10][CH:11]=2)=[CH:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)=[N:19]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)nn3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 f], {6-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as brown crystals.
Reaction SMILES: [C@H:1]1([NH:11][C:12]([C@H:14]2[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:30]([NH:37][C@H:38]([C:42](O)=[O:43])[CH:39]([CH3:41])[CH3:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:33]([O:32][C:30]([NH:37][C@@H:38]([CH:39]([CH3:41])[CH3:40])[C:42]([N:19]1[CH2:18][CH2:17][N:16]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:15][C@H:14]1[C:12]([NH:11][C@H:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:13])=[O:43])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Yield: 63.5 %

Procedure:
The deprotected piperazine 3 (16.20 g, 41.2 mmol) is coupled with BOC-L-valine (8.95 g, 41.2 mmol) using DIEA (36.0 mL, 0.21 mol), HBTU (17.19 g, 45.3 mmol) and HOBt (6.12 g, 45.3 mmol) in DMF (700 mL) under the same conditions as in step 1 above. Purification is carried out by flash chromatography on silica gel (CH2Cl2 as eluent initially, followed by 10% Et2O/CH2Cl2 to elute the desired product). The desired coupled product 4 is isolated as a white foam (15.51 g, 64% yield): 1H NMR δ (CDCl3) 6.99-7.64 (m, 9H), 5.99-6.34 (br m, 1H), 2.68-5.26 (br m, 11H), 1.51-2.15 (br m, 6H), 1.42 (s, 9H), 1.15 (s, 3H), 0.64-1.02 (br m, 5H); LCMS (APCl+) 594.2 (MH+), 537.9 (MH+-tBu), 493.7 (MH+-BOC, 100%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[N:23]1[CH:24]=[CH:25][N:26]2[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][C:27]=12>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:30]3[CH:29]=[CH:28][C:27]4[N:26]([CH:25]=[CH:24][N:23]=4)[CH:31]=3)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: OB(O)c1ccc2nccn2c1
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5nccn5c4)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (16.7 mg, 0.0400 mmol)(Example 3, Step 4) and imidazo[1,2-a]pyridin-6-ylboronic acid (Combi-Blocks, Cat. No. BB-3457). LCMS (M+H)+=409.0.