Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH2:36][C:37]1([CH3:43])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.NC1CCN(CC2C=CN3C=2C(NC2C=CC(OCC4C=CC=C(F)C=4)=C(Cl)C=2)=NC=N3)CC1.C(O)(C(F)(F)F)=O>CO>[NH2:36][C:37]1([CH3:43])[CH2:42][CH2:41][N:40]([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)[CH2:39][CH2:38]1
Reactant: CC1(N)CCNCC1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)c1ccccc1
Agent: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC1(N)CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1

Procedure:
The title compound was prepared from 7B and excess 4-amino-4-methylpiperidine (WO 9732880) by a route analogous to that used for the preparation of 7C. Analytical HPLC retention time=1.43 min. (YMC Xterra S7 C 18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm) and a LC/MS M++1=495.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(N(CC)CC)C.[CH3:14][SiH:15]([CH3:17])Cl>O1CCCC1>[CH3:14][SiH:15]([CH3:17])[N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6]
Reactant: C[SiH](C)Cl
Reactant: O=C1NCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[SiH](C)N1CCOC1=O

Procedure:
A 3-dimethylsilyl-2-oxazolidinone was prepared in accordance with the following procedure. To a stirred mixture of 34.8 grams of 2-oxazolidinone and 40.4 grams of triethylamine in 600 ml of a tetrahydrofuran solvent, 45 ml of dimethylchlorosilane was added dropwise over a 30-minute period. The mixture was then heated in a distillation apparatus with continuous reflux for a period of 30 minutes. The resultant mixture was cooled and then filtered.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH2:25]Cl)=[CH:23][CH:24]=1)=[O:19]>CN(C)C=O>[CH3:16][O:17][C:18]([C:20]1[O:21][C:22]([CH2:25][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:14][CH:13]=2)=[CH:23][CH:24]=1)=[O:19]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Temperature: 5 °C
Reaction time: 2.5 h
Yield: 47491.2 %

Procedure:
N,N-Dimethylformamide (400 mL) was added to sodium hydride (60% dispersion, ˜16 g, 0.4 mol) which had been washed with hexanes. The mixture was cooled to ˜5° C., and then a solution of 4-phenylphenol (73.12 g, 0.43 mmol) in N,N-dimethylformamide (150 mL) was added. The mixture was allowed to stir at room temperature for 2.5 h, and then a solution of 5-chloromethylfuran-2-carboxylic acid methyl ester (25 g, 0.14 mmol) in N,N-dimethylformamide (100 mL) was added. The reaction mixture was heated at ˜105° C. for 2 h, and then it was allowed to cool, evaporated under reduced pressure, and water was added. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated brine, dried (magnesium sulfate), filtered, evaporated, and purified using a Biotage 75 L purification system, eluting with 0-10% methylene chloride/toluene to give 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid methyl ester (20.5 g, 46%).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH2:16][CH2:17][NH2:18].CCN(CC)CC.CO>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]([CH2:16][CH2:17][NH:18][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCc1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NCCc2cccc(Br)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
TsCl (11 g, 57.5 mmol, 1.15 eq.) was dissolved in DCM (150 mL) and cooled to 0° C. To this solution was added a solution of 3-bromo-phenethyamine (10 g, 50 mmol) in DCM (50 mL), followed by Et3N (18 mL). The solution was stirred at r.t. overnight when TLC (5% MeOH in DCM) showed that the reaction was complete. LCMS: t=4.158, MS 354/356. 3 g of polymer-supported-amine was added, stirred for 1 h at r.t. The solution was filtered through a Celite pad, rinsed with DCM and the solvent was evaporated to dryness, re-dissolved in DCM (100 mL) and water (20 mL). The two layers were separated, and the aqueous layer was extracted with DCM (20 mL×2). The combined DCM extracts were washed with 1N H3PO4 (2×20 mL) and sodium bicarbonate (20 mL), and brine (15 mL×2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with DCM (TLC: DCM) to get 17.89 g (100%) of the title compound as a off-white solid, on standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][O:27][C:28]1[CH:35]=[CH:34]C=C[C:29]=1[CH2:30]N.C([N:38]([CH2:41][CH3:42])CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:38][CH2:41][C:42]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)=[O:20]
Reactant: CCN(CC)CC
Reactant: COc1ccccc1CN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: COc1ccc(CNC(=O)C2=C(C(=O)Nc3cc(OC4CCCC4)c(Cl)cc3F)CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), 2-methoxybenzylamine (0.380 g, 2.77 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (20 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized from ether/hexane to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-methoxybenzyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.520 g, 37.8% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([OH:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].O>C(#N)C>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:20])=[C:15]([O:18][S:47]([CH3:46])(=[O:49])=[O:48])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: -40 °C
Yield: 94 %

Procedure:
Benzhydryl 7β-[(phenylacetyl)amino]-3-hydroxy-3-cephem-4-carboxylate (500 g, 1 mol) was dissolved in acetonitrile (2 L) and ethyldiisopropylamine (183 mL, 1.05 mol) was added dropwise over 10 min with stirring at −40° C. Then, methanesulfonyl chloride (86 mL, 1.1 mol) was added dropwise over 10 min and the mixture was stirred at −40° C. for 40 min. The reaction mixture was poured into iced water (8 L) and the precipitate was collected by filtration. The precipitate was washed with water (2 L) and ethyl acetate (300 mL) and dried under reduced pressure to give the title compound (544 g, 0.94 mol) as pale-yellow crystals. yield: 94%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11]2)=[CH:6][CH:5]=1)[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][N:31]2[CH:35]=[CH:34][N:33]=[C:32]2[CH3:36])[N:27]=[N:28][CH:29]=1>>[ClH:23].[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:24]3[CH:25]=[C:26]([CH2:30][N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[CH3:36])[N:27]=[N:28][CH:29]=3)=[CH:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2ccc(B3OC(C)(C)C(C)(C)O3)cc2c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: CCOc1ccc2ccc(-c3cnnc(Cn4ccnc4C)c3)cc2c1
Product: Cl

Procedure:
The title compound, MS: m/e=345.4 (M+H+), was prepared from 2-(7-ethoxy-naphthalen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-ylmethyl)-pyridazine.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:20])[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][NH:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)CCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Product: CC(C)CCNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the general method of Example 41, 4-hydroxy-3-nitroquinoline (19 g, 0.10 mole) was chlorinated and then reacted with isoamylamine (10.5 g, 0.12 mole) to provide the crude product as a yellow solid. This solid was recrystallized from hexane to provide the desired product as a solid, m.p. 99-100° C. Analysis: Calculated: %C, 64.8; %H, 6.6; N, 16.2; Found: %C, 64.8; %H, 6.6; %N, 16.1.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][C:16]=3[S:17][C:11]=2[N:10]=[C:9]1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-:40][Cr](Cl)(=O)=O>ClCCl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]3[CH2:21][CH2:20][CH2:19][C:18](=[O:40])[C:16]=3[S:17][C:11]=2[N:10]=[C:9]1[C:22]1[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCCC4)cc(OC)c1OC
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCCC4=O)cc(OC)c1OC

Procedure:
3-Benzyl-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one (Compound No.1) (8.2 g, 17.7 mmol) dissolved in dry dichloromethane (30 ml) was added quickly to a mixture of PCC (19.2 g, 89.0 mmol, 500 mol-%) in dichloromethane (200 ml). During refluxing PCC was added several times until the reaction was completed. The reaction mixture was filtered through Celite with dichloromethane. The crude product was purified by flash chromatography. The yield of the compound No. 2 was 4.1 g (48%).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:18])[O:10]CC1C=CC=CC=1>C(O)=O.CO.[Pd]>[CH:9]([O-:18])=[O:10].[F:1][C:2]1([F:19])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH3+:8]
Reactant: O=C(NC1CCCCC1(F)F)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: O=C[O-]
Product: [NH3+]C1CCCCC1(F)F
Reaction time: 18 h
Yield: 78.8 %

Procedure:
To a solution of benzyl (2,2-difluorocyclohexyl)carbamate (0.200 g, 0.7 mmol) in 4% formic acid in methanol (10 mL) was added 10% palladium on carbon (0.15 g, 50% wet). The reaction mixture was stirred under an atmosphere of hydrogen for 18 hrs, filtered through Celite, washing with methanol, and concentrated under vacuum to give an off-white solid (0.1 g). 1H NMR (d6-DMSO, 300 MHz) δ 8.21 (s, 1H), 3.03-2.95 (m, 1H), 2.07-2.04 (m, 1H), 1.76-1.34 (m, 7H). ESI (m/z): 136.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([O:23]C)=O)[C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.[NH3:25]>CO>[OH:1][C:2]1[C:3]2[C:4]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:25])=[O:23])[C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: N
Reactant: COC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cccc(O)c12
Solvent: CO
Product: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cccc(O)c12
Temperature: 80 °C
Yield: 58 %

Procedure:
A mixture of methyl 9-(benzyloxy)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (1.28 g, 3.13 mmol), 10% Pd on carbon (0.567 g, 0.533 mmol) and ammonium formate (0.988 g, 15.7 mmol) in EtOH (8 mL) was heated at reflux for 1 hr. This was filtered and the solvent was removed from the filtrate to leave methyl 9-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (1.10 g) which was carried on. A suspension of methyl 9-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (1.1 g, 3.11 mmol) in 7 N NH3 in MeOH (40 mL) in a sealed microwave vial was heated at 80° C. for 48 h. Filtration afford 9-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide (675 mg, 1.78 mmol, 58% yield) as a solid. MS (ESI) m/z 304.12 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.36 (1H, s), 8.07-8.11 (2H, m), 7.52-7.66 (4H, m), 7.24 (1H, d, J=7.93 Hz), 6.79 (1H, d, J=7.93 Hz).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1C[CH2:18][CH2:17][CH2:16]1.C([Mg]Cl)C=C.[Cl-].[NH4+]>C(OCC)C>[Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH2:18][CH:17]=[CH2:16])([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Reactant: C1CCOC1
Agent: C=CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC1(O)C=CC(O[Si](C)(C)C(C)(C)C)C1
Yield: 98 %

Procedure:
To a solution mixture of 3.5 g of (RS)-4-oxo-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether obtained according to the method described in Org. Syn., Vol 73, p. 36 and 35 ml of tetrahydrofuran was added under nitrogen stream and at 0° C. 11 ml of 2.0 M diethyl ether solution of allylmagnesium chloride and the resulting mixture was stirred at the same temperature for 1 hour. Then the reaction liquid was poured into ice-cooled saturated aqueous ammonium chloride solution and extracted two times with diethyl ether. The combined ether layer was washed with saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 4.1 g of (1RS,4RS)-4-allyl-4-hydroxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 98%
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:8]([C:22](=[O:36])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](=[O:35])(=[O:34])[NH:32][CH3:33])=[CH:27][CH:26]=2)[CH:7]=1)=[O:5])C.[OH-].[K+].Cl>O.CCO.C(OCC)(=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[C:13]3[C:9](=[C:8]([C:22](=[O:36])[NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([S:31](=[O:34])(=[O:35])[NH:32][CH3:33])=[CH:27][CH:26]=4)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:14]=3)[CH:10]=[N:11]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(C(=O)NCc2ccc(S(=O)(=O)NC)cc2)c2cnn(-c3ccc(F)cc3)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(C(=O)O)cc3c2cnn3-c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-4-(4-methylsulfamoyl-benzylcarbamoyl)-1H-indazole-6-carboxylic acid ethyl ester (0.13 g, 0.26 mmol) in H2O (10 mL) and EtOH (20 mL) was added a 2 N solution of aqueous KOH (10 mL, 20 mmol). The mixture was warmed at reflux for 1 hour and cooled to room temperature. The mixture was acidified with 2 N aqueous HCl (pH=3-4) and diluted with ethyl acetate (30 mL). The organic layer was separated and washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether (10 mL) to afford the title compound.
Reaction SMILES: Cl.NC[C:4]1[NH:8][C:7]([C:9](OC)=[O:10])=[CH:6][CH:5]=1.[NH:13]1[CH:17]=CC=[CH:14]1.C(C1NC(C(OC)=O)=CC=1)=O.CN(C(N(C)C)=C1N=CC=C1)C>>[CH:9]([C:7]1[NH:8][CH:4]=[CH:5][CH:6]=1)=[O:10].[CH3:14][NH:13][CH3:17]
Reactant: c1cc[nH]c1
Reactant: COC(=O)c1ccc(CN)[nH]1
Agent: CN(C)C(=C1C=CC=N1)N(C)C
Agent: COC(=O)c1ccc(C=O)[nH]1
Agent: Cl
Product: CNC
Product: O=Cc1ccc[nH]1

Procedure:
Preparation of methyl 5-(aminomethyl)pyrrole-2-carboxylate hydrochloride (X) can be accomplished by the approach shown in Scheme 11. A three-step conversion of pyrrole into methyl 5-formylpyrrole-2-carboxylate has been described (Org. Syn., Coll Vol. 4, 1963, p831). Alternatively, Muchowski (Tetrahedron Lett., 1988, 29, 777) has described the bis(dimethylamino)azafulvene dimer resulting from treatment of 2-formylpyrrole with dimethylamine. Such species may be lithiated at low temperatures and captured with a variety of electrophiles, including methyl chloroformate, to also give methyl 5-formylpyrrole-2-carboxylate. The aldehyde group is then converted to the oxime under standard conditions and finally reduced by catalytic hydrogenation in the presence of hydrochloric acid to give the target linker (X). ##STR44##
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:5]([N:14]=1)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2.[F:15][C:16]([F:30])([F:29])[C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>CC(C)CCO.[Cu]I>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:9]=[C:4]2[N:3]=[C:2]([N:26]3[CH2:27][CH2:28][N:23]([C:18]4[C:17]([C:16]([F:30])([F:15])[F:29])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:24][CH2:25]3)[NH:14][C:5]2=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cnc2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: FC(F)(F)c1cnc2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-imidazo[4,5-b]pyridine from step (d) above (45 mg, 0.203 mmol), 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (47 mg, 0.203 mmol, Fluorochem), triethylamine (59 μL, 0.406 mmol, Aldrich) and copper(I) iodide (1 mg, 0.005 mmol, Aldrich) in 3-methyl-butan-1-ol (0.5 mL, Aldrich) was subjected to microwave irradiation at 220° C. for 0.5 h. The reaction mixture was cooled to room temperature and was filtered. The filtrate was purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound as a colorless solid. MS (ESI, positive ion) m/z: 417 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([CH:21](OS(C)(=O)=O)[CH3:22])[CH:12]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:12]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH3:13])[CH:21]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(OC1CCCCO1)C(CCNC(=O)OC(C)(C)C)C(C)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(OC1CCCCO1)C1CCN(C(=O)OC(C)(C)C)C1C
Temperature: 38 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a solution of N-t-butyloxycarbonyl-N-{3-(1-methanesulfonyloxyethyl)-4-(tetrahydropyran-2-yloxy)pentyl}amine (17 g) in dimethylformamide (200 ml) was added sodium hydride (6.6 g in 60% oil) at 0° C. After stirring for 4 hours at 38° C., the solution was poured into a mixture of ethyl acetate (400 ml) and water (400 ml). The organic layer was washed with water, 1N-hydrochloride solution, saturated sodium bicarbonate, and brine successively. The dried solution was evaporated and then the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (3:1, V/V) to give 1-t-butyloxycarbonyl-2-methyl-3-(1-tetrahydropyranyloxyethyl)pyrrolidine (10.5 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C=CC(C2C=CC(C3OC(C4C=CC=CC=4)=CN=3)=CC=2)=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:36][CH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2ccccc2c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(-c2ccc(-c3ncc(-c4ccccc4)o3)cc2)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1[nH]c(CBr)cc2ccccc12
Temperature: 25 °C

Procedure:
To a refluxing solution of 3-methylisoquinolin-1(2H)-one (1.7 g, 10.69 mmol) and 2-(4-biphenyl)-5-phenyloxazole (120 mg) in CCl4 (30 mL) was added N-bromosuccinimide (1.9 g, 10.7 mmol) in portions. The reaction mixture was stirred at reflux for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered and concentrated to give the crude product, which was used for the next step without further purification. LC-MS: m/z 238 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16]CN[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.F[C:18](F)(F)[C:19](O)=O>C(Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:12][CH2:13][CH2:11][N:10]([CH:6]([C:19]4[CH:18]=[CH:8][CH:9]=[CH:4][CH:3]=4)[CH3:5])[CH2:16]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1cc2[nH]ncc2cc1NC1CCNCC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound prepared in Example 181 (700 mg) was dissolved in chloroform (3 ml), and 95% trifluoroacetic acid (3 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 2 hr and was then concentrated. Potassium carbonate (690 mg) and dimethylformamide (3 ml) were added to the concentrate, and the mixture was stirred. A solution (2 ml) of (1-bromoethyl)benzene (408 mg) in acetonitrile was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (3 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give 185 mg of the title compound as two diastereomers (ratio=ca. 50:50).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH:1]1([NH:4][C:5]2[N:6]=[CH:7][C:8]([C:11]#[C:12][C:14]3[CH:15]=[C:16]([C:21]4[NH:25][C:24]5[CH:26]=[C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]6)[CH:28]=[CH:29][C:23]=5[N:22]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])=[CH:9][N:10]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Reactant: C#Cc1cnc(NC2CC2)nc1
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1cnc(NC2CC2)nc1

Procedure:
The title compound was synthesized from N-cyclopropyl-5-ethynylpyrimidin-2-amine (as prepared above) and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The title compound was obtained as a brown solid. Mp: 136-137° C.; 1H NMR (300 MHz, CDCl3) δ: 8.40 (2H, s), 8.21 (1H, s), 7.96-7.99 (1H, d, J=9.0 Hz), 7.52-7.55 (1H, d, J=9.0 Hz), 7.49-7.52 (1H, d, J=9.0 Hz), 7.23-7.26 (1H, d, J=9.0 Hz), 7.15-7.18 (1H, d, J=9.0 Hz), 5.81 (1H, s), 5.28 (1H, s), 3.57 (2H, s), 2.78 (1H, s), 2.55 (8H, brs), 2.46 (3H, s), 2.32 (3H, s), 0.83-0.87 (2H, m), 0.56 (2H, brs). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C29H32N7: 478.2714. found: 478.2718.