Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:17]([O:18][C:19](=[O:22])[CH2:20][CH3:21])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1.[N+:30]([O-])([OH:32])=[O:31].OS(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([N+:30]([O-:32])=[O:31])=[CH:9][N:8]([C@@H:11]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:17]([O:18][C:19](=[O:22])[CH2:20][CH3:21])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2ccc3c(Cl)ncnc32)O[C@@H]1COC(C)=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc([N+](=O)[O-])c3c(Cl)ncnc32)O[C@@H]1COC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of the product from Step 2 (700 mg, 1.64 mmol) in DCM was cooled to 0° C. in ice/water bath. Meanwhile fuming HNO3 (1 mL) and H2SO4 (1 mL) were premixed and added dropwise to a vigorously stirred DCM solution containing the protected nucleoside and the mixture. The solution was stirred at 0° C. for 1.5 hours then quenched by pouring into an ice cold saturated Na2CO3 solution (125 mL). The product was extracted with DCM and the organic layers were dried over Na2SO4 and concentrated in vacuo. The crude purified by Isco CombiFlash purification system with a 40 g silica gel column and 0-35% MeOH gradient in DCM over 30 minutes to afford 440 mg (52%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][C:24]1[O:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][C:24]2[O:32][C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: c1cnc2oc(CC3CCCCN3)cc2c1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3cccnc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared, using the method of Example 4, from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.171 g, 0.72 mmol) and (RS)-2-piperidin-2-ylmethyl-furo[2,3-b]pyridine, D11 (0.13 g, 0.60 mmol) as a colourless solid (0.129 g, 49%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[C:19]1([CH2:25][CH2:26][C:27](OC)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.C(O)(=O)C.O>[O:28]=[C:27]([CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)CCc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COP(=O)(CC(=O)CCc1ccccc1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a stirred solution of dimethyl methylphosphonate (8.85 g, 0.071 mol) in 150 ml of anhydrous THF at -78° C. was added dropwise a solution of n-butyl lithium in hexane (1.67N, 43.1 ml, 0.072 mol) under argon atmosphere, and the mixture was stirred for 30 minutes. To this reaction solution was added methyl 3-phenylpropionate (5.0 g, 0.030 mol) in 10 ml of anhydrous THF. After being stirred for 30 minutes, the reaction mixture was allowed to warm to 0° C., diluted with 5.5 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue and the mixture was extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 2-oxo-4-phenylbutylphosphonate (7.39 g, 0.029 mol, yield 96%, b.p. 104°-105° C./0.23 mmHg).
Reaction SMILES: CC1N=C(C2C=CC=C(C)N=2)C=CC=1.CC1C=CN=C(C2C=C(C)C=CN=2)C=1.CC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.Cl[C:45]1[C:46]([C:54]([OH:56])=[O:55])=[N:47][C:48]([Cl:53])=[C:49]([Cl:52])[C:50]=1[Cl:51]>[Zn].C(#N)C>[Cl:51][C:50]1[C:49]([Cl:52])=[C:48]([Cl:53])[N:47]=[C:46]([C:54]([OH:56])=[O:55])[CH:45]=1
Reactant: O=C(O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: Cc1cc2cccnc2c2ncccc12
Agent: Cc1cccc(-c2cccc(C)n2)n1
Agent: Cc1ccnc(-c2cc(C)ccn2)c1
Solvent: CC#N
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reaction time: 0.08 h

Procedure:
Three 8 mL scintillation vials were charged with NiCl2.6H2O (12.0 mg, 0.051 mmol) and one of the following ligands: 6,6′-dimethyl-2,2′-bipyridyl, 4,4′-dimethyl-2,2′-bipyridyl or 5-methyl-1,10-phenanthroline (2:1 ligand/metal ratio). The vials were closed and purged with nitrogen for 5 min, after which the vials were charged with DMF (4.5 mL) and water (0.5 mL). The mixtures were allowed to stir for 5 min. To each of the vials was added zinc dust (0.22 g, 3.4 mmol), and the mixtures were allowed to stir under nitrogen for 35 min. Solid 3,4,5,6-tetrachloropicolinic acid (0.10 g, 0.4 mmol) was added to each through the top of the reactor. The reaction mixtures were allowed to stir at ambient temperature, and samples were removed periodically to determine reaction kinetics. The samples (˜0.01 mL of reaction mixture diluted to 1.5 mL with acetonitrile) were analyzed by a calibrated HPLC method.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:17]=[CH:16][C:15]2[C:11](=[CH:12][N:13]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=2)[C:10]=1[CH3:25])=[O:8].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:2][O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:17]=[CH:16][C:15]2[C:11](=[CH:12][N:13]([CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:30][CH:31]=4)[CH2:23][CH2:24]3)[N:14]=2)[C:10]=1[CH3:25])=[O:8]
Reactant: COCCNC(=O)c1ccc2nn(CC3CCNCC3)cc2c1C
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCCNC(=O)c1ccc2nn(CC3CCN(C(=O)c4ccc(OC(F)(F)F)cc4)CC3)cc2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg of the amine prepared in Example 1a were first dissolved in 1.5 ml pyridine. 101 mg of 4-(trifluoromethoxy)benzoyl chloride were then added and the mixture stirred for 30 min at RT. The reaction mixture was then treated with some toluene and concentrated. The residue was taken up in ethyl acetate and washed twice with water, twice with saturated sodium hydrogen carbonate solution (pH 9) and once with saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated. The residue was purified chromatographically on the Biotage SP4. Gradient: ethyl acetate/methanol 0-10%. Yield: 118.2 mg of the title compound.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>CC(N(C)C)=O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:28]2[NH:18][C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: NC(=O)c1ccccc1N
Reactant: COc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.8 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.1 g, 0.3 mmol) was added to a solution of 2-aminobenzamide (30) (1.0 g, 7.3 mmol) and 3-methoxybenzaldehyde (34) (1.0 g, 7.3 mmol) in DMAC (20 ml). The mixture was stirred at room temperature for 2 h and then poured into ice water (200 ml). The precipitate was collected, washed with water, then dried and purified by column chromatography (silica gel-ethyl acetate/n-hexane) to afford 43 (70.0 mg, 4.0%) and 61 (1.7 g, 89.0%) as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[C:4]([NH:12][C:21]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=2)=[O:22])[CH:3]=1
Reactant: Nc1cc(F)cc2cnccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cc(F)cc2cnccc12

Procedure:
Prepared from 7-fluoroisoquinolin-5-amine (Description 90) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 364 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:28]2
Reactant: OCc1cccc2c1CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3cccc(CO)c3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 58.5 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of 4-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 250 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(CO)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a solution of 3-bromo-4-methoxy-benzoic acid (8 g, 34.62 mmol) in diethyl ether (120 mL) cooled to 0° C. was added lithium aluminum hydride (1.49 g, 38.08 mmol) in several portions. At the end of addition, the reaction mixture was stirred at 0° C. for 15 min before the icebath was removed. The reaction was continued at room temperature for 12 h. It was cooled back to 0° C. and water (2-5 mL) was carefully added to quench the excess lithium aluminum hydride. Sodium hydroxide (5% solution, 5-10 mL) was then added and the layers were separated after 1 h of stirring. The product was extracted with diethyl ether (2×100 mL). The organic layers were washed with sodium bicarbonate solution (1×10 mL), brine (1×10 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40% ethyl acetate in hexanes yielded (3-bromo-4-methoxy-phenyl)-methanol as a white solid (6.262 g, 83%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:26]=1[C:27]#[N:28]
Reactant: CNC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of (S)-2-(1-aminoethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]imidazole-7-carboxamide (95 mg, 0.37 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (56.8 mg, 0.368 mmol) and 1,1′-dimethyltriethylamine (128 μL, 0.74 mmol) in n-butanol (2 mL) was stirred at 120° C. for 5 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) as eluent to give 2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-1-cyclopropyl-N-methyl-1H-benzimidazole-7-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 8.45-8.40 (m, 1H), 8.05 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.62 (d, J=4 Hz, 1H), 7.31 (br, 2H), 7.24 (d, J=8 Hz, 1H), 7.19 (dd, J=8, 8 Hz, 1H), 5.89-5.81 (m, 1H), 2.83 (d, J=4 Hz, 3H), 1.62 (d, J=8 Hz, 3H), 1.12-1.04 (m, 2H), 0.95-0.79 (m, 2H); LC-MS (ESI) m/z 377.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH:14]=[CH:15][S:16][C:12]=3[C:11]([CH:17]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].N1C=CC=CC=1>CO.CCOCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH:14]=[CH:15][S:16][C:12]=3[C:11]([CH:17]=[N:20][OH:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc(O)cc2)c2ccsc12
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: ON=Cc1ccc(-c2ccc(O)cc2)c2ccsc12
Yield: 85.5 %

Procedure:
To a 5 ml round bottom flask was added 4-(4-hydroxyphenyl)-1-benzothiophene-7-carbaldehyde (42.0 mg, 0.165 mmol), hydroxylamine hydrochloride (23 mg, 0.331 mmol), and anhydrous pyridine (0.027 ml, 0.331 mmol) in MeOH (1.0 ml) was brought to reflux for 1.5 h and then allowed to cool. The mixture was then diluted with ether, washed with water (2 ml) and the organic layer was dried over anhydrous Na2SO4 then passed through a silica plug. Concentration under reduced pressure produced 38 mg (85%) of product as white solid. Further purification by column chromatography (30% EtOAc-hexanes) afforded 22 mg of product suitable for analytical analysis: mp 229.5–230.5° C.; 1H NMR (300 MHz, DMSO-d6): δ 6.92 (2H, d, J=8.4 Hz), 7.41 (3H, appt), 7.49 (1H, d, J=5.7 Hz), 7.59 (1H, d, J=7.6 Hz), 7.85 (1H, d, J=5.6 Hz), 8.49 (1H, s), 9.68 (1H, s), 11.62 (1H, s); MS (ESI) m/z 268 ([M−H]).
Reaction SMILES: C(Cl)(C(Cl)=O)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]1[N:23]2[C@@H:17]([S:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:22]2=[O:24])[CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[CH:12]([C@H:13]1[N:23]2[C@@H:17]([S:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[C:22]2=[O:24])[CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](CO)N2C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C=O)N2C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
To a round bottom flask was added DCM (10 mL) and a 2 M solution of (COCl)2 in DCM (1.57 mL, 3.14 mmol). The reaction mixture was cooled to −78° C. Then, DMSO (0.445 mL, 6.27 mmol) was slowly added to the reaction mixture over 10 min. The reaction mixture was stirred at −78° C. for 15 min. Then, tert-butyl (4S,7S,10aS)-7-(hydroxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (740 mg, 2.24 mmol) in DCM (5 mL) was added to the reaction mixture over 10 min. The reaction mixture was stirred at −78° C. for 1 hr. Then, TEA (1.37 mL, 9.85 mmol) was added to the reaction, which was slowly warmed to 0° C. over 20 min. The reaction mixture was diluted with DCM (50 mL). The organics were washed with saturated aqueous NaHCO3(50 mL), water (100 mL) and saturated aqueous NaCl (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-50% EtOAc/Hex to give tert-butyl (4S,7S,10aS)-7-formyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (450 mg, 1.37 mmol, 61.2% yield) as a white solid. Anal. Calcd. for C15H24N2O4S m/z 328.4. found: 329.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 9.73 (s, 1H), 5.95 (d, J=6.2 Hz, 1H), 5.44-5.21 (m, 1H), 5.02 (d, J=6.0 Hz, 1H), 4.97-4.74 (m, 1H), 3.54-3.24 (m, 1H), 3.06-2.78 (m, 1H), 2.63-2.26 (m, 2H), 2.16-1.75 (m, 3H), 1.52 (d, J=53.2 Hz, 12H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:4]1[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:2].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[CH2:24]([N:8]1[CH2:9][CH2:10][C:11]2[N:3]([CH2:1][CH3:2])[C:4]([CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:5][C:6]=2[CH2:7]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCn1c(Cn2ccnc2-c2ncccn2)nc2cnccc21
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: CCn1c(Cn2ccnc2-c2ncccn2)nc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of 1-ethyl-2-(2-pyrimidin-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine (100 mg, prepared as described in Example 2) and benzyl bromide (42 mg) in 5 mL of acetone in a sealed tube is refluxed overnight and then allowed to cool. The solvent is decanted and 10 mL of MeOH is added to the residue. The resultant solution is transferred to a 25 mL flask, excess NaBH4 is added to the solution. The reaction mixture is then stirred at room temperature for about one hour, treated with 5 mL of 1 N HCl solution and evaporated. The residue is made basic with 1N NaOH solution and extracted with CH2Cl2. The organic extract is dried over Na2SO4, filtered and the solvents removed under reduced pressure. Column chromatography of the residue on silica gel (10% MeOH in CH2Cl2 as eluent) gives 5-benzyl-1-ethyl-2-(2-pyrimidin-2-yl-imidazol-1-ylmethyl)-4,5,6,7-tetrahydro-1H -imidazo[4,5-c]pyridine (50 mg). 1H NMR (CDCl3): 8.85 (d, 1H), 7.20-7.40 (m, 8H), 7.10 (s, H), 6.05(s, 2H), 3.80 (q, 2H), 3.70 (s, 2H), 3,55(s, 2H), 2.78(t, 2H), 2.58 (t, 2H), 0.96 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]OS(C)(=O)=O)=[CH:10][CH:9]=[CH:8][C:7]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].[I-:32].[Na+].C(#N)C>CCOCC>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[C:7]([O:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][I:32]
Reactant: [I-]
Reactant: COC(=O)CCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CCCOc1cccc(CCCCCCI)c1CCC(=O)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.2 %

Procedure:
A mixture of 10.81 g (ca. 23.37 mmol) of crude 2-(4-methoxy-4-oxobutoxy)-6-[6[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester (preceding example), 7.01 g (46.7 mmol) of anhydrous sodium iodide, and 44 mL of dry acetonitrile was stirred at room temperature for 17 hr and then refluxed for 3.5 hr. After being cooled, the mixture was diluted with 200 mL of ether and filtered with suction. The solids were washed thoroughly with ether. The filtrate and washes were combined and washed with 12% aqueous sodium bisulfite, and work-up was completed in the usual manner. There was obtained 11.14 g (97.3%) of 2-(6-iodohexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester as a yellow oil.
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]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Cl>>[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]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:41][C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[O:38][CH3:37])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1
Reactant: COc1ccccc1CCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(O)c3ccccc3c2)C1
Product: COc1ccccc1COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCO)cc2)cc2ccccc12

Procedure:
In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(4-hydroxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-methoxybenzyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-[4-(2-methoxy-benzyloxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless oil; MS: 652 (M+K)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:28])[C:14]([C:16]2[C:24]3[C:19](=[C:20](Cl)[N:21]=[CH:22][C:23]=3[O:25][CH3:26])[NH:18][CH:17]=2)=[O:15])[CH2:9][CH2:8]1.[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[Sn](CCCC)(CCCC)CCCC>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:28])[C:14]([C:16]2[C:24]3[C:19](=[C:20]([C:30]4[S:29][CH:33]=[CH:32][N:31]=4)[N:21]=[CH:22][C:23]=3[O:25][CH3:26])[NH:18][CH:17]=2)=[O:15])[CH2:9][CH2:8]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(c4ccccn4)CC3)c12
Product: COc1cnc(-c2nccs2)c2[nH]cc(C(=O)C(=O)N3CCN(c4ccccn4)CC3)c12

Procedure:
Example 50, was prepared from 1-(pyridin-2-yl)-4-[(4-methoxy-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine and thiazol-2-yl tributyltin, Precursor 14a-21, according to the general method above to provide 1-(pyridin-2-yl)-4-[(4-methoxy-7-(thiazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MS m/z: (M+H)+ Calc'd for C24H25N6O4S: 477.13; found 477.22. HPLC retention time: 0.98 minutes (column A).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[C:8]([C:12](OCC)=[O:13])=[CH:7][N:6]([CH3:17])[C:5]=2[S:4][C:3]=1[CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CO>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:12]([C:8]2[C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[C:3]([CH2:18][N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[S:4][C:5]=3[N:6]([CH3:17])[CH:7]=2)=[O:13])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cn(C)c2sc(CN3CCOCC3)c(C)c2c1=O
Reactant: NCc1ccc(Cl)cc1
Solvent: CO
Product: Cc1c(CN2CCOCC2)sc2c1c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 190 °C

Procedure:
A mixture of ethyl 3,7-dimethyl-2-(morpholin-4-ylmethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (Preparation 28, 700 mg) and 4-chloro-benzylamine (1.25 mL) is heated to 190° C. under a nitrogen atmosphere for 1 h. The reaction mixture is allowed to cool briefly and methanol (10 mL) is added. After cooling to room temperature, the product is filtered and washed with methanol and diethyl ether to afford 634 mg of the title compound as a white solid. Physical characteristics. M.p. 222-224° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.67, 8.66, 7.41-7.33, 4.52, 3.92, 3.67, 3.59, 2.51, 2.47; MS (ESI+) m/z 446 (M+H)+. Anal. Found: C, 59.11; H, 5.47; N, 9.32; Cl, 7.96; S, 7.17.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C[O-].[Na+].I[CH2:15][CH2:16][CH3:17]>C(O)C>[CH2:15]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH2:10])=[O:9])[CH2:16][CH3:17]
Reactant: CCCI
Reactant: NC(=O)c1ccccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1C(N)=O

Procedure:
A 130 gm. portion of salicylamide in 500 ml. of ethanol is reacted with 52.4 gm. of sodium methoxide and 164.9 gm. of 1-iodopropane by heating at reflux. The mixture is cooled, precipitated in 1500 ml. of water and the solid is recrystallized from hot ethanol giving o-propoxybenzamide.