Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:19]1[N:23](COCCO)[C:22]2[N:29]=[C:30]([NH2:34])[N:31]=[C:32]([OH:33])[C:21]=2[N:20]=1>CN(C)C=O.CN(C)C1C=CN=CC=1>[O:3]([CH2:4][CH2:5][N:11]([C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[C@H:12]([C:16]([O:18][N:23]1[CH:19]=[N:20][C:21]2[C:32](=[O:33])[NH:31][C:30]([NH2:34])=[N:29][C:22]1=2)=[O:17])[CH:13]([CH3:14])[CH3:15])[CH3:1]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COCCN(C(=O)OCc1ccccc1)[C@H](C(=O)On1cnc2c(=O)[nH]c(N)nc21)C(C)C
Reaction time: 8 h
Yield: 141.3 %

Procedure:
CBZ-L-valine (167 g) was dissolved in dimethylformamide (DMF) (750 ml) and cooled. A cold solution of N,N-dicyclohexyl-carbodiimide (DCC) (153.5 g) in DMF (266 ml) was added followed by acyclovir (111.7 g) in a single portion. 4-(dimethyl-amino)pyridine (9.4 g) was then added and the mixture stirred cold overnight. A white precipitate of the by-product was then removed by filtration. The filtrate was reduced in volume as before to give the title compound (215.3 g).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[ClH:20]>O>[CH2:1]([Cl:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCl

Procedure:
A 1 l jacketed glass reactor with a glass paddle stirrer and immersed tube for reactant metering is initially charged with 220 g of N-n-octylalkylpyridinium chloride (prepared according to Example 2) and adjusted to a temperature of 150° C. 447 g of n-octadecanol are introduced uniformly via an immersed tube over 5 hours. Gaseous hydrogen chloride is metered in via an immersed tube in a slight stoichiometric excess over the entire reaction time, and the water of reaction formed is simultaneously removed via distillation. The performance of the reaction and the workup of the reaction mixture are analogous to Example 4a. After a total reaction time of 8 h (including 3 hours of postreaction), the conversion based on n-octadecanol is 99.8%.
Reaction SMILES: CO[C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:27]2[O:31]C3C=CC=CC=3[CH:28]=2)[C:14](=[O:26])[CH:15]=[CH:16][CH2:17][O:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:6][CH:5]=1.[NH2:37][OH:38].CO.[ClH:41]>C1COCC1.O.[OH-].[Na+]>[ClH:41].[O:31]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:28]=[C:27]1[N:13]([C:14](=[O:26])[CH:15]=[CH:16][CH2:17][O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:37][OH:38])=[O:36])=[CH:5][CH:6]=1
Reactant: NO
Reactant: COC(=O)c1ccc(OCCN(C(=O)C=CCOCCN2CCCC2)c2cc3ccccc3o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(NO)c1ccc(OCCN(C(=O)C=CCOCCN2CCCC2)c2cc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{2-[3-benzofuran-2-yl-4-(2-pyrrolidin-1-ylethoxy)but-2-enoyl-amino]ethoxy}benzoic acid methyl ester (90 mg, 0.182 mmol) in THF (1 ml), a solution of hydroxylamine in 50% water (1 ml) and 1N NaOH (0.050 ul) were added. Methanol was added dropwise until a homogeneous solution was obtained and the reaction mixture was stirred overnight at rt. After cooling the mixture at 0° C., 6 N HCl was added until pH 7 was reached. The crude solid was filtered and purified by HPLC to give the title compound (17 mg) as white solid. LC/MS, M+1: 494.3; M−1: 492.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C@@H:20]([OH:36])[C@H:19]([CH3:37])[O:18][C:17]1=[O:38])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:11]([O:10][C:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:16]1[C:17](=[O:38])[O:18][C@@H:19]([CH3:37])[C@H:20]([O:36][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[C@@H:21]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:22][O:23][CH2:24]1)=[O:15])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)C(=O)Cl
Reactant: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](Cc2cccc3ccccc23)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)O[C@@H]1[C@@H](Cc2cccc3ccccc23)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.2 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-hydroxy-9-methyl-7-(1-naphthylmethyl)-2-oxo-1,5-dioxonan-3-yl]carbamate (290 mg, 0.548 mmol) and DMAP (201 mg, 1.64 mmol) in CH2Cl2 (2.7 mL) was added isobutyryl chloride (86 μL, 0.821 mmol) slowly to the flask and the resulting solution was stirred at room temperature for 20 h. The reaction mixture was dissolved in CH2Cl2 (4 mL), treated with Celite®, the solvent evaporated, and the adsorbed crude material purified by flash chromatography (SiO2, 0→15% EtOAc/hexanes) to provide [(3S,6S,7R,8S)-3-[bis(tert-butoxycarbonyl)amino]-6-methyl-8-(1-naphthylmethyl)-4-oxo-1,5-dioxonan-7-yl]2-methylpropanoate (270 mg, 82%) as a white powder: mp 130-132° C.; 1H NMR (400 MHz, CDCl3) δ 8.01-7.93 (m, 1H), 7.84 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.54-7.41 (m, 2H), 7.37 (dd, J=8.2, 7.0 Hz, 1H), 7.28 (dd, J=7.0, 1.3 Hz, 1H), 5.20 (dd, J=8.7, 5.7 Hz, 1H), 5.11 (app t, J=9.3 Hz, 1H), 5.08-4.97 (m, 1H), 4.06 (dd, J=11.8, 5.7 Hz, 1H), 3.86 (dd, J=11.9, 8.7 Hz, 1H), 3.66 (d, J=11.0 Hz, 1H), 3.50 (dd, J=10.8, 6.4 Hz, 1H), 3.23 (dd, J=14.0, 3.1 Hz, 1H), 2.74-2.55 (m, 2H), 2.37-2.20 (m, 1H), 1.42 (s, 18H), 1.37 (d, J=6.2 Hz, 3H), 1.26 (app dd, J=7.0, 4.4 Hz, 6H); ESIMS m/z 622 ([M+Na]+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[SH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CN(C=O)C.O>[OH:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])=[CH:27][CH:28]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccco1
Temperature: 80 °C
Yield: 97.1 %

Procedure:
The product of Example 18a (1.00 g, 2.89 mmol) was dissolved in DMF to which K2CO3 (801 mg, 5.79 mmol), and 4-mercapto-phenol (366 mg, 2.89 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water which was then extracted with ethyl acetate to isolate the desired compound (1.00 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:15])[C:11]=2[O:13][CH3:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>O1CCCC1>[NH2:15][C:10]1[C:11]([O:13][CH3:14])=[C:12]2[C:7]([CH2:6][CH2:5][C:4]2=[CH:3][CH2:2][NH:1][C:23](=[O:25])[CH3:24])=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(N)ccc2c1C(=CCN)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(N)ccc2c1C(=CCNC(C)=O)CC2
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
3-(2-Aminoethylidene)-4-methoxyindan-5-amine (15.3 mg, 0.076 mmol) and triethylamine (21.2 μL, 0.152 mmol) were dissolved in tetrahydrofuran (0.9 mL), a solution of acetic anhydride (7.18 μL, 0.076 mmol) in tetrahydrofuran (0.1 mL) was added under ice-cooling, and the mixture was stirred for 15 min. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) to give the title compound (16.2 mg, yield 87%).
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[Cl-].[Cl-].[NH4+]>O1CCCC1.O>[ClH:1].[CH2:8]([C:10]1([OH:15])[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1C(c1ccccc1)N1CCCCC1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(Cc2ccccc2)CCCCC1C(c1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.7 %

Procedure:
The base was freed from 2.5 g (8.12 mmole) of the hydrochloride of 2-(phenylpiperidin-1-ylmethyl)cyclohexanone obtained according to stage 1 with 25 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without Heating (500 to 10 mbar). 2.00 g (7.4 mmole) of this base were dissolved in 10 ml of tetrahydrofuran, added dropwise to 4.4 ml (8.8 mmole) of benzylmagnesiun chloride (2 M solution in tetrahydrofuran) while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on a rotary evaporator (500 to 10 mbar). 2.29 g of crude base (85.4% of theory) were obtained, from which 1.05 g of 1-benzyl-2-(phenylpiperidin-1-ylmethyl)cyclohexanol, hydrochloride (35.7% of theory) was obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 218° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19]Cl)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19][N:42]3[CH2:43][CH2:44][CH:39]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:40][CH2:41]3)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2nc3ccc(OCCCl)cc3n2Cc2ccccc2)cc(OC)c1OC
Reactant: C1CCN(C2CCNCC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(-c2nc3ccc(OCCN4CCC(N5CCCCC5)CC4)cc3n2Cc2ccccc2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
The title compound was prepared by reacting the compound of Example 76, supra, (0.45 g, 1.0 mmol) with 4-(piperdin-1-yl)piperidine (2.0 g, 11.9 mmol) in the presence of the base N,N-diisopropylethylamine, tetra-n-butylammonium iodide and acetonitrile at 80° C. After incubating overnight at 80° C. the reaction was washed with water (2×500 ml), followed by a wash with a saturated sodium chloride solution (1×500 ml). The organic phase was then dried over potassium carbonate and the solvents were removed in vacuo to yield a light brown oil. The desired product was purified by chromatography and triturated with diethyl ether to yield a light brown powder, which was removed by filtration and washed with diethyl ether to yield the purified title compound. MS 584, 585, NMR, IR, mp 143° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6](=[O:36])[C:7]([NH:32][C:33](=[O:35])[CH3:34])([CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=2)[C:14]1=[O:31])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]>C(O)C>[CH2:3]([O:5][C:6](=[O:36])[C:7]([NH:32][C:33](=[O:35])[CH3:34])([CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=2)[CH:14]1[OH:31])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2O
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a solution of sodium borohydride (75 mg, 2.00 mmol) in 5 ml of ethanol at room temperature is added 2-acetylamino-2-(6-octyl-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-malonic acid diethyl ester (compound 5) (1.00 g, 2.1 mmol) in 5 ml of ethanol. The reaction mixture is stirred at room temperature under argon for an additional hour, quenched by the addition of water (20 mL) and methylene chloride (20 mL). The organic layer is removed and the aqueous layer is extracted with methylene chloride (2×20 mL). The combined organic layers were washed with brine (2×20 mL) and dried over magnesium sulfate and concentrated under vacuum. The residue is purified by column chromatography (silica gel, 20% ethyl acetate in hexanes) to provide 755 mg of compound A (75%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[I:15])=[CH:5][CH:4]=1.[CH2:16]([C:20]1[NH:21][C:22]([CH:26]=[O:27])=[C:23]([Cl:25])[N:24]=1)[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:16]([C:20]1[N:21]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[I:15])=[CH:5][CH:4]=2)[C:22]([CH:26]=[O:27])=[C:23]([Cl:25])[N:24]=1)[CH2:17][CH2:18][CH3:19]
Reactant: BrCc1ccc(-c2ccccc2I)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2I)cc1
Reaction time: 24 h

Procedure:
A solution of 4-(bromomethyl)-2'-iodobiphenyl (9.23 g; preparable as described in Example 2(b)) in dry dimethylformamide (50 ml) was added to a stirring mixture of 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (preparable as described in Drugs of the Future (1991), Vol. 16, p 305), anhydrous potassium carbonate (6.9 g) and dry dimethylformamide (100 ml), at ambient temperature. Stirring was continued at ambient temperature for 24 hours. Water (200 ml) was added and the resulting mixture was extracted with diethyl ether (500 ml then 200 ml). The combined extracts were washed with water (2×100 ml) and dried over magnesium sulphate. The organic solvent was evaporated and the residual orange oil was purified by flash chromatography on silica gel (eluting with 5% then 30% ethyl acetate in petroleum ether (b.p. 60°-80° C.)) to give the intermediate compound 2-butyl-4-chloro-1-(2'-iodobiphenyl-4-ylmethyl)-1H-imidazol-5-carboxaldehyde as a yellow oil (8.06 g).
Reaction SMILES: [NH2:1][C:2]1([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[C:24]([N:32]=[C:33]=[S:34])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:24]([NH:32][C:33]([NH:1][C:2]1([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1)=[S:34])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC1(c2cccs2)CN(C(=O)OCc2ccccc2)CC1CO
Solvent: C1CCOC1
Product: O=C(NC(=S)NC1(c2cccs2)CN(C(=O)OCc2ccccc2)CC1CO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of benzyl 3-amino-4-(hydroxymethyl)-3-(2-thienyl)pyrrolidine-1-carboxylate (21 g, 63 mmol) in tetrahydrofuran (210 mL) at 0° C. is treated with benzoyl isothiocyanate (8.95 mL, 66.3 mmol. The resulting solution is stirred for 2 hours at 0° C. and quenched by adding an aqueous solution of sodium chloride and methyl-t-butyl ether. The organic layer is separated, dried over magnesium sulfate, and the solvent evaporated to give the title compound (30 g, 95%). ES/MS (m/e): 496 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[NH:3]1>CO.[OH-].[OH-].[Pd+2]>[O:1]=[C:2]1[N:10]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[NH:3]1
Reactant: O=c1[nH]c2ccncc2n1C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]c2ccncc2n1C1CCNCC1
Yield: 85.9 %

Procedure:
A solution of 2-oxo-3-(1-benzylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine (0.5 g, 1.6 mmol) in methanol (250 mL) was shaken with 20% Pd(OH)2 under a hydrogen atmosphere for 48 h at room temperature. The reaction was filtered and concentrated to give the title compound as a white solid (0.3 g). MS 219 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[N:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)CCc2ccncc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)CCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
A mixture of 4-(2-((4-nitrophenyl)sulfonyl)ethyl)pyridine (210 mg, 0.76 mmol) and 10% Pd/C (100 mg) in EtOH (100 mL) was stirred at room temperature for 3 h under H2 atmosphere (balloon). The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (MeOH/DCM=1/50) to afford 100 mg of 4-((2-(pyridin-4-yl)ethyl)sulfonyl)aniline as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.48 (m, 2H), 7.67 (m, 2H), 7.05 (m, 2H), 6.70 (m, 2H), 4.23 (bs, 2H), 3.34-3.28 (m, 2H), 3.07-3.01 (m, 2H).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([O:20]C)[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].ClC1C=CC(OC2C=CC=CC=2)=C(OC)C=1.B(Br)(Br)Br>ClCCl>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([OH:20])[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(Oc2ccccc2)c(OC)c1
Agent: BrB(Br)Br
Agent: COc1cc(Cl)ccc1Oc1ccccc1
Solvent: ClCCl
Product: CCCCCCc1ccc(Oc2ccccc2)c(O)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Compound (4a), 1.4 mmol, was dissolved in 3 mL of anhydrous dichloromethane under nitrogen. The temperature of the solution was lowered to −70° C. To the solution of (3) was added 455 mg (1.8 mmol) of boron tribromide (1.8 mL of a 1.0M boron tribromide in dichloromethane solution). The reaction mixture was stirred at −70° C. for one hour, followed by stirring at room temperature for three hours. The reaction progress was monitored by thin layer chromatography. The solution was then quenched with methanol at −70° C. and concentrated. A suspension of the concentrate was washed with 10% aqueous sodium bicarbonate solution. The organic phase was removed, washed with water and then brine (NaCl), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give the crude product. Purification by flash chromatography on silica gel afforded the analytically pure product (5a): 1H NMR (300 MHz) (CDCl3): δ 7.44-6.76 (m, 8H), 5.58 (s, 1H), 2.66-2.61 (t, 2H), 1.71-1.66 (m, 2H), 1.40-1.34 (m, 6H), 1.00-0.95 (t, 3H).
Reaction SMILES: [N:1]([C:4]1[N:12]2[C:8](=[N:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=32)[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:5]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[NH2:1][C:4]1[N:12]2[C:8](=[N:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=32)[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:5]=1
Reactant: COc1ccc(-c2cc(N=[N+]=[N-])n3c(c2)nc2ccccc23)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1ccc(-c2cc(N)n3c(c2)nc2ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-azido-3-(4-Methoxyphenyl)-pyrido[1,2-a]benzimidazole (12.0 mg, 0.038 mmol) in benzene (2 mL) was added triphenylphosphine (15.0 mg, 0.057 mmol). The mixture was stirred at room temperature for 3 hours and concentrated to a residue. Methanol (2 mL) was added to above residue followed by HCl (conc., 1 mL). Reaction mixture was heated at 60° C. for 2 hours and concentrated. The residue was purified by HPLC (acetonitrile/water) to give 4.6 mg (42%) of T662 as a light yellow solid. 1H NMR (CD3OD): δ 8.50 (1H, d, J=8.8 Hz), 7.80 (2H, m), 7.72 (2H, m), 7.54 (1H, m), 7.27 (1H, s), 7.10 (2H, m), 6.99 (1H, s); MS: 290 (M+H+).
Reaction SMILES: [CH3:1][C:2]([N+:9]([O-:11])=[O:10])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>ClCCl.O.C(N(CC)CC)C>[CH2:24]([NH:31][C:5](=[O:7])[CH2:4][CH2:3][C:2]([CH3:1])([N+:9]([O-:11])=[O:10])[CH3:8])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(CCC(=O)O)[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCC(=O)NCc1ccccc1)[N+](=O)[O-]
Reaction time: 1 h
Yield: 37.4 %

Procedure:
The 4-methyl-4-nitropentanoic acid (4.3 g) obtained above was dissolved in dichloromethane, and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.1 g) and triethylamine (4.5 ml) were added thereto and stirred for 1 hour. Benzylamine (3.4 g) was added thereto and stirred for 1 day. Water was added to the reaction mixture which was then acidified by 2 N hydrochloric acid and extracted with chloroform. The organic phase was washed with a saturated sodium bicarbonate solution and a saturated saline solution and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; ethyl acetate:n-hexane 1:1.5) to give N-benzyl-4-methyl-4-nitropentanoic acid amide (2.5 g, Y.:38%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22](OC)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[NH3:30]>CO>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([NH2:30])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 75 °C
Yield: 64 %

Procedure:
A sealed tube containing a solution of methyl 3-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoate (0.1 g, 0.21 mmol) and NH3 (3 mL of a 7 N solution in MeOH, 21 mmol) was heated at 75° C. for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Trituration with Et2O/MeOH afforded a white solid (0.06 g, 64%): mp 198-201° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.02-8.00 (m, 2H), 7.85-7.75 (m, 2H), 7.70-7.60 (m, 1H), 7.45-7.30 (m, 4H), 7.17 (t, J=3 Hz, 1H), 6.60 (d, J=9 Hz, 1H), 5.32 (s, 2H), 5.18 (s, 2H). ESHRMS m/z 449.0295 (M+H C20H16BrF2N2O3 requires 449.0307).