Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]I.[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][CH2:11][C:12]#[CH:13].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[CH:21]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH2:20][CH2:19]2>O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:13]#[C:12][CH2:11][O:10][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][O:4]1)([OH:26])[CH:21]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH2:20][CH2:19]2
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2=O)cc1
Reactant: C#CCOC1CCCCO1
Agent: C[Mg]I
Solvent: C1CCOC1
Product: COc1ccc(C2CCc3cc(OC)ccc3C2(O)C#CCOC2CCCCO2)cc1
Temperature: 0 °C

Procedure:
A solution of methyl magnesium iodide (22.3 ml. of a 2.86 molar solution in tetrahydrofuran) was added dropwise to a stirred solution of the propargyl tetrahydropyranyl ether thus obtained (10.0 g.) in tetrahydrofuran (200 ml.) which was maintained under an atmosphere of argon, and the mixture was heated under reflux for 30 minutes. A solution of 3,4-dihydro-6-methoxy-2-p-methoxyphenylnaphthalen-1(2H)-one (7.2 g.; prepared by the method described in the Journal of Medicinal Chemistry, 1966, 9, 172) in tetrahydrofuran (100 ml.) was added to the boiling solution and the mixture was heated under reflux for 30 minutes, cooled and poured into ice-cold saturated aqueous ammonium chloride solution (300 ml.). The mixture was extracted three times with diethyl ether (150 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 5:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 6-methoxy-2-p-methoxyphenyl-1,2,3,4-tetrahydro-1-(3-tetrahydropyranyloxypropynyl)naphth-1-ol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH2:35])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(OCC)C>[N+:18]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:35][CH2:34][CH:31]1[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][CH2:30]1)=[CH:10][CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:7]=2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CNc2c([N+](=O)[O-])cnc3cc(-c4ccccc4)ccc23)CC1
Yield: 94.3 %

Procedure:
4-Chloro-3-nitro-7-phenylquinoline (8.35 g, 29.3 mmol) was treated with 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (7.54 g, 35.2 mmol) according to the method described in Part A of Examples 152-156. The crude solid was triturated with water, isolated by filtration, sonicated with diethyl ether, isolated by filtration, and dried for four hours in a vacuum oven at 40° C. to provide 12.78 g of tert-butyl 4-[(3-nitro-7-phenylquinolin-4-ylamino)methyl]piperidine-1-carboxylate as a yellow solid, mp 153-154° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]#[N:19].CN(C)[CH:22]=[O:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[C:18]([C:14]1[S:13][C:17]([CH:22]=[O:23])=[CH:16][CH:15]=1)#[N:19]
Reactant: CN(C)C=O
Reactant: N#Cc1cccs1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C=O)s1
Reaction time: 0.08 h
Yield: 50.3 %

Procedure:
A solution of diisopropylamine (35.3 ml, 0.251 moles) in tetrahydrofuran (500 ml) was cooled to −78° C. under a nitrogen blanket. To this was added 1.6M n-butyllithium in hexanes (157 ml, 0.251 moles) and allowed to stir for 5 min. Then slowly added thiopene-2-carbonitrile (21.33 ml, 0.229 moles) in tetrahydrofuran (115 ml) and allowed to stir. After 45 min. was added N,N-dimethylformamide (88.66 ml, 1.145 moles) at −78° C. Citric acid (40 g) was added after 2 h. followed by water (240 ml) and stirred for 18 h. The reaction was concentrated in vacuo, transferred to a separatory funnel, diluted with brine, and extracted twice with ether. The combined ether layers were washed with brine, dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Chromatography yielded 15.8 g (50%) of 2-cyano-5-formylthiophene (EX-55A) as a brown solid: 1H NMR (300 MHZ, CDCl3) d 10.02 (s, 1H), 7.79 (m, 1H), 7.30 (m, 1H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:5]1=[O:28])[CH:2]=[CH2:3].I[CH2:30][CH2:31][O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35]>>[CH2:1]([C:4]1([CH2:30][CH2:31][O:32][Si:33]([CH:37]([CH3:38])[CH3:39])([CH:34]([CH3:36])[CH3:35])[CH:40]([CH3:41])[CH3:42])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:5]1=[O:28])[CH:2]=[CH2:3]
Reactant: CC(C)[Si](OCCI)(C(C)C)C(C)C
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Product: C=CCC1(CCO[Si](C(C)C)(C(C)C)C(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3.70 g (8.9 mmol) of a mixture of C-3 diastereomers of (5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-oneoxopentanoate (Example 35, Step B) and 20.7 g (63 mmol) of (2-iodoethoxy)triisopropylsilane in dry, degassed THF (60 mL) was added 54.5 mL (54.5 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF slowly via syringe over 6 min. After 10 min, the orange solution was warmed to 40° C. and stirred for an additional 2.25 h. The reaction was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2-25% EtOAc/hexanes, gradient elution) provided the title compound (mixture of C-3 epimers) as a light yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]([OH:27])[OH:26])=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])#[N:2].BrC1C=CC(CCCC(NC2C=CC(S(CC)(=O)=O)=C(C=2)CN[C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=O)=CC=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.B(O)O>>[C:51]([O:50][C:49]([NH:2][CH2:1][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([B:25]([OH:26])[OH:27])=[CH:23][CH:24]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[O:55])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CNC(=O)OC(C)(C)C
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: OBO
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1CNC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 15B (0.541 g, 1.0 mmol) was coupled to 5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl](0.249 g, 1.1 mmol) and then hydrolyzed to the free boronic acid to give 15C (334 mg, 82%) as a peach colored foam. MS (ESI) m/z 505.03 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]2[N:7]=[CH:8][N:9]([C:42]=2[N:43]=[CH:44][N:45]=1)[C@@H:10]1[O:41][C@H:15]([CH2:16][O:17][C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C@@H:13]([OH:14])[C@H:11]1[OH:12])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:55]([CH2:57][CH2:58][O:59][CH2:60]Cl)#[N:56].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[C:6]2[N:7]=[CH:8][N:9]([C:42]=2[N:43]=[CH:44][N:45]=1)[C@@H:10]1[O:41][C@H:15]([CH2:16][O:17][C:18]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C@@H:13]([OH:14])[C@H:11]1[O:12][CH2:60][O:59][CH2:58][CH2:57][C:55]#[N:56])(=[O:3])[CH3:2]
Reactant: N#CCCOCCl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(C)=O)ncnc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(C)=O)ncnc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
N6-Acetyl-5′-O-(4,4′-dimethoxytrityl)adenosine (22.0 g, 36.0 mmol) was dissolved in 170 mL of 1,2-dichloroethane, and 16.3 g of diisopropylethylamine (126 mmol) was added, and 12.1 g of dibutylstannyl dichloride (39.7 mmol) was added subsequently. Then, the reaction was performed at room temperature for 1 hour. Then, the reaction solution was heated up to 80° C., and 4.30 g of chloromethyl 2-cyanoethyl ether (36.0 mmol) was added dropwise, and the solution was stirred for 30 minutes. After the reaction completed, the reaction solution was added to an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by silica gel column chromatography to obtain N6-acetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl) adenosine (7.47 g, yield 33%).
Reaction SMILES: ClC1C=CC(OCC2CCNCC2C2C=CC(Cl)=CC=2)=[N:6]C=1.Cl.C([N:31]1[CH2:36][CH2:35][C@H:34]([C@@H:37]([O:39][C:40]2[CH:45]=[CH:44][C:43]([C:46](F)(F)F)=[CH:42][N:41]=2)[CH3:38])[C@@H:33]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)[CH2:32]1)C1C=CC=CC=1>>[Cl:56][C:53]1[CH:52]=[CH:51][C:50]([C@@H:33]2[C@@H:34]([C@@H:37]([O:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]#[N:6])=[CH:42][N:41]=3)[CH3:38])[CH2:35][CH2:36][NH:31][CH2:32]2)=[CH:55][CH:54]=1
Reactant: Clc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cn1)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: Cl
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CCNC[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of 5-chloro-2-[(3RS, 4RS)-3-(4-chloro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride (example 1, step h) the title compound was prepared from 2-{(S)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethoxy}-5-trifluoromethyl-pyridine as white foam as the respective HCl salt. MS (m/e): 342.1 [(M+H)+].
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=1)CCC.Br[C:29]1[N:30]=[C:31]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:45]([N:42]1[CH2:41][CH2:40][N:39]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:38]=[C:29]([C:6]3[CH:7]=[CH:8][C:9]([CH:12]([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=3)[N:30]=2)[CH2:44][CH2:43]1)[CH3:46]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(C)CC(=O)OCC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CC(C)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Yield: 74.8 %

Procedure:
Ethyl 3-(4-Tributylstannylphenyl)butyrate (5.46 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.33 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.19 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted in ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(1-ethoxycarbonylpropan-2-yl)phenyl]isoquinoline (1.34 g) as a pale yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[N:4].Cl[O-].[Na+].S(=O)(=O)(O)O.S(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[N:1]([C:2]([CH3:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[N:4])=[N:1][C:2]([CH3:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[N:4]
Reactant: CC(C)CC(C)(N)C#N
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
In the same manner as in Example 1, 2-amino-2,4-dimethylpentanonitrile and sodium hypochlorite were reacted. By iodometry, it was found that the total oxidative compounds in both the water and ethyl acetate phases after reaction was 0.05 equivalent. The reaction mixture was adjusted to a pH of 6 with a dilute sulfuric acid, and a solution of 6.5 g (0.125 equivalent) of sodium bisulfite in 30 ml of water was added thereto. The resulting mixture was stirred at 15° C. for 30 minutes to effect the reduction. Thereafter, the ethyl acetate phase was separated from the water phase, and the ethyl acetate in the organic phase was removed by distillation. Water was added to the residue and precipitated white crystals were filtered, washed with water and dried to obtain 26.0 g of 2,2'-azobis(2,4-dimethylvaleronitrile). Yield was 89 mole %. The product was analyzed by iodometry, and it was found that the amount of oxidative impurities was 100 ppm or less and that the purity of the product was 99.5%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Si](C)(C)C)=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2].[I:28]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:28])=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)c1[nH]c2c(F)cncc2c1Nc1ccc([Si](C)(C)C)cc1F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2c(F)cncc2c1Nc1ccc(I)cc1F
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A solution of 7-fluoro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (500 mg, 1.28 mmol) in CH2Cl2 (15 mL) was cooled to 0-5° C. and treated dropwise with iodine monochloride solution (2.6 mL, 1M in CH2Cl2). The mixture was stirred at 0-5° C. for one hour and then quenched by addition of a saturated aqueous sodium thiosulfate solution (10 mL). The mixture was diluted with water and dichloromethane. The precipitate formed was filtered off, washed with diethyl ether and dried under vacuum at 50° C. to give the title compound as a yellow solid (218 mg, 38%). LCMS (method B): RT=2.87 min, M+H+= 444.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1.CI.O>C1COCC1>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH2:16][CH3:2])[CH:8]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Yield: 67 %

Procedure:
To a yellow solution of 2,2,6,6-TMPH (8.30 g, 58.88 mmol) in THF (9 mL) was added n-BuLi (25 mL) slowly at −78° C. under protection of nitrogen. Thereto, the mixture was warmed up to room temperature, stirred at this temperature for an hour, and then cooled to −78° C. again. A solution of 4-bromo-2-methylbenzoic acid (6.0 g, 28.04 mmol) in THF (60 mL) was added slowly, kept stirring at this temperature for an hour, added MeI (7.96 g, 56.07 mmol) solution (in 35 mL THF), the mixture above was then stirred overnight at room temperature. LCMS showed the reaction was completed. Water was added, the mixture was then washed with ethyl acetate. The aqueous phase was acidified to pH=1, extracted with ethyl acetate twice, and concentrated the organic phase to a residue which was trituated with PE/EA=1/1 to give 4.28 g of the title compound (67%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=O)=[N:6][CH:7]=1.FC1C=CC2N(C(C3(N(C)C)CCCC3)=NN=2)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)N(C(=O)NNc1ccc(F)cn1)C(C)C
Agent: CN(C)C1(c2nnc3ccc(F)cn23)CCCC1
Product: CC(C)N(c1nnc2ccc(F)cn12)C(C)C

Procedure:
The title compound was prepared starting from Intermediate 103a using analogous procedures to those described in Intermediate 99c. 1H NMR (400 MHz, CDCl3): 1.09 (12H, d, J=6.5 Hz), 3.60-3.79 (2H, m), 7.11-7.24 (1H, m), 7.44-7.62 (1H, m), 7.98-8.05 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: CCCn1c(=O)cc(N)n(C)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCn1c(=O)c(N=O)c(N)n(C)c1=O
Temperature: 65 °C
Yield: 535.8 %

Procedure:
6-Amino-1-methyl-3-n-propyluracil (13.2 g, 7.3 mmol) was dissolved in 10-15 ml of acetic acid and the solution was warmed on a hot plate to 60-70° C. Then, with stirring, a solution of sodium nitrite (5.3 g, 7.7 mmol) in 100 ml of water was added in 10 ml portions over 10 minutes. A brownish-purple precipitate formed. The reaction mixture was cooled to 10° C. and the precipitate was collected by vacuum filtration, washed with 10 ml of acetone, and air-dried to give 8.3 g (55%) of 6-amino-1-methyl-5-nitroso-3-propyluracil as a purple solid. 1H NMR (DMSO-d6 +D2O) δ 0.90 (t, J=7 Hz, 3 H), 1.62 (sextet, J=7 Hz, 2 H), 3.26 (s, 3 H), 3.87 (t J=7 Hz, 2 H).
Reaction SMILES: [C:1]1([Se:7][C:8]2[CH:21]=[CH:20][C:11]3[N:12]=[C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])[NH:14][C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(O)(=O)C>[C:1]1([Se:7]([C:8]2[CH:21]=[CH:20][C:11]3[N:12]=[C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])[NH:14][C:10]=3[CH:9]=2)=[O:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Nc1nc2ccc([Se]c3ccccc3)cc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc([Se](=O)c3ccccc3)cc2[nH]1
Temperature: 25 °C

Procedure:
A solution of methyl 5-phenylseleno-2-benzimidazolecarbamate (5.0 g, 14.5 mmole) in acetic acid (50 ml.) was cooled to 10°-15° C. while 85% 3-chloroperbenzoic acid (3.0 g, 14.7 mmole) was added in portions. The solution was then allowed to warm to room temperature, and the solvent was evaporated under reduced pressure. The residue was stirred with sodium carbonate solution and filtered, and the solid product was crystallised from a mixture of equal parts of acetic acid and methanol, to give methyl 5-phenylseleninyl-2-benzimidazolecarbamate, m.p. 222° C. with decomposition. All other 5-phenylseleninylbenzimidazole carbamates of the invention may be manufactured in exactly the same manner, by using the appropriate 1-6C alkyl 5-(optionally substituted phenyl)seleno-2-benzimidazolecarbamate in place of methyl 5-phenylseleno-2-benzimidazolecarbamate.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.[N:27]1([CH2:32][CH2:33]O)[CH:31]=[N:30][CH:29]=[N:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:33][CH2:32][N:27]3[CH:31]=[N:30][CH:29]=[N:28]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: OCCn1cncn1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ccnc2cc1OCCn1cncn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 44.6 %

Procedure:
Diethyl azodicarboxylate (1 ml, 6.5 mmol) was added dropwise to a solution of 4-chloro-7-hydroxy-6-methoxyquinoline (845 mg, 4.0 mmol), (prepared as described for the starting material in Example 3), 2-([1,2,4]-triazol-1-yl)ethanol (500 mg, 4.4 mmol), (Ann. Pharm. Fr. 1977, 35, 503-508), and triphenylphosphine (1.7 g, 6.5 mmol) in methylene chloride (40 ml) under argon. After stirring for 4 days at ambient temperature, the insoluble materials were removed by filtration. The volatiles were removed by evaporation and the residue was purified by column chromatography on silica eluting with methylene chloride/acetonitrile/methanol (75/20/5). The product was purified by a second chromatography on neutral alumina eluting with methylene chloride/acetonitrile/methanol (75/20/5). The purified product was triturated with ether, collected by filtration and dried under vacuum to give 4-chloro-6-methoxy-7-(2-([1,2,4]-triazol-1-yl)ethoxy)quinoline (544 mg, 45%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[O:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Yield: 99 %

Procedure:
The title compound (2.8 g, 99%) was prepared from the compound from step 1 (3.0 g, 8.45 mmol) and 4N HCl in dioxane using the procedure described in step 2 of Example 4: MS (ESI) m/z 255 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 3.22 (br, 4H), 3.34 (t, J=4.8 Hz, 4H), 6.91-6.98 (m, 4H), 7.03-7.09 (m, 3H), 7.34 (m, 2H), 9.23 (br, 2H). Anal. Calcd for C16H18N2O.2HCl.0.8H2O: C, 58.72; H, 6.16; N, 8.56. Found: C, 56.25; H, 6.37; N, 8.20.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]([F:35])([C:31]([F:34])([F:33])[F:32])[C:7]([F:30])([F:29])[C:8]([F:28])([F:27])[C:9]([F:26])([F:25])[C:10]([F:24])([F:23])[C:11]([F:22])([F:21])[C:12]([F:20])([F:19])[C:13]([F:18])([F:17])[C:14](Cl)=[O:15]>C(OC(C)C)(C)C>[CH2:1]([NH:4][C:14](=[O:15])[C:13]([F:17])([F:18])[C:12]([F:19])([F:20])[C:11]([F:21])([F:22])[C:10]([F:23])([F:24])[C:9]([F:25])([F:26])[C:8]([F:28])([F:27])[C:7]([F:30])([F:29])[C:6]([F:35])([F:5])[C:31]([F:34])([F:33])[F:32])[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CCN
Solvent: CC(C)OC(C)C
Product: C=CCNC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 30 °C

Procedure:
Allyl amine (6.03 milliliters, 3.0 molar equivalent) and isopropyl ether (35.0 milliliters) were added to a 3-neck 100-milliliter round bottom flask equipped with water cooled condenser (to a nitrogen inlet), dropping funnel and thermometer adapter (to a Thermowatch device) at room temperature under a nitrogen blanket. A solution of nonadecafluoro-1-decanoyl chloride (14.27 grams, 1.0 molar equivalent) in 5.0 milliliters isopropyl ether was added by the dropping funnel over 2 hours while maintaining the temperature below 30° C. After the addition was completed, the reaction mixture was heated for 2 hours at 30° C., followed by additional treating for 2 hours at 40° C. After cooling the mixture to room temperature, the mixture was diluted with 100 milliliters isopropyl ether and washed with 9% aqueous hydrochloric acid solution (75 milliliters). The aqueous layer was extracted with 50 milliliters isopropyl ether. The combined organic layers were evaporated in vacuo to give a red solid. High vacuum distillation produced 13.03 grams (88% isolated yield) of a light yellow solid (boiling point 100° C., 0.1 millimeters Hg).