Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][NH:12][CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][N:28]=[CH:27][C:26]=1[CH3:34].C(N(CC)CC)C>C(O)(C)C>[Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:25]2[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][N:28]=[CH:27][C:26]=2[CH3:34])[CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cncc([N+](=O)[O-])c1Cl
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1cncc([N+](=O)[O-])c1N1C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 48 h
Yield: 37.3 %

Procedure:
A solution of tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (23 mg, 0.067 mmol, Example 26, Step 7), 4-chloro-3-methyl-5-nitropyridine (from ACES Pharma, 16 mg, 0.096 mmol), and triethylamine (37 μL, 0.27 mmol) in isopropyl alcohol (0.60 mL) was heated at 75° C. in a sealed vial for 16 h. Another portion of 4-chloro-3-methyl-5-nitropyridine (19 mg) was added and stirring was continued for 2 days at 100° C. The crude reaction mixture was purified by flash chromatography (24 g silica gel column, eluting with 0-100% EtOAc/hexanes) to afford the sub-title compound (12 mg, 37% yield). LCMS (ESI) calc. for C23H41N4O5Si [M+H]+: m/z=481.3. found 481.3.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Br:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:24][CH2:23][N:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([Br:15])[CH:17]=4)[CH2:27][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2cccc(Br)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(3-bromophenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 84% overall yield. mp 144°-145°. FDMS m/e=429 (M+ of free base). α[D]589 =-8.12 (c=0.81, methanol).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[S:18])[NH:6][C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[NH:4][C:5](=[S:18])[NH:6][C:7]=1[C:8](=[S:20])[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)[CH3:2]
Reactant: CCc1[nH]c(=S)[nH]c1C(=O)c1ccc(F)c(F)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCc1[nH]c(=S)[nH]c1C(=S)c1ccc(F)c(F)c1

Procedure:
Ten grams of 1,3-dihydro-4-ethyl-5-(3,4-difluorobenzoyl)-2H-imidazole-2-thione in toluene and phosphorus pentasulfide was heated at reflux temperature for 5 hours. Evaporation of the solvent provides the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=C=NC(C)(C)C)=[O:5])[CH3:2].[F:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:28][CH3:29])[C:20]=2[C:24]([F:27])([F:26])[F:25])[C:15]=1[C:30]([N:32]([CH3:37])[CH2:33][C:34]([OH:36])=O)=[O:31]>C1COCC1>[CH2:1]([O:3][C:4]([NH:6][C:34](=[O:36])[CH2:33][N:32]([CH3:37])[C:30]([C:15]1[C:16]2[C:21](=[C:20]([C:24]([F:27])([F:25])[F:26])[C:19]([O:28][CH3:29])=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[F:13])=[O:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C=NC(C)(C)C
Reactant: COc1ccc2c(C(=O)N(C)CC(=O)O)c(F)ccc2c1C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)CN(C)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Yield: 50 %

Procedure:
According to the procedure of O. M. Mitsunobu et al, Bull. Chem. Soc. Japan, 45, 3607 (1972), a solution of ethoxycarbonyl-t-butylcarbodiimide (0.436, 1.10 q) and N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-methylglycine (0.838 g, 2.38 mmole) in anhydrous THF (13.5 mL) was heated to reflux under a dry nitrogen atmosphere for 10 hours. The reaction was cooled to room temperature and the organic solvent was removed. The solid was flash chromatographed (1:1 pertroleum ether:ethyl acetate, silica). The resultant foam was triturated with petroleum ether and dried to provide the title compound as a white solid (0.567 g, 50%), m.p. 130°-132° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:18][NH2:19])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26](OC(=O)CCl)=O.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>CN(C)C=O.CCOCC>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:26]([CH2:25][Cl:24])=[N:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: O=C(CCl)OC(=O)CCl
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
A suspension of 3.06 g (9.22 mmol) of (S)-8-chloro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2, 1-c][1,4]benzodiazepine-1-carboxylic acid hydrazide in 30 ml of N,N-dimethylformamide was treated with 1.97 g (0.0115 mol) of chloroacetic anhydride. The yellow solution obtained was stirred at room temperature for 11/2 hr. and then completely freed from the solvents. The residue was suspended in ether and filtered off under suction. The beige crystals obtained (3.75 g, m.p. 262°-264° (dec.)) were treated with 27 ml of methanesulphonic acid and 3 g of phosphorus pentoxide, whereupon the mixture was stirred at room temperature for 65 hrs. The orange-brown solution was poured into 150 ml of ice-water, made basic with aqueous sodium hydroxide solution and extracted with methylene chloride. The crystalline product was chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 2.03 g (56%) of (S)-8-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one as white crystals; m.p. 230°-232° and [a]D20 =+104.5° (DMF, c=1%).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25]C(=O)CC4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][CH:18]2O)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl.CO>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[CH:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[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
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
To a suspension of 3-hydroxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (3e) in dichloromethane (13 parts) cooling at -5° to 0° C. under nitrogen are added at -5° to 0° C. pyridine (3 equivalents) and at -20° to -25° C. phosphorus pentachloride (2.7 equivalents). After stirring at -15° to -10° C. for 4 hours, the mixture is diluted with methanol (20 parts) cooled at -40° to -30° C. and stirred for 3 hours at -10° to -15° C. The mixture is cooled to -20° to -25° C., mixed dropwise with triethylamine (12 equivalents), and kept at 0° to 5° C. overnight. The mixture is diluted with ice-water (20 parts) and stirred at 0° to 5° C. for 20 minutes. The formed organic layer is washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate, and water, dried, and concentrated. The residue is crystallized from ethyl acetate to give 7beta-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (5). Yield: 47.3%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1.Cl.CCOCC>C(O)(C)C>[ClH:19].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([Cl:22])=[CH:24][C:25]=3[F:30])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: N#Cc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCc1ccccc1
Yield: 80.5 %

Procedure:
A suspension of 7-benzyloxy-4-chloro-6-cyanoquinoline (2 g, 6.8mmol), 4-chloro-2-fluoroaniline (1.1 g, 7.5 mmol) in isopropanol (50 ml) containing 1M ethereal hydrogen chloride (8 ml) was heated at reflux for 2 hours. After cooling to ambient temperature ether was added. The precipitate was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-cyanoquinoline hydrochloride (2.41 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:4]=1.[Cl:17][C:18]([Cl:24])([Cl:23])[C:19](=N)OC>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]2[N:7]=[C:19]([C:18]([Cl:24])([Cl:23])[Cl:17])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]=2[CH:4]=1
Reactant: COCCCCNc1cc(OC)ccc1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COCCCCn1c(C(Cl)(Cl)Cl)nc2ccc(OC)cc21
Reaction time: 1.5 h

Procedure:
4-Methoxy-2-(4-methoxybutylamino)aniline (2.50 g) was dissolved in acetic acid (30 ml), methyl 2,2,2-trichloroethanimidate (1.62 ml) was added, and the mixture was stirred for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diisopropyl ether, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object product (1.75 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]1([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[CH2:31][CH2:30]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:32]([CH:29]2[CH2:31][CH2:30]2)[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)=[O:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cccc(CNC2CC2)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Product: Cc1cccc(CN(C(=O)CN(c2ccc3ncccc3c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with cyclopropyl-(3-methyl-benzyl)-amine
Reaction SMILES: Br.Br.[NH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:14])[CH2:7][CH2:6]1.[NH2:22][C:23]1[C:31]([Cl:32])=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([O:33][CH3:34])[CH:24]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[NH2:22][C:23]1[C:31]([Cl:32])=[CH:30][C:26]([C:27]([NH:3][CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)=[O:14])[CH2:7][CH2:6]2)=[O:28])=[C:25]([O:33][CH3:34])[CH:24]=1
Reactant: NCC1CCN(CCC(=O)c2ccc(O)cc2)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCC(=O)c2ccc(O)cc2)CC1
Yield: 35.9 %

Procedure:
4-Aminomethyl-1-(3-(4-hydroxyphenyl)-3-oxopropyl)piperidine dihydrobromide (9.00 g) as a starting compound, 4-amino-5-chloro-2-methoxybenzoic acid (4.28 g), triethylamine (8.82 ml), 1-hydroxybenzotriazole (3.00 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (4.27 g) were reacted and purified in the same manner as in Example 270 to give 3.40 g of 4-amino-5-chloro-2-methoxy-N-((1-(3-(4-hydroxyphenyl)-3-oxopropyl)piperidin-4-yl)methyl)benzamide, m.p. 191°-193° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[C:12]([F:32])=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH2:28]Cl)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1.[NH2:33][C:34]([C:36]1([NH:47][CH3:48])[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1)=[O:35].O>CN(C)C=O>[NH2:33][C:34]([C:36]1([N:47]([CH2:28][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][C:24]=2[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]3[NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[C:12]=2[F:32])[CH3:48])[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:37]1)=[O:35]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Reactant: CNC1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N,N-diisopropylethylamine (0.22 ml, 1.24 mmol) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (160 mg, 0.41 mmol prepared as described in Example 62) in dimethylformamide (1 ml). After 5 minutes of stirring, the reaction mixture became homogeneous and tert-butyl 3-(aminocarbonyl)-3-(methylamino)azetidine-1-carboxylate (98 mg, 0.43 mmol) was added. After 30 minutes of stirring at 80° C., the reaction mixture was cooled down to room temperature, water was added and the aqueous layer was extracted with ethyl acetate (×2). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residues were purified by column chromatography on silica eluting with increasingly polar mixtures of methanol/dichloromethane (0/100-5/95) to give tert-butyl 3-(aminocarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-1-carboxylate as a yellow solid, (100 mg, 44%); 1H NMR Spectrum: (CDCl3) 1.46 (s, 9H), 2.39 (s, 3H), 3.82 (s, 2H), 3.99 (s, 3H), 4.17 (d, 2H), 4.25 (brd, 2H), 5.47 (brs, 1H), 6.79 (brs, 1H), 7.17 (m, 2H), 7.29 (s, 1H), 7.66 (brs, 1H), 7.83 (s, 1H), 8.49 (brs, 1H), 8.75 (s, 1H); Mass Spectrum: (M+H)+ 545.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[CH:8]=1.[CH:35]1([NH2:38])[CH2:37][CH2:36]1>>[CH:35]1([NH:38][C:23]([C:22]2[CH:21]=[N:20][N:17]3[CH:18]=[CH:19][C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:9]4[C:7]4[CH:8]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=4[O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:15][C:16]=23)=[O:25])[CH2:37][CH2:36]1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCN3CCOCC3)nc12
Reactant: NC1CC1
Agent: Cl
Product: O=C(NC1CC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCN3CCOCC3)nc12
Yield: 70 %

Procedure:
Prepared by the method described in Example 76, Step F using ((R)-5-(2-(5-fluoro-2-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid hydrochloride and cyclopropylamine to yield the title compound as a white solid (35.4 mg, 70% yield). MS (apci) m/z=495.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=1>C1COCC1.C(OCC)(=O)C.O>[OH:55][C:52]1[CH:53]=[CH:54][C:49]([NH:48][C:21](=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([C:16]#[C:15][Se:14][C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:1])([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)=[CH:25][CH:24]=2)=[CH:50][CH:51]=1
Reactant: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(C(=O)O)cc3)ccc21
Reactant: Nc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(C(=O)Nc4ccc(O)cc4)cc3)ccc21
Yield: 63.2 %

Procedure:
A solution of 250 mg (0.63 mmol) of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid obtained in Example 5, 169 mg (1.25 mmol) of 1-hydroxybenzotriazole, 240 mg (1.25 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 82 mg (0.75 mmol) of 4-aminophenol in 20 ml of THF is stirred at room temperature for 15 h. Water and ethyl acetate are then added. After stirring and separation of the phases by settling, the aqueous phase is extracted with ethyl acetate. The organic phases are then combined and washed with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified on a column of silica (ethyl acetate 20/heptane 80). 200 mg (65%) of a white solid are obtained. m.p.=202° C.
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.[C:18]([C:20]1[N:21]=[C:22]([C:36]2([CH3:40])[CH2:39][O:38][CH2:37]2)[NH:23][C:24]=1[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[CH3:35])[C:28]([O:30]C)=[O:29])#[N:19].CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1>>[C:18]([C:20]1[N:21]=[C:22]([C:36]2([CH3:40])[CH2:39][O:38][CH2:37]2)[NH:23][C:24]=1[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[CH3:35])[C:28]([OH:30])=[O:29])#[N:19]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C3(C)COC3)nc2C#N)c1
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2(C)COC2)nc1C#N

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except methyl 3-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 202.4) was used in place of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 298 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:17])[F:18])[C:12]([CH3:19])=[N:11]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 120 °C
Yield: 87 %

Procedure:
A stirred mixture of 1.0 g (0.0032 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-4-difluoromethyl -4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.66 g (0.0048 mole) of potassium carbonate, and 0.76 g (0.0048 mole) of 4-chloronitrobenzene in 20 ml of N,N-dimethylformamide was heated at 120° C. for approximately 18 hours. The reaction mixture was cooled and was poured into ice-water. This aqueous mixture was neutralized with hydrochloric acid and then was extracted with ethyl acetate. The organic phase was washed with water and then was dried over anhydrous magnesium sulfate. This mixture was filtered, and the filtrate was evaporated under reduced pressure leaving an orange oil. The orange oil was purified by column chromatography on silica gel, eluting with methylene chloride to yield 1.2 g of 1-[2,4-dichloro-5-(4-nitrophenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid, m.p. 99°-101° C., compound 92 of Table 1.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(=O)=O.CC(C)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][CH2:15][S:16]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:6]
Reactant: O=[N+]([O-])c1ccc(SCCCCl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(S(=O)CCCCl)cc1
Reaction time: 2 h
Yield: 4.2 %

Procedure:
A solution of m-chloroperoxybenzoic acid (80% 16.6 g, 86.3 mmol) in methylene chloride (100 mL) was added dropwise to a solution of 1-[(3-chloropropyl)thio]-4-nitrobenzene (20.0 g, 86.3 mmol) in methylene chloride (20 mL) maintained at -78° C. (dry ice/acetone bath). After 2 h the reaction was allowed to warm to ambient temperature (~1 h) and 200 mL of 10% aqueous sodium hydroxide was added. The layers were allowed to separate and the aqueous layer was extracted (100 mL) with methylene chloride. The combined organic extracts were washed (water, 100 mL), dried (MgSO4) and concentrated in vacuo. A 1.0 g sample of the residue (21.2 g) was chromatographed (Chromatatron, SiO2 4000 μ, 99/1 methylene chloride:methanol) to give 0.89 g (88%) of white solid, mp 72.5°-74.5° C.
Reaction SMILES: Cl.[CH:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[CH:10](C1C=CC(C)=C(C)C=1C)C.[H][H].C12CCC(CC1)CC2C(C1(C)CCCCC1(C)C)C>[Ru].CC1CCCCC1>[CH3:9][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1ccc(C(C)C2CC3CCC2CC3)c(C)c1C
Reactant: [H][H]
Agent: [Ru]
Agent: CC(C1CC2CCC1CC2)C1(C)CCCCC1(C)C
Agent: Cl
Solvent: CC1CCCCC1
Product: Cc1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 2 liter four neck flask equipped with a thermometer and a hydrogen chloride gas trap, 500 ml of 1,2,4-trimethylbenzene and 150 ml of titanium tetrachloride were placed and 150 ml of 2-(1-hydroxyethyl) bicyclo [2.2.2] octane obtained in (1) above was dropped therein over 30 minutes with stirring at room temperature. The so obtained mixture was maintained at 30° C. in an ice-cold water bath and further stirred for 30 minutes. After the evolution of hydrogen chloride gas was stopped, the content of the flask was poured into 1 liter of ice-cold water to stop the reaction. The mixture was stirred well in the ice-cold water, and an organic layer produced therein was washed twice with 200 ml of 2N NaOH aqueous solution, followed by washing twice with 200 ml of water. The so treated organic layer was dried with anhydrous MgSO4 and distilled to obtain 180 g of a fraction having a boiling point of 150 to 160° C./2 mmHg. The analysis with NMR and MS resulted in a finding that the so obtained reaction product was 1-(2-bicyclo [2.2.2] octyl)-1-(trimethylphenyl)-ethane. Said reaction product was placed in a 1 liter autoclave, 20 g of 5% ruthenium/carbon catalyst and 300 ml of methylcyclohexane as the solvent were added and the resulting mixture was hydrogenated under the conditions of a hydrogen pressure of 80 kg/cm2G, a reaction temperature of 200° C. and a reaction time of 6 hours. The NMR analysis showed that the degree of hydrogenation was 99%. The so obtained reaction product was analyzed with NMR, IR and MS, resulting in a finding that it was 1-(2-bicyclo [2.2.2] octyl)-1-(trimethylcyclohexyl)-ethane. Further, the traction coefficient of the obtained reaction product was determined in a temperature range of 40° C. to 140° C. and the results are shown in FIG. 1. The graphs of 1H-NMR, 13C-NMR and MS of the reaction product are respectively shown in FIGS. 4 to 6.