Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:64])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:35][CH:34]=1>CN(C=O)C>[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:64][C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:37][CH:38]=1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C

Procedure:
Analogously to Example 7, 106 mg (0.56 mmol) of N-ethoxycarbonyl-(L)-valine, 201 mg (1.05 mmol) of EDC and 95 mg (0.7 mmol) of HOBT in 4.6 ml of DMF and 293 μl (2.1 mmol) of TEA are reacted with 0.35 mmol of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane to form the title compound: Anal. (C35H48N6O7S (0.20 H2O)) calc. C 60.01, H 6.96, N 12.00, S 4.58, H2O 0.51: found C 60.07, H 6.78, N 11.93, S 4.70, H2O 0.52; HPLC20-100 : tRet =14.6; FAB MS (M+H)+ =697.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][S:31][CH2:32][CH3:33])[CH:24]=2)=[N:15][N:16]([CH3:22])[C:17]=1[O:18][CH:19]([F:21])[F:20]>ClCCl>[Cl:12][C:13]1[C:14]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][S:31]([CH2:32][CH3:33])=[O:9])[CH:24]=2)=[N:15][N:16]([CH3:22])[C:17]=1[O:18][CH:19]([F:21])[F:20]
Reactant: CCSCc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Reaction time: 0.5 h

Procedure:
1.4 g (4 mmol) of m-chloroperbenzoic acid were added a little at a time at 0° C. to a solution of 1.5 g (4 mmol) of 4-chloro-3-[4-chloro-3-(ethylthiomethyl)phenyl]-5-difluoromethoxy-1-methyl-1H-pyrazole in 40 ml of dichloromethane. The mixture was stirred at 0° for 30 minutes was subsequently stirred at room temperature for 4 hours and then the solids were removed by filtration. The filtrate was concentrated, and the crude product thus obtained was purified by chromatography on silica gel (eluent: hexane/ethyl acetate=1:1). Yield: 0.2 g.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:17])[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:17])[C:9]1=[O:18]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2c(C)cccc2C1=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc2c1CC(CC=O)C2=O
Reaction time: 1.5 h
Yield: 94 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 90 minutes while stirring through a solution, cooled to -70°, of 12.0 g of (RS)-2-(2-buten-1-yl)-4-methyl-1-indanone in 220 ml of anhydrous dichloromethane and 45 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 6.6 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 160 ml of dichoromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 10.6 g (94%) of (RS)-2-(2-oxoethyl)-4-methyl-1-indanone were obtained as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].[CH:16](Br)([CH3:18])[CH3:17].BrC1C=CC(C2OC(=O)N(C)C2)=NC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:16]([CH3:18])[CH3:17])[CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)Br
Reactant: O=C1NCC(c2ccc(Br)cn2)O1
Agent: CN1CC(c2ccc(Br)cn2)OC1=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CC(c2ccc(Br)cn2)OC1=O
Yield: 46.1 %

Procedure:
Compound 14b (125 mg, 0.51 mmol), NaH (51 mg, 1.28 mmol) and isopropyl bromide (125 mg, 1.02 mmol) reacted following the synthetic method of compound 14c to afford 67 mg colorless liquid, yield 46%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([OH:18])=O)=[O:5])[CH3:2].[NH2:19][CH2:20][C:21]1[N:25]2[C:26]3[S:40][C:39]([CH2:41][CH3:42])=[CH:38][C:27]=3[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[N:29][CH2:30][C:24]2=[N:23][N:22]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[C:27]2[CH:38]=[C:39]([CH2:41][CH3:42])[S:40][C:26]=2[N:25]2[C:21]([CH2:20][NH:19][C:16]([C:8]3[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[CH:13][CH:14]=4)=[O:18])=[N:22][N:23]=[C:24]2[CH2:30][N:29]=1
Reactant: CCc1cc2c(s1)-n1c(CN)nnc1CN=C2c1ccccc1Cl
Reactant: CCOC(=O)Cn1c(C(=O)O)cc2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)NCc2nnc3n2-c2sc(CC)cc2C(c2ccccc2Cl)=NC3)cc2ccccc21
Reaction time: 24 h
Yield: 60.3 %

Procedure:
1-Ethoxycarbonylmethylindole-2-carboxylic acid (1.36 g) synthesized by a known method such as the method described in Japanese Patent Unexamined Publication No. 279374/1991, 9-aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (1.79 g) and triethylamine (1.4 ml) were dissolved in dimethylformamide (15 ml). 1-Benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 2.43 g) was added at room temperature, and the mixture was stirred for one day. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was crystallized from ethanol and isopropyl ether to give 2.78 g of crude crystals. The crystals were recrystallized from ethanol to give 1.77 g of ethyl 2-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-ylmethylcarbamoyl)indole-1-acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].N1C=CC=CC=1>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9](=[O:10])[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: Nc1ccccn1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-aminopyridine (2.0 mL, 21.25 mmol) in DCM (35 mL) at 0° C. was added a solution of 4-nitrophenyl chloroformate (4.28 g, 21.25 mmol) in DCM (35 mL) and pyridine (1.73 mL, 21.25 mmol, anhydrous). After the addition was completed, the reaction mixture was stirred at RT for 16 h under an atmosphere of nitrogen. A white precipitated was observed and it was collected by filtration. The filtrate was washed with DCM (3×50 mL) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 260 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CNS(C)(=O)=O)c1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.2 g (8.1 mmol) of 4-formylbenzeneboronic acid and 1.1 g (8.1 mmol) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis(triphenyl-phosphine)palladium(0). The mixture was heated to 100° C. for 4 hours whereupon 0.3 g (2.0 mmol) of 4-formylbenzeneboronic acid and 0.1 g (0.09 mmol) of tetrakis(triphenylphosphine)-palladium(0) was added and heating continued for 16 hours. To this solution was added 5 mL of water and heating continued for 1 hour. The mixture was then cooled to ambient temperature and 10 mL of water was added. The organic portion was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[C:16]1([CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:25]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:23][NH:24][C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: NCC(c1ccccc1)c1ccccc1
Product: Cc1ccc(-c2oncc2C(=O)NCC(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 2,2-diphenylethylamine (11.8 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.0 mg). Calcd for C25H22N2O2: 382.1681, found 382.1682.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C1OCCOCCOCCOCCOCCOC1.[F:30][C:31]([F:45])([F:44])[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O>COCCOCCOC>[F:30][C:31]([F:45])([F:44])[CH2:32][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
Potassium hydroxide pellets (85%, 13.2 g, 0.2 mol) are added to 4-hydroxybenzaldehyde (24.4 g, 0.2 mol) and 18-crown-6 (2.6 g, 5% mol) in diglyme (150 mL). The red reaction mixture is stirred for 16 hours at room temperature and then a solution of 2,2,2-trifluoroethyl-p-toluenesulfonate (50.8 g, 0.2 mol) in diglyme (100 mL) is added over 30 minutes, after which the mixture is allowed to stir at room temperature for 45 minutes. The resulting suspension is then heated at reflux for 24 hours. The mixture is cooled to 10° C. and poured into ice water (1300 mL). The organic materials are extracted with ether (4×200 mL), and the extracts washed with 5% sodium hydroxide (2×100 mL), water (2×100 mL) and saturated sodium chloride (1×100 mL), and dried over MgSO4. Evaporation of the ether gives an amber oil which is purified by high performance liquid chromatography using silica gel on a Waters 500 unit and 50:50 hexane and methylene chloride as eluant to give 12.3 g of the title product with Rf 0.25. Anal. Calcd for C9H7F3O2 (204.15) C, 52.94; H, 3.43. Found C, 52.04; H, 3.59.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1>C(N(CC)CC)C.C(O)=O>[CH2:2]([C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=c1cc(O)c2ccccc2o1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=c1oc2ccccc2c(O)c1Cc1ccccc1

Procedure:
Scheme 2 provides an alternative synthesis of C-3 substituted 4-hydroxycoumarins when R1 is aryl groups. 4-hydroxycoumarin and an aromatic aldehyde can be heated in a mixture of triethylamine and formic acid (2:5 molar ratio) to give 3-benzyl-4-hydroxycoumarin, which was in turn treated with 2.2 eq. of BuLi and quenched with carbon dioxide to give coumarin substituted phenyl-acetic acid. Corresponding esters can be obtained by treating the acid with various alcohols in the presence of concentrated sulfuric acid.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]([CH3:32])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=4)[N:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl.C(Cl)(Cl)Cl.C(OCC)C>CO.O1CCCC1>[CH3:32][N:12]([CH2:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]1)[C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=3)[N:19]=2)=[CH:16][N:17]=1
Reactant: COC(=O)[C@H]1CC[C@H](CN(C)c2ncc(-c3cccc(Nc4cc(C)ccn4)n3)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccnc(Nc2cccc(-c3cnc(N(C)C[C@H]4CC[C@H](C(=O)O)CC4)s3)n2)c1

Procedure:
A solution of trans-4-[(N-methyl-N-{5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}amino)methyl]cyclohexanecarboxylic acid methyl ester (217 mg, 0.48 mmol) obtained in Step 5, 1N aqueous sodium hydroxide (2 ml, 2 mmol) in methanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 16 hours. The solution was neutralized with 1N hydrochloric acid and extracted with chloroform (50 ml×2). The organic layer was washed with a saturated brine (20 ml) and dried over magnesium sulfate and filtrated and vacuum concentrated. The solid obtained by adding chloroform-diethyl ether (1:1) (10 ml) to the residue was collected by filtration, dried in vacuo and thereby trans-4-[(N-methyl-N-{5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}amino)methyl]cyclohexanecarboxylic acid (190 mg, 90%) was obtained.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[NH:31])[CH3:30])=[CH:24][C:12]=3[C:13](=[O:23])[C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[ClH:32]>C(O)C>[ClH:32].[OH:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[NH:31])[CH3:30])=[CH:24][C:12]=3[C:13](=[O:23])[C:14]=2[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3ccc(NC(C)=N)cc3c(=O)c2OCc2ccccc2)cn1
Agent: Cl
Solvent: CCO
Product: CC(=N)Nc1ccc2oc(-c3ccc(O)nc3)c(OCc3ccccc3)c(=O)c2c1
Yield: 40 %

Procedure:
To a suspension of 2-(6-methoxypyridin-3-yl)-3-benzyloxy-6-[(1-iminoethyl)amino]-4H-1-benzopyran-4-one (0.6 g) in ethanol (30 ml) was added HCl 6N (2 ml). The mixture was stirred under reflux for 30 hours, cooled and the hydrochloride was filtered off. Yield: 40%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[C:6]=2[CH:20]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B(O)O)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=5)[C:6]=4[CH:20]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(C(F)(F)F)cc4)c3c2)cc1

Procedure:
The title compound, light brown solid (67 mg, 54%), MS (ISP) m/z=423.3 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-trifluoromethyl-phenyl)-1H-benzo[d]imidazole (intermediate I) (100 mg, 293 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (72.5 mg, 352 μmol).
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C(=O)([O-])[O-].[K+].[K+].C1(S(O[CH2:32][C:33]([N:35]2[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]2[C:41]([NH2:43])=[O:42])=[O:34])(=O)=O)C=CC=CC=1>CN(C)C=O>[CH2:14]([O:13][C:11]([C:6]12[CH2:5][CH2:4][C:3]([NH:2][CH2:32][C:33]([N:35]3[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]3[C:41]([NH2:43])=[O:42])=[O:34])([CH2:10][CH2:9]1)[CH2:8][CH2:7]2)=[O:12])[CH3:15]
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Temperature: 45 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
Ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride (4.63 g), potassium carbonate (5.47 g) and N,N-dimethylformamide (40 mL) were mixed together. To this mixture, a solution of (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide (5.93 g) in N,N-dimethylformamide (10 mL) was added at 40° C. and the mixture was stirred at 45° C. for 3 hours. Subsequently, the reaction mixture was concentrated under reduced pressure. Water (50 mL) was then added to the residue and the resulting crystal was collected by filtration, washed with water (30 mL), and dried at 50° C. under reduced pressure. The crude crystal was recrystallized from ethyl acetate (40 mL), washed with ethyl acetate (20 mL), and dried at room temperature under reduced pressure. This gave (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carboxamide as a white solid in the form of colorless powder (1.81 g). The filtrate and the wash were combined and concentrated to 20 mL. The resulting crystal was collected by filtration, washed with a mixture of ethyl acetate and diisopropyl ether (1:1, 20 mL) to give additional 1.19 g of the product. The total amount of the product was 3.00 g (45% yield).
Reaction SMILES: C12CC(C=C1)CC2C1NC(C([O-])=O)CS1.C(OC([NH:23][CH2:24][C:25]([N:27]1[C@H:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][S:29][CH:28]1[CH:39]1[CH2:44][CH:43]2[CH2:45][CH:40]1[CH:41]=[CH:42]2)=[O:26])=O)(C)(C)C.I[Si](C)(C)C>>[NH2:23][CH2:24][C:25]([N:27]1[C@H:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][S:29][CH:28]1[CH:39]1[CH2:44][CH:43]2[CH2:45][CH:40]1[CH:41]=[CH:42]2)=[O:26]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1C(C2CC3C=CC2C3)SC[C@H]1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)I
Agent: O=C([O-])C1CSC(C2CC3C=CC2C3)N1
Product: CC(C)(C)OC(=O)[C@@H]1CSC(C2CC3C=CC2C3)N1C(=O)CN
Yield: 99.8 %

Procedure:
tert-Butyl (4R)-3-2-aminoacetyl)-2-[(2RS)-5-norbornen-2-yl]-4-thiazolidinecarboxylate (mixture of isomers C and D) may be prepared in a manner similar to that described in Example 1B, but starting with 1.0 g of tert-butyl (4R)-3-(2-tert-butoxycarbonylaminoacetyl)-2-[(2RS)-5-norbornen-2-yl]-4-thiazolidinecarboxylate (mixture of isomers C and D) and 0.36 cm3 of iodotrimethylsilane. 0.77 g of tert-butyl (4R)-3-(2-aminoacetyl)-2-[(2RS)-5-norbornen-2-yl]-4-thiazolidinecarboxylate (mixture of isomers C and D) is thereby obtained in the form of a yellow oil, which is used in the subsequent syntheses without further treatment.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH2:8]1[O:10][CH:9]1[CH2:11][OH:12].C(S([C:17]1[S:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])=[O:23])=[CH:20][N:21]=1)=O)C>O.C(OCC)(=O)C>[O:10]1[CH:9]([CH2:11][O:12][C:17]2[S:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])=[O:23])=[CH:20][N:21]=2)[CH2:8]1
Reactant: OCC1CO1
Reactant: C=CCCCCNC(=O)c1cnc(S(=O)CC)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCCCNC(=O)c1cnc(OCC2CO2)s1
Temperature: -5 °C

Procedure:
In this preparation 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole of glycidol is added dropwise. The mixture is allowed to warm to -5° C and stirred for ten minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfinyl-5-(hex-5-enylaminocarbonyl)thiazole in 100 ml. of anhydrous tetrahydrofuran is added dropwise and the resulting mixture allowed to warm to 0° C. Additional solvent is added as needed to facilitate stirring. The mixture is maintained for 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extacted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording an oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate-60% hexane, by vol., affording 1,2-epoxy-3-[5-(hex-5-enylaminocarbonyl)thiazole-2-yloxy]propane.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:25][N:24]=[C:23]([C:26](=O)[C:27]([OH:29])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][CH2:32][O:33][NH2:34].[OH-].[Na+]>C(O)C.O>[C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:34]/[O:33][CH2:32][F:31])/[C:27]([OH:29])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NOCF
Reactant: O=C(O)C(=O)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)/C(=N\OCF)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
2-(5-Tritylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (1 g) was added to a mixture of a solution of fluoromethoxyamine (0.58 g) in ethanol (25 ml) and water (0.45 ml). After adjusting the pH of the resulting mixture to 4-5 with a 10% aqueous solution of sodium hydroxide, the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, followed by addition of water (20 ml) and sodium chloride (10 g) to the residue. The pH of the resulting solution was adjusted to 1 with concentrated hydrochloric acid. The solution was extracted four times with ethyl acetate (30 ml). After washing the extract with saturated saline, anhydrous magnesium sulfate was added to the extract to dry the same. The dry was distilled off and the residue was crystallized from a 1:10 mixture of acetone and isopropyl ether, thereby obtaining the target product (0.55 g).