Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.C(=O)([O-])N.[Cl:26][C:27]1[CH:28]=[C:29]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:30]([N:32]=[C:33]=[O:34])=[O:31]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:30]([NH:32][C:33](=[O:34])[O:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=1)=[O:31]
Reactant: O=C=NC(=O)c1cc(Cl)cc(Cl)c1
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: NC(=O)[O-]
Product: CCn1c(COC(=O)NC(=O)c2cc(Cl)cc(Cl)c2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 78 %

Procedure:
The compound 19 (300 mg, 0.869 mmol) was converted to the carbamate with 3,5-dichlorobenzoyl isocyanate (1.5 eq.) in the same manner as the example 66 to give the compound 87 (380 mg, 78%) as crystals. Mp.124-125° C. Rf 0.23 (1:2 EtOAc-hexane)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[N:6]1[CH:5]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:3]=[C:2]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1cccnc1
Product: c1cncc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 3-pyridinylboronic acid according to General Method B: LC-MS Method B (ESI+) m/z 307.0 (M+H)+, retention time 1.54 minutes.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[C:7](N(OC)C)=[O:8].Cl.O>O1CCCC1>[Br:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[C:7](=[O:8])[CH3:1]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Cl)ccc1Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)ccc1Br
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (4.26 mL of a 1.4M solution in tetrahydrofuran/toulene, 5.97 mmol) was added dropwise to a stirred solution of 2-bromo-5-chloro-N-methoxy-N-methylbenzamide (0.554 g, 1.99 mmol) in tetrahydrofuran (20 mL) at approximatately 0° C. After 1 h, 1N hydrochloric acid (5 mL) was added and the resulting biphasic mixture was stirred vigorously for about 10 min. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0–10% ethyl acetate/hexanes as eluent) provided the title compound as a colorless oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=4)[NH:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:27]([Sn](CCCC)(CCCC)CCCC)=[N+:28]=[N-:29]>C1(C)C=CC=CC=1>[NH:27]1[C:25]([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)=[N:26][N:29]=[N:28]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2[nH]nc(-c3ccc(OCCN4CCOCC4)cc3)c2c1
Solvent: Cc1ccccc1
Product: c1cc(-c2n[nH]c3ccc(-c4nnn[nH]4)cc23)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.9 %

Procedure:
A mixture of 3-[4-(2-morpholin-4-ylethoxy)phenyl]-1H-indazole-5-carbonitrile (290 mg, 0.832 mmol), azidotributyltin (Bu3SnN3, 1.56 g, 4.70 mmol, 5.65 equiv.), and 9.0 mL toluene was refluxed for 17.5 h and concentrated to an oil. To the oil was added 6.5 mL of dioxane and 6.5 mL of 6.0 N aq. HCl. The mixture was stirred at room temperature for 4 h and then added to 25 mL of 6.0 N aq. NaOH. The mixture was extracted with 3× hexanes, and 3× Et2O. The aqueous layer was filtered to remove particulates. The pH was adjusted with 6.0 N aq. HCl to give maximum visual turbidity (approximately pH 5.0–5.5) and then the mixture was extracted with 2×EtOAc. The combined organics were dried (Na2SO4), filtered, and concentrated. The product was triturated in 5% EtOAc in hexanes. Filtration and drying of the solid afforded the title compound (29.0 mg, 8.90% yield): 1H NMR (CDCl3/CD3OD) δ 8.75 (s, 1H), 8.08 (d, 1H), 7.95 (d, 2H), 7.70 (m, 1H), 7.13 (d, 2H), 4.30 (t, 2H), 3.85–3.79 (m, 4H), 3.07 (t, 2H), 2.89–2.80 (m, 4H); ES-MS (m/z) 392 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: Fc1cccc(CCl)c1
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 61.8 %

Procedure:
A suspension of 0.207 g (1 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 0.173 g (1.2 mmol) of 3-fluorobenzyl chloride and 0.276 g (2 mmol) of potassium carbonate in 10 ml of dimethylformamide is stirred for 24 hours at 60° C. The reaction mixture is then cooled and poured into a mixture of ice-water and ethyl acetate. After allowing the phases to separate by settling, the organic phase is separated out and then washed with twice 50 ml of water and then with 50 ml of saturated sodium chloride solution. The solution is dried over magnesium sulfate and filtered, and the filtrate is then concentrated under reduced pressure. 0.195 g of an oil is obtained, which is used without further purification in the following step.
Reaction SMILES: C(OC([N:8]1[CH:13](C)[CH2:12]C(=O)[CH2:10][CH:9]1C)=O)(C)(C)C.[CH3:17][CH2:18][O:19][C:20]([CH2:22][C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:24])=[O:21].C(=O)C>>[CH3:10][CH:9]1[CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:23](=[O:24])[CH:22]([C:20]([O:19][CH2:18][CH3:17])=[O:21])[CH:13]([CH3:12])[NH:8]1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: CC1CC(=O)CC(C)N1C(=O)OC(C)(C)C
Agent: CC=O
Product: CCOC(=O)C1C(=O)C(C(=O)OCC)C(C)NC1C
Reaction time: 8 h
Yield: 54 %

Procedure:
Compound 5-3 was made in a manner similar to Hall, H. K. Jr.; J. Am. Chem. Soc., 1957, 79, 5444-5447. Step 2a: Into a mixture of diethyl acetonedicarboxylate (103.6 g, 0.512 mol) and acetaldehyde (45.3 g, 1.33 mol) was bubbled ammonia gas until that liquid was saturated at −30° C. The solution was stored in freezer overnight. The yellow sludge was dissolved in dichloromethane (15 mL), filtered though silica gel and washed with EtOAc. The organic layer was concentrated to give diethyl 2,6-dimethyl-4-oxopiperidine-3,5-dicarboxylate as a thick yellow oil (92 g, 54%). Step 2b: A solution of the diester (90 g, 0.332 mol) in 10% aqueous hydrochloric acid solution (400 mL) was refluxed for overnight. Water was evaporated to yield 2,6-Dimethyl-4-piperidone/HCl, which was used for the next step without further purification. Step 2c: 2,6-Dimethyl-4-piperidone HCl salt (25.0 g, 0.153 mol) was partitioned into dioxane (250 mL) and H2O (250 mL), and sodium bicarbonate (50 g, 0.59 mol) was added in several portions. Boc anhydride (80 g, 0.37 mol) was added and the resulting reaction mixture was stirred at rt overnight. The reaction mixture was evaporated to remove dioxane. The residue was extracted with Et2O and the organic layer was washed with brine and dried over sodium sulfate. After evaporation, the crude product was purified by chromatography (gradient elution of 9-14% EtOAc in hexane) to give Compound 5-3 as a white solid (18.0 g, 52%, mixture of 70:30 trans:cis) (based on comparison to NMR spectra of trans Compound 5-3 reported by Beak, P.; Lee, W. K.; J. Org. Chem. 1993, 58, 1109-1117). MS (ES+) m/z 128 (M-Boc+1).
Reaction SMILES: [O:1]=[C:2]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[N:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](COCC[Si](C)(C)C)[N:16]=[C:15]3[C:29](=[NH:31])[OH:30])=[O:10])[CH2:5]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]([N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[N:45]=[CH:46][CH:47]=[CH:48][N:49]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:29](=[NH:31])[OH:30])=[O:10])[CH2:5]1
Reactant: C[Si](C)(C)CCOCn1nc(C(=N)O)c2cc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(O)c1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 108.4 %

Procedure:
To a solution of 33 from Step 1 (18 mg, 0.03 mmol) in CH2Cl2 (2 mL) was added TFA (2 mL) at rt. The crude was stirred at rt for 5 hrs. The crude was evaporated and quenched with sat. NaHCO3 at rt. The crude was evaporated and filtered through a plug of silica gel and evaporated. The crude was purified via preparation plate to give 18 mg of the product.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[N:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>CN(C)C=O>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:4]1[N:3]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[S:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(-c2cccs2)ns1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccs3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of 5-chloro-3-(2-thienyl)-1,2,4-thiadiazole (4.80 g, 23.7 mmol) and tert-butyl piperazine-1-carboxylate (4.41 g, 23.7 mmol) in dimethylformamide (50 ml) was added triethylamine (13.2 ml, 94.7 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 4.33 g (51.9%) of the desired product as a solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:14])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[C:13](=[O:14])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCC(=O)c2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCC(=O)c2ccc3ccccc3c2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 4-[2-(2-naphthalenyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.57 g) in methanol (3 mL) and tetrahydrofuran (8 mL) was treated with 1N sodium hydroxide (1.7 mL) and a white precipitate formed after 1 minutes. After 5 minutes, the reaction mixture was concentrated, the residue was acidified with excess hydrochloric acid and partitioned between dichloromethane (100 mL) and water (10 mL). The organic layer was dried (MgSO4) and concentrated. The resulting residue was crystallized from ethyl acetate-hexane-tetrahydrofuran to give 0.343 of 4-[2-(2-naphthalenyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid, mp 167°-170° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[Br:29][CH2:8][C:6]1[O:7][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(CO)o1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=Cc1ccc(CBr)o1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 3.4 g (26.7 mmol) of 5-(hydroxymethyl)furan-2-carboxaldehyde and 7.78 g (29.4 mmol) of triphenylphosphine in 300 ml of dichloromethane at −5° C. are added 5.28 g (29.4 mmol) of N-bromosuccinimide in 10 min. The mixture is stirred at −5° C. for 30 min. The mixture is then concentrated and the residue is purified by chromatography on silica (cyclohexane/AcOet: 7:3) to yield 4.38 g (87%) of 5-(bromomethyl)furan-2-carboxaldehyde in the form of a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>>[CH2:14]([N:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([O:1][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[C:3]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:4]=2)[CH2:13][CH2:12]1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1O
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(COc2ccc(C(=O)N3CCN(CC(C)C)CC3)cc2CC(C)C)cc1
Yield: 82.4 %

Procedure:
As in the case of Example 18, 1-(4-hydroxy-3-isobutylbenzoyl)-4-isobutylpiperazine (1.59 g) was benzylated with 4-methoxybenzyl bromide (0.94 g), thereby yielding 1.69 g of the aimed compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]([OH:23])[CH2:21][N:22]=1>ClCCCl>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:18][CH:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]([O:23][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:21][N:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: OC1CN=C(c2ccccc2F)OC1c1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccccc2F)OC1c1ccccc1
Yield: 39.7 %

Procedure:
Phenyl isocyanate (1 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(2-fluorophenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (2.3 g) in 1,2-dichloroethane (30 cc). The solution obtained is stirred under reflux for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 100 g), contained in a column 2.5 cm in diameter [eluent: cyclohexane/ethyl acetate (7:3 by volume)], collecting 20-cc fractions. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in ethyl acetate, (5RS, 6SR)-2-(2-fluorophenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.3 g), m.p. 128° C., is obtained.
Reaction SMILES: [CH2:1]([CH2:6][O:7][CH2:8][CH2:9][NH2:10])[O:2][CH2:3][CH2:4][NH2:5].[CH3:11][CH:12]([CH3:17])[CH2:13][C:14](=O)[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH2:6]([O:7][CH2:8][CH2:9][NH:10][CH:14]([CH2:13][CH:12]([CH3:17])[CH3:11])[CH3:15])[CH2:1][O:2][CH2:3][CH2:4][NH:5][CH:14]([CH2:13][CH:12]([CH3:17])[CH3:11])[CH3:15]
Reactant: NCCOCCOCCN
Reactant: CC(=O)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)CC(C)NCCOCCOCCNC(C)CC(C)C
Temperature: 23 °C

Procedure:
A 1 liter 3 necked round bottomed flask fitted with condenser, mechanical stirrer, dropping funnel, thermocouple and nitrogen inlet at <20 mL/min was charged with 20 g (0.1350 mol) of 2,2′-(ethylenedioxy)bis(ethylamine) in 450 mL of dichloromethane. STAB (31.44 g) was added with stirring. 31.0 g of 4-methyl-2-pentanone was then added drop-wise to the suspension over 40 mins. After cooling to 23° C. with an ice bath the mixture was stirred at room temperature for about 1.5 hours and left standing for a further day. The crude product was stirred with a mixture of saturated aqueous sodium carbonate solution (30%) (120 ml) and water (60 ml). The aqueous phase was diluted with water (100 ml), shaken, separated and washed with DCM (50 ml). The combined organic phase was washed with water (2×150 ml). It was then dried by shaking with magnesium sulphate and filtered.
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[S:8][C:9]([Cl:12])=[CH:10][CH:11]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[H-].[Na+].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[N:6]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[N:5]=[C:4]([C:7]2[S:8][C:9]([Cl:12])=[CH:10][CH:11]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:4]([C:7]2[S:8][C:9]([Cl:12])=[CH:10][CH:11]=2)[N:5]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[N:6]=1
Reactant: Clc1ccc(-c2n[nH]c(Br)c2-c2ccncc2)s1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(-c3ccc(Cl)s3)c(-c3ccncc3)c2Br)cc1
Product: COc1ccc(Cn2nc(Br)c(-c3ccncc3)c2-c2ccc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 168.3 %
Yield: 80 %

Procedure:
To a solution of 4-[5-bromo-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (14.7 mmol) in 80 mL of N,N-dimethylformamide was added slowly at 0° C. sodium hydride (16.1 mmol). The mixture was stirred 30 min at room temperature prior to dropwise addition of 4-methoxybenzyl chloride (16.1 mmol). The mixture was then stirred for further 5 hours. The mixture was then poured on water and ethyl acetate was added. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/ethyl acetate 4:1 to 1:1) to afford 5.7 g of 4-[5-bromo-3-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine and 4-[3-bromo-5-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine (80% yield) as a mixture 2:1 which was used as such in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:35])([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([OH:35])([C:27]([F:28])([F:29])[F:30])[C:31]([F:32])([F:33])[F:34])=[CH:24][CH:25]=2)[CH2:9][CH2:10]1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
4-(2-Bromo-4-nitrophenoxy)piperidine (10.96 mmol, 3.3 g), 2-(4-(bromomethyl)-phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (10.96 mmol, 3.69 g) and potassium carbonate (32.9 mmol, 4.54 g) were combined in acetonitrile (40 mL) and the mixture stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue dissolved in dichloromethane (150 mL). The organic phase was washed with water (2×50 mL) then brine (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with dichloromethane to 10% methanol/dichloromethane) to afford the title compound (5.25 g). MS (ESI) m/z 558.8 [M+H]+
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[N:10]=[C:9]2[Br:21].[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[Br:21][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:5]3[N:4]=[N:3][N:2]([C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:1]=3)[CH:7]=2)[N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:10]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3nn[nH]n3)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1nn(C2CCCCO2)c2ccc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Temperature: 25 °C

Procedure:
To a solution of 2-(5-(2H-1,2,3,4-tetrazol-5-yl)-3-bromo-1H-indazolyl)perhydro-2H-pyran (0.554 g 1.59 mmol) in dimethyl formamide (5 mL) was added triphenylmethyl chloride (0.662 g, 2.38 mmol), and triethyl amine (1.110 mL, 7.95 mmol). The reaction was heated to reflux temperature for 3.5 hours and maintained at room temperature overnight. The solvent was removed under reduced pressure. The resulting solid was dissolved in 20 mL of ethyl acetate was washed with 10 ml-portions of water. The title compound was purified by column chromatography (SiO2, 20% ethyl acetate in hexanes) (0.74 g, 70%): ES-MS (m/z) mass not detected.
Reaction SMILES: CO.[O-2].[Ba+2].O.[NH2:6][NH2:7].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[CH:8](=[N:6][NH2:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: O=Cc1ccccc1
Agent: [Ba+2]
Agent: [O-2]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: NN=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 7.8 %

Procedure:
A 1 L flask equipped with a mechanical stirrer, thermometer, and addition funnel was charged with 250 mL of methanol and cooled to 0° C. Barium oxide (9.8 g, 64 mmol) was added portion-wise with exotherm. The reaction was cooled to 0° C., and hydrazine monohydrate (64.1 g, 1.28 mol) was slowly added. The reaction mixture was stirred for 10 minutes, after which time benzaldehyde (135.8 g, 1.28 mol) was added drop-wise over a 30 minute period. The reaction was then stirred for 1 hour, while maintaining a temperature below 8 (C. 1H NMR indicated the absence of ketone and a complete reaction. Ether (200 mL) was added, and the BaO was filtered through a bed of silica gel. The resultant clear filtrate was liberated of methanol on a rotary evaporator at or below room temperature. A large mass of bright yellow solid azine (1H-NMR (300 MHz, CDCl3) δ (ppm): 8.67 (s, 2H), 7.85 (m, 4H), 7.47 (m, 6H)), was removed by filtration, and the filtrate was distilled to provide ca. 12 g of distillate benzylidene-hydrazine. The material was stored under refrigeration. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.74 (s, 1H), 7.53 (m, 2H), 7.35 (m, 3H), 5.5 (br, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][C:28]=1[F:35].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH:17]5[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=4[CH:24]=3)[C:4](=[O:25])[CH:3]=2)=[CH:29][C:28]=1[F:35]
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(Cl)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)c(F)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (4-chloro-3-fluorophenyl)methanol (0.073 ml), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. overnight. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from IPA-EtOAc to give the title compound (59.7 mg) as an off-white solid.