Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].CON(C)[C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:9].O.[Cl-].[NH4+]>C1COCC1>[C:10]12([C:8](=[O:9])[CH:1]=[CH2:2])[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:13][CH:12]([CH2:18]3)[CH2:11]1)[CH2:19]2
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C12CC3CC(CC(C3)C1)C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A THF solution (20.0 mL, 10.0 mmol) comprising 1 mol/L of vinylmagnesium bromide was slowly added dropwise to a THF (45 mL) solution comprising 2.23 g (5.00 mmol) of N-methoxy-N-methyladamantan-1-carboxamide that had been cooled in a bath containing ice and salt while keeping the THF solution at −10 to 0° C. Thereafter, the mixture was stirred at 0° C. for 1 hour, and stirred at room temperature overnight. The reaction mixture was slowly added dropwise, using a Pasteur pipette, to saturated ammonium chloride water that had been cooled in a bath containing ice and salt, while keeping it at −10 to −5° C. After the completion of the dropwise addition, the mixture was heated to 0° C. Since the mixture comprises two layers, the water layer was separated, and ethyl acetate extraction was performed three times. Subsequently, the primarily separated organic layer and the combined ethyl acetate layers were combined, and the organic layer was washed with saturated ammonium chloride water 5 times, and with brine once. Drying over sodium sulfate, filtration, condensation, and drying under reduced pressure at room temperature for 3 hours were performed, thereby giving the crude product of 1-(adamantan-1-yl)prop-2-en-1-on (containing 1.56 g of impurities such as 3-[methoxy(methyl)amino]-1-(adamantan-1-yl)propan-1-on, etc.) The crude product was used in the next reaction without purification. Under an Ar atmosphere, 1.43 g of 1,8-diazabicyclo[5.4.0]undeca-7-en (DBU) was added to an ice-cooled suspension comprising 1.18 g of the crude product of 1-(adamantan-1-yl)prop-2-en-1-on, 1.60 g of 1-(2-oxopropyl)pyridinium chloride, 1.18 g of molecular sieves 4A, and ethanol (24 mL), and the mixture was stirred at room temperature for 2 days. Under ice-cooling, 1N HClaq. was added to the reaction mixture, the pH was adjusted to 1, and ethyl acetate extraction was performed. The organic layer was separated, and washed with brine three times, followed by drying over sodium sulfate, filtration, condensation, and drying under reduced pressure at room temperature for 1 hour, thereby giving the crude product (936 mg) of 3-(adamantan-1-yl)phenol. This crude product and the crude product of 3-(adamantan-1-yl)phenol (456 mg) obtained from the crude product of 400 mg of 1-(adamantan-1-yl)propa-2-en-1-on under the same conditions were combined. Then this crude product was separated and purified by silica gel column chromatography, thereby giving 222 mg of 3-(adamantan-1-yl)phenol (yield: 9.7%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:9][NH2:10].C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:9][NH:10][S:31]([C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cn1cccc1C(CCN)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cccc1C(CCNS(=O)(=O)c1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
3-(1-Methyl-2-pyrrolyl)-3-(3-pyridyl)propylamine (0.59 g) and triethylamine (0.31 g) were dissolved in 20 ml of methylene chloride, followed by addition of 0.64 g of p-chlorobenzene sulfonylchloride, and stirred at room temperature for 18 hours. To the reaction mixture was added 2N hydrogen chloride, and the organic phase was separated, which was then extracted with methylene chloride from the aqueous phase. After washing in saturated aqueous sodium hydrogencarbonate and in aqueous saturated sodium chloride solution and drying over magnesium sulfate, the solvent was distilled off to obtain 0.96 g of N-[3-(1-methyl-2-pyrrolyl)-3-(3-pyridyl)propyl ]-4-chlorobenzenesulfonamide.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:16])([CH3:15])[C:4](=[N:13][OH:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:17][C:18]1[N:23]=[C:22](Cl)[C:21]([N+:25]([O-:27])=[O:26])=[C:20]([OH:28])[N:19]=1.C(N(CC)CC)C>C(O)C>[NH2:17][C:18]1[N:19]=[C:20]([OH:28])[C:21]([N+:25]([O-:27])=[O:26])=[C:22]([NH:2][C:3]([CH3:16])([CH3:15])[C:4](=[N:13][OH:14])[CH2:5][O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:23]=1
Reactant: CC(C)(N)C(COc1ccccc1)=NO
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(Nc1nc(N)nc(O)c1[N+](=O)[O-])C(COc1ccccc1)=NO
Yield: 16.1 %

Procedure:
A mixture of 3-amino-1-(p-chloro)-phenoxy-3-methylbutan-2-one oxime hydrochloride (IV) (5.58 g), 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine (III) (Hal = Cl) (3.81 g) and dry triethylamine (8.2 g) was heated to reflux in dry ethanol (240 ml) for 16 hours and filtered hot. The filtrate was reduced in volume and the solid so obtained was filtered off. Recrystallisation from ethanol gave the nitropyrimidine oxime (II) (1.17 g) as a pale yellow gelatinous solid, m.p. >250°C (decomp.).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]([CH3:23])([CH3:22])[C:13]=34)[O:6][N:5]=2)[CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH:11]=[N:10][C:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]=3)=[C:13]2[C:14]1([CH3:23])[CH3:22])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Nc2ccccc2-n2cnc(-c3nc(C4CC4)no3)c21
Product: CC(=O)N1c2ccccc2-n2cnc(-c3nc(C4CC4)no3)c2C1(C)C
Reaction time: 72 h

Procedure:
A mixture of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-4,4-dimethylimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 99, 0.19 g) and acetic anhydride (3 ml) is stirred at 100° for 3 days. Excess acetic anhydride is then removed under reduced pressure and the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The phases are separated and the organic phase is filtered through sodium sulfate and concentrated. The crude product is chromatographed on silica gel (200 ml) eluting with ethyl acetate/dichloromethane (20/80). The appropriate fractions are pooled and concentrated to give the title compound, mp 169°-171°; MS (m/z) at 349; IR (mineral oil) 1666, 1613, 1327, 1281 and 1504 cm-1 ; NMR (CDCl3) 1.12, 1.94, 2.16, 2.18, 7.20, 7.33, 7.52 and 8.14 δ.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][OH:31])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:34]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][O:31][CH3:34])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(CO)nccc4o3)n2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1nccc2oc(-c3nc(COC4CCN(C(=O)OC(C)(C)C)CC4)no3)cc12
Reaction time: 1.5 h

Procedure:
To a stirred solution of 4-[5-(4-hydroxymethylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 24, 50 mg, 116 μmol) in THF was added sodium hydride (60% dispersion in mineral oil, 6 mg, 150 μmol). After effervescence had ceased, MeI (10 μL, 161 μmol) was added. After 90 min, the mixture was poured into H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried and concentrated. Purification via column chromatography afforded the title compound: RT=3.54 min; m/z (ES+)=445.1 [M+H]+.
Reaction SMILES: S([O-])([O-])(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].C([O:13][CH:14]=[C:15]([C:21]([O-])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.[OH-].[Na+]>O>[CH2:19]([O:18][C:16]([C:15]1[C:14]([OH:13])=[N:10][C:8]([O:7][CH3:6])=[N:9][CH:21]=1)=[O:17])[CH3:20]
Reactant: COC(=N)N
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cnc(OC)nc1O
Yield: 80 %

Procedure:
The applicant company has found that the operation can more advantageously be carried out in water: an aqueous solution of 1 mol of the neutral sulphate of O-methylisourea (concentration of between 5 and 10%) has the corresponding amount (2 mols) of ethyl ethoxymethylenemalonate added thereto, and the mixture is stirred vigorously so as to keep the second reagent emulsified. An aqueous solution of an alkali metal hydroxide is then added thereto at a rate such that the temperature of the mixture remains between 20° and 30° C. The mixture is stirred for another two hours at room temperature, after the addition of the alkaline reagent. If sodium hydroxide solution is used as the reagent, the sodium salt of the ester (XVI) precipitates in the medium which is brought to pH 5 by the addition of an inorganic or organic acid when the reaction has finished. The solution obtained, which is filtered if necessary in order to remove a small amount of insoluble matter, is extracted with an appropriate solvent chosen, preferably, from the polyhalogenated aliphatic hydrocarbons, more especially chloroform. After washing and drying the organic solution, evaporation in vacuo leaves 5-ethoxycarbonyl-4-hydroxy-2-methoxy-pyrimidine (XVI), which is practically pure, with a yield of about 80%. The product can then be purified by recrystallisation from a suitable solvent, especially isopropanol.
Reaction SMILES: C([N:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16]/[CH:17]=[CH:18]\[CH2:19][O:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]1=[O:40])(=O)C1C=CC=CC=1.C(Cl)Cl.CO>CO[Na].CO>[C:21]([O:20][CH2:19][CH:18]=[CH:17][CH2:16][N:11]1[CH:12]=[CH:13][C:14](=[O:15])[NH:9][C:10]1=[O:40])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(c1ccccc1)n1c(=O)ccn(C/C=C\COC(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Agent: CO[Na]
Solvent: CO
Solvent: ClCCl
Product: O=c1ccn(CC=CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.2 %

Procedure:
A suspension of compound (2) (50 mg; 0.095 mmol) in MeONa/MeOH 0.2 M (5 ml) was stirred at room temperature for 24 hours. During such period of time the suspension became a colourless solution and the TLC (DCM/MeOH 90:10) showed the complete disappearance of the starting amide, and the presence of a new spot at lower Rf. The solution was neutralised with Dowex ion exchange resin. The resin was filtered off and washed twice with MeOH (5 ml). The filtrate was concentrated under reduced pressure and purified by flash chromatography using MeOH/DCM 10:90 as eluent which gave the title compound as a white solid (38 mg, 90%). Rf: 0.66 in DCM/MeOH 90:10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 70.8 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (85 mg, 0.23 mmol) and 3-(trifluoromethyl)benzyl bromide (200 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) was added and the solution was washed with water (3×20 mL), 50% aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50-100% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(3-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (108 mg, 71%) as a white solid. APCI(+)-MS (M+H) 463.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[C:17]([O:21][C:22](=[O:29])[NH:23][C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:5]1([O:4][C:2]([N:26]2[CH2:27][CH2:28][C@@H:24]([NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:29])[CH2:25]2)=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)Oc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (1 eq.) is added dropwise to a solution of pyridine in DCM. The reaction mixture is cooled to 0° C. and a solution of (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at RT for 1 hour. The reaction mixture is partitioned between (0.2 M) HCl)(aq) and DCM. The organics are washed with water, (sat)NaHCO3(aq) and brine. The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([F:14])[CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[F:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:2])=[O:4])[N:6]2[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc2c(F)cccc2[nH]1
Product: O=C(O)c1cc2c(F)cccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 4-fluoro-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 318.1 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH3:23])[OH:15].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH3:23])=[O:15]
Reactant: Cc1cc(Cl)ccc1C(O)c1c(-c2ccccn2)nn(C)c1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C(=O)c1c(-c2ccccn2)nn(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)(4-chloro-2-methylphenyl)methanol (31.6 g, 91 mmol) in DCM (500 mL) at about 0° C. was added Dess-Martin periodinane (42.3 g, 100 mmol). The cold bath was removed and the mixture was allowed to warm to rt. After about 3 h additional Dess-Martin periodinane (1.92 g, 4.54 mmol) was added and the mixture was stirred for about 30 min. A saturated aqueous NaHCO3 solution (500 mL) was added then the mixture was filtered. The solvent layers of the filtrate were separated. The filter cake was triturated with DCM then filtered. The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was heated in EtOAc (300 mL) to just below the boiling point then filtered. The filtrate was allowed to cool to rt and the precipitate was collected by filtration. Additional crops of desired product were obtained by concentration of the filtrate followed by precipitation with Et2O/heptane. The crops were combined to give (5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)(4-chloro-2-methylphenyl)methanone (23.47 g, 75%): LC-MS (Table 1, Method g) Rt=2.43 min, m/z 346/348 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.20-8.15 (m, 1H), 7.77-7.67 (m, 2H), 7.33-7.28 (m, 1H), 7.21-7.13 (m, 2H), 7.08-7.01 (m, 1H), 3.96-3.89 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:18]=[CH:17][O:16][N:15]=3)[N:11]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:10]=2)[N:3]=1.C[O-:28].[Na+]>CO>[F:8][C:7]1[C:2]([OH:28])=[N:3][C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:18]=[CH:17][O:16][N:15]=3)[N:11]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:10]=2)=[N:5][CH:6]=1
Reactant: Fc1ccccc1Cn1nc(-c2ncc(F)c(Cl)n2)cc1-c1ccon1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: Oc1nc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)ncc1F
Temperature: 40 °C
Yield: 55 %

Procedure:
To a solution of 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (Compound 30, 0.040 g, 0.107 mmol) in 1 mL methanol was added sodium methoxide (0.024 ml, 0.107 mmol) as a 25% weight solution. The reaction was stirred at 40° C. until judged complete by LC/MS. Once complete, the reaction mixture was directly concentrated in vacuo, and the resulting crude oil was purified using silica gel chromatography employing a 0-100% ethyl acetate in hexane gradient to afford the desired compound as a white solid in 55% yield.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:28]([CH2:30][NH2:31])[OH:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:29][CH2:28][CH2:30][NH:31][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCCO)ccc21
Yield: 82 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (91 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), ethanolamine (17 mg), HBTU (116 mg), and DIEA (67 uL). LC/MS: m/z 436.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.46 (bs, 1H), 8.38 (s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.77 (s, 2H), 7.67 (d, 1H), 7.48 (d, 1H), 4.72 (t, 1H), 3.65 (bs, 3H), 3.52 (q, 2H), 3.34 (q, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-5-nitropyridine (2.5 g, 15.7 mmol) in THF (25 mL), are added 1-isopropylpiperazine (2.01 g, 15.7 mmol) and K2CO3 (3.25 g, 23.6 mmol). The reaction mixture is stirred at 50° C. for 4 hours and then at 70° C. overnight. The solvent is removed in vacuo and the resultant orange solid is triturated using 10:1 petroleum ether-diethyl ether. The isolated compound (3.7 g, 94%) is used in the next step without further purification.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[CH2:23]([C:25]1[NH:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=1)[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:26]4[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:29]=[C:25]4[CH2:23][CH3:24])[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(Cl)cc1
Reactant: CCc1nc(C(F)(F)F)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc(C(F)(F)F)cn1C1CCN(c2cnn(-c3ccc(Cl)cc3)c2C(C)C)C1=O
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 1.3 %

Procedure:
A mixture of 3-bromo-1-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.200 g, 0.52 mmol), 2-ethyl-4-(trifluoromethyl)-1H-imidazole (0.060 g, 0.36 mmol) and K2CO3 (0.080 g, 0.58 mmol) in DMF (1.5 mL) was stirred at 65° C. for 1.5 hrs. The mixture was then cooled to room temperature, quenched with water (30 mL), extracted with EtOAc (50 mL), and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.0022 g, TFA salt, 1.0%). 1H NMR (TFA salt) (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.49 (m, 2H), 7.35 (m, 2H), 7.21 (s, 1H), 5.03 (dd, J=10.4, 8.8 Hz, 1H), 3.88 (m, 1H), 3.81 (m, 1H), 3.03 (heptet, J=7.0 Hz, 1H), 2.88 (m, 2H), 2.30 (m, 2H), 1.40 (t, J=7.4 Hz, 3H), 1.23 (m, 6H); MS: (ES) m/z calculated for C22H23ClF3N5O [M+H]+ 466.1. found 466.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[NH:12][N:13]=[CH:14][CH:15]=2)=[N:8][C:7]=1[CH3:16])=[O:5])[CH3:2].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:12]=2)=[N:8][C:7]=1[CH3:16])=[O:5])[CH3:2]
Reactant: Fc1ccc(CCBr)cc1
Reactant: CCOC(=O)c1sc(-c2ccn[nH]2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(-c2ccn(CCc3ccc(F)cc3)n2)nc1C
Temperature: 90 °C
Yield: 41.4 %

Procedure:
A solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid ethyl ester (2.5 g, 10.54 mmol) in dimethyl sulfoxide (50 mL) was treated with 1-(2-bromo-ethyl)-4-fluoro-benzene (2.10 g, 10.54 mmol) and potassium carbonate (4.30 g, 31.64 mmol), and the reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (hexanes:ethyl acetate, 1:1) to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.57 g, 45% yield) as a white solid. MS (M+H)+=360; Rt=1.65 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)C(=O)[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:12]([NH:11][C:7](=[N:8][OH:9])[C:3]1[C:2]([NH:1][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:6][O:5][N:4]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1nonc1-c1noc(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1nonc1C(=NO)NCc1ccccc1)c1ccccc1

Procedure:
This compound was prepared according to the procedure of Example 35 using 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-benzyl-1,2,4-oxadiazol-5(4H)-one and benzoyl chloride as the starting materials. LCMS for C17H16N5O3 (M+H)+: m/z=338.2.