Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[CH2:3]([O:5][C:6]([CH2:8][C:9]([CH3:17])([CH3:16])[CH:10](C(O)=O)[C:11]#[N:12])=[O:7])[CH3:4].C([O-])(=O)C.[Na+].Cl>O>[CH2:3]([O:5][C:6]([CH2:8][C:9]([CH3:17])([CH3:16])[CH:10]([Cl:1])[C:11]#[N:12])=[O:7])[CH3:4]
Reactant: CCOC(=O)CC(C)(C)C(C#N)C(=O)O
Reactant: ClCl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(C)(C)C(Cl)C#N
Temperature: 20 °C
Reaction time: 5 h
Yield: 68.7 %

Procedure:
17.8 g (0.25 mol) of chlorine were passed into a solution of 42.6 g (0.2 mol) of 3-carboxy-3-cyano-2,2-dimethyl-propane-1-carboxylic acid ethyl ester and 41 g of sodium acetate in 400 ml of water at 20° C. The mixture was subsequently stirred at 20° C. for 5 hours and then acidified with dilute HCl. The acid solution was worked up as described under Example 1. 28 g (69% of theory) of 3-chloro-3-cyano-2,2-dimethyl-propane-1-carboxylic acid ethyl ester were obtained in the form of a colorless oil of boiling point 80°-82° C./1 mm Hg.
Reaction SMILES: C(C1CCC2C(=C(C(=O)C)C=CC=2[F:14])C1=O)(=O)C.[C:19]([NH:22][CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[C:26]([NH:33]C(=O)C)[CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:37])(=[O:21])[CH3:20]>>[C:19]([NH:22][CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[C:26]([NH2:33])[CH:27]=[CH:28][C:29]=2[F:14])[C:24]1=[O:37])(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(F)c2c1C(=O)C(C(C)=O)CC2
Reactant: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Product: CC(=O)NC1CCc2c(F)ccc(N)c2C1=O

Procedure:
The reaction was carried out in the same manner as in Example 1-(4), except that 300 mg of the compound prepared in (1) above was used instead of 2,8-diacetylamino-1-tetralone of Example 1-(4), and post-treated to produce 182 mg of the title compound.
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH3:3]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(-c2ccccc2)cc1
Yield: 166 %

Procedure:
Iodoethane (68.7 g, 35,57 mL, 440.6 mmol) was added to a suspension of 50 g (170.2 mmol) of 4-hydroxy-1,1′-biphenyl and 40.6 g (293.75 mmol) K2CO3 in 600 mL acetone. The resulting reaction mixture was stirred under reflux for 16 hours. After cooling to room temperature the acetone was removed under reduced pressure, the residue was dissolved in ethyl acetate and extracted with water. The aqueous layers where extracted 3 times with ethyl acetate, the combined organic phases dried (Na2SO4) and evaporated to yield 56 g of the desired compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([Cl:20])[N:14]=1.O>N1C=CC=CC=1>[Cl:12][C:13]1[C:18]([NH:19][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:17][CH:16]=[C:15]([Cl:20])[N:14]=1
Reactant: Nc1ccc(Cl)nc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccc(Cl)nc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
4-Methoxy-benzoyl chloride (4.15 mL, 30.7 mmol) was added dropwise to a stirred, cooled 0° C. mixture of 2,6-dichloro-pyridin-3-ylamine (5 g, 30.7 mmol) in pyridine (31 mL). Following addition, the reaction mixture was allowed to warm to room temperature and stirring was continued for 30 minutes, at which point the reaction mixture was poured into water causing the formation of a precipitate which was collected by filtration. The collected solids were washed with additional water before drying overnight in vacuo affording N-(2,6-dichloro-pyridin-3-yl)-4-methoxy-benzamide (8.66 g, 29.1 mmol, 95% yield) which was used in subsequent reactions without further purification. ES MS (M+H+)=297.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](O)[CH2:15]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.ClCCl.COCCN(S(F)(F)[F:32])CCOC.C(=O)(O)[O-].[Na+]>O>[CH:1]([N:14]1[CH2:17][CH:16]([F:32])[CH2:15]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
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
A 250 mL, round bottom flask was charged with 3.0 g (12.5 mmol) of 1-benzhydryl-3-hydroxyazetidine and 80 mL of dichloromethane. To the stirring solution at −78° C. was added 4.6 mL (25 mmol) of [bis(2-methoxyethyl)amino]sulfur trifluoride via addition funnel over a period of about 3 h. The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was added portionwise (with caution) to a large extractor containing water and saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with 80 mL of dichloromethane. The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography using a Biotage® system (gradient, hexane to 80% ethyl acetate/hexane) afforded the desired product. LC/MS 242.1 (M+1).
Reaction SMILES: C(C(C(OC(C([O:20][C:21]([C:24]([O:30][C:31]([C:34]([C:37]([F:40])([F:39])[F:38])([F:36])[F:35])([F:33])[F:32])([C:26]([F:29])([F:28])[F:27])[F:25])(F)[F:22])=O)(C(F)(F)F)F)(F)F)(F)F)(F)(F)F.[F-].[Na+]>>[C:37]([C:34]([C:31]([O:30][C:24]([C:21]([F:22])=[O:20])([C:26]([F:29])([F:28])[F:27])[F:25])([F:33])[F:32])([F:36])[F:35])([F:40])([F:39])[F:38]
Reactant: O=C(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [F-]
Agent: [Na+]
Product: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 140 °C

Procedure:
The reaction product containing CF3CF2CF2OCF(CF3)—COOCF2CF(CF3)OCF2CF2CF3 (83.0 g) obtained in Example 1-2 was charged together with NaF powder (1.1 g) into a flask and heated at 140° C. for 15 hours in an oil bath, while vigorously stirring. At an upper portion of the flask, a liquid sample (81.3 g) was recovered through a reflux condenser having the temperature adjusted to 70° C. A product obtained by distilling the liquid sample for purification was analyzed by GC-MS, whereupon formation of CF3CF2CF2OCF(CF3)COF was confirmed.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][S:15](=[O:25])(=[O:24])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1.C(O)(=O)C[C:35](CC(O)=O)([C:37](O)=[O:38])[OH:36]>C(O)CO>[OH:36][CH2:35][CH2:37][O:38][C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][S:15](=[O:25])(=[O:24])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=S(=O)(NCc1ccccc1)Nc1ncnc(Cl)c1-c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: OCCO
Product: O=S(=O)(NCc1ccccc1)Nc1ncnc(OCCO)c1-c1ccc(Cl)cc1
Temperature: 102 °C

Procedure:
Potassium tert.-butoxide (3.5 g) was dissolved in ethyleneglycol (35 ml), benzyl sulfamic acid-[6-chloro-5-(4-chlorophenyl)-4-pyrimidinyl]-amide (1.8 g, Referential Example 15) was added and the mixture was heated to 102° C. for 11 h. The mixture was poured onto ice/water and acidified to pH=4 with solid citric acid. The precipitated product was filtered off, washed with water and dried at HV to give benzyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(4-chlorophenyl)-4-pyrimidinyl]-amide (1.77 g). tR=4.36 (LC); [M+H]+=435.09 (ES+).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1>C1COCC1>[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=2)=[O:36])=[CH:33][N:32]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: COC(=O)c1ccc(N)nc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2ccc(Br)nc2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.7 %

Procedure:
2-Chloro-1-methylpyridinium iodide (2.2 g, 9.8 mmol) and DIPEA (1 ml) were added to a mixture of 5-fluoropyridin-2-amine 1 (554 mg, 4.9 mmol) and 6-bromonicotinic acid 2 (1 g, 4.9 mmol) in THF. The reaction mixture was stirred at rt for 2 days. At the conclusion of the reaction, the reaction mixture was concentrated to ⅓ of its volume and the precipitated product was filtered off. The filtrate was concentrated, diluted with chloroform (100 ml), washed with water and brine and then dried over Na2SO4. Evaporation of the solvent gave a crude yellow product, which crystallized in EtOAc to give 6-bromo-N-(5-fluoropyridin-2-yl)nicotinamide 3 (1.05 g, 71%) as a white solid. Mp. 173-174° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.CN([CH:17]=[O:18])C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:17][OH:18])=[N:8][CH:9]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCc1ccc(F)cn1
Temperature: -78 °C
Yield: 90 %

Procedure:
At −78° C. under nitrogen, add n-butyllithium (2.5 M in hexane, 16.4 mL, 40.9 mmol) via syringe to a solution of 2-bromo-5-fluoro-pyridine (6.0 g, 34.1 mmol) in toluene (220 mL), while keeping the reaction temperature below −60° C. Stir the mixture at −78° C. and then add DMF (3.4 mL, 44.3 mmol) and stir for 1 h at this temperature. Warm to −10° C. and quench with methanol (10 mL). Concentrate the mixture to half of the volume in vacuo. Dilute with methanol (150 mL), cool the mixture to −78° C. and add sodium borohydride (3.2 g, 85.2 mmol) portion wise over 5 min. Warm the mixture to ambient temperature and stir for 2 h. Quench with water (10 mL) and remove the organic solvent in vacuo to obtain an oil/water mixture. Extract with diethyl ether (3×100 mL), dry the combined organic extracts, wash with brine, dry and concentrate in vacuo to obtain the desired intermediate as an oil (3.9 g, 91%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.C[Si]([N:39]=[N+:40]=[N-:41])(C)C.C([Sn](=O)CCCC)CCC.C(Cl)Cl>C1(C)C=CC=CC=1.CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([C:32]4[NH:41][N:40]=[N:39][N:33]=4)=[CH:30][CH:31]=3)=[CH:4][C:3]=2[O:2]1
Reactant: N#Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(-c2nnn[nH]2)cc1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Yield: 70 %

Procedure:
To a solution of Example 32 (0.25 g, 0.56 mmol) in 10 mL of toluene were added successively trimethylsilylazide (0.30 mL, 4 equiv.) and dibutyltinoxide (0.06 g, 0.4 equiv.). The resulting mixture was stirred at reflux for two days. T/c monitoring showed formation of a new compound (DCM:MeOH (80.20), Rf=0.35). The reaction mixture was concentrated in vacuo. The resulting yellow gum was dissolved in MeOH and concentrated in vacuo. The residue was partitioned between EtOAc (25 mL) and an aqueous saturated solution of NaHCO3 (25 mL). The organic phase was extracted with an additional portion of an aqueous saturated solution of NaHCO3 (25 mL). The combined aqueous extracts were acidified to pH=2 with HCl (1N) and then extracted with EtOAc (2×25 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated to give a yellow powder that was purified via flash chromatography (SiO2, DCM:MeOH (90:10)). Recrystallization from 2-propanol:iPr2O (1:1) gave the title compound (0.19 g, 70%) as white crystals.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[CH3:9][N:10]([CH3:29])[C:11]1([C:27]#N)[CH2:16][CH2:15][C:14]([CH2:23][N:24]([CH3:26])[CH3:25])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1.[NH4+].[Cl-].[OH-].[Na+]>O.C1COCC1>[CH3:25][N:24]([CH2:23][C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12][C:11]([N:10]([CH3:9])[CH3:29])([C:27]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:16][CH2:15]1)[CH3:26]
Reactant: CN(C)CC1(c2ccccc2)CCC(C#N)(N(C)C)CC1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1(c2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2M phenylmagnesium chloride solution in THF (3.5 mL, 7.0 mmol) was slowly added in drops to a solution of the title compound of step 7 (1.00 g, 3.5 mmol) in abs. THF (10 mL) in a nitrogen atmosphere and with ice cooling at 10° C. The solution was stirred for 20 h at RT. Then 20% NH4Cl solution (5 mL) and water (2 mL) were added and the solution was extracted with ether (3×5 mL). The combined organic phases were washed with water (2 mL) and saturated NaCl solution (2 mL), dried over Na2SO4 and concentrated to low volume in a vacuum. By flash chromatography of the residue with chloroform/methanol (20:1) a salt of the product was obtained that was released with 1N NaOH, extracted with chloroform, dried over Na2SO4, and the solvent removed from it in a vacuum.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([O:23][CH3:24])[CH:17]=[CH:16]2.[Cl-].[NH4+]>CCCCCC.C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([O:23][CH3:24])[CH:17]=[CH:16]2
Reactant: COc1ccc2cc(Br)ccc2n1
Reactant: Cn1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(-c3nccn3C)ccc2n1
Temperature: 25 °C

Procedure:
n-Butyl lithium (9 cm3 of a 1.6M solution in hexane) was added at -45° to a stirred solution of 1-methyl-(1H)-imidazole (1.03 cm3) in THF (30 cm3) under nitrogen. After 1.25 hours a solution of anhydrous zinc chloride (1.95 g) in THF (30 cm3) was added dropwise over 5 minutes giving a white precipitate. The mixture was warmed to room temperature, a solution of 6-bromo-2-methoxyquinoline (3 g) and tetrakis (triphenylphosphine) palladium(O) (0.2 g) in THF (20 cm3) was added, and the solution was heated under reflux for 16 hours. Saturated ammonium chloride (2 cm3) was added, the reaction mixture was concentrated in vacuo, and the residue partitioned between chloroform (100 cm3) and a solution of ethylenediaminetetraacetic acid disodium salt (10 g) in water (100 cm3). The aqueous phase was extracted further with chloroform (2×50 cm3) and the combined and dried (MgSO4) extracts were evaporated in vacuo to give a solid, which was chromatographed on silica (Merck "MK 60.9385"), eluting with chloroform:methanol, 19:1 (by volume). The requisite fractions were combined and evaporated in vacuo to afford a foam which was recrystallised from ethyl acetate-hexane to give 6-[1-methyl-(1H)-imidazol-2-yl]-2-methoxyquinoline, m.p. 116.5°-118.5°, (0.517 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].S(Cl)(Cl)=O.[Cl:17][S:18](O)(=[O:20])=[O:19]>O>[Cl:17][S:18]([C:10]1[CH:11]=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
Molten 2-ethoxybenzoic acid (25.0 g, 0.150 mol) was added to a stirred, ice-cooled mixture of thionyl chloride (11 ml, 0.151 mol) and chlorosulphonic acid (41.3 ml, 0.621 mol), whilst maintaining the temperature of the reaction mixture below 25° C. The resulting mixture was stirred at room temperature for 18 hours and then poured into a stirred mixture of ice (270 g) and water (60 ml) to give an off-white precipitate. Stirring was continued for 1 hour, then the product was collected by filtration, washed with water and dried under vacuum to provide the title compound (36.08 g). A reference sample, m.p. 115-116° C., was obtained by crystallisation from hexane:toluene. Found: C,41.02; H, 3.27. C9H9ClO5S requires C,40.84; H, 3.43%. δ (CDCl3): 1.64(3H, t), 4.45(2H, q), 7.26(1H, d), 8.20(1H, dd), 8.80(1H, d).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:21])C>S(=O)(=O)(O)O>[OH:21][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(OCC(F)(F)C(F)(F)F)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: Cc1c(OCC(F)(F)C(F)(F)F)ccnc1CO
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (2 drops) was added to a solution of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide (2.5 g) in acetic anhydride (8 ml) and the mixture was stirred at 110° C. for 2 hours and then concentrated. The residue was dissolved in methanol (30 ml), 2 N aqueous sodium hydroxide (20 ml) was added, and the mixture was stirred at room temperature for 2 hours. After concentration, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was then distilled off, and the residue was applied to a silica gel (50 g) column. Elution with chloroform-methanol (10:1) and recrystallization from isopropyl ether gave 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine as a brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6](=[O:25])[C:5]=1O)(=O)[CH3:2].O.[NH2:28][NH2:29]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:29][NH:28][C:5]=3[C:6](=[O:25])[N:7]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:10][CH:11]=1
Reactant: NN
Reactant: COc1ccc(CN2C(=O)C(O)=C(C(C)=O)C2c2ccc(Cl)cc2)cc1
Solvent: O
Product: COc1ccc(CN2C(=O)c3[nH]nc(C)c3C2c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 4-acetyl-5-(4-chlorophenyl)-3-hydroxy-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (Step 71.2) and hydrazine hydrate at 100° C. for 16 hr. tR: 4.75 min (HPLC 1); tR: 1.05 min (LC-MS 2); ESI-MS: 368 [M+H]+ (LC-MS 2); ESI-MS: 366 [M−H]− (LC-MS 2).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[NH2:18])[S:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[C:35](O)=[O:36]>O>[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[C:35]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[C:14]1[S:13][C:10]2[C:9]([N:15]=1)=[CH:8][C:7]([CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[CH:12][N:11]=2)=[O:36]
Reactant: Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 5-methyl-2-phenyloxazole-4-carboxylic acid. The product was isolated by precipitation by the addition of water, triturated with hot methanol and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C28H25N5O2S: 495.17. Found (M+H)+ m/z=496.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1)#[N:2].Cl.N#[C:13][NH2:14]>C(O)CC>[C:13]([N:2]=[C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1)[O:10][CH2:9][CH2:7][CH3:6])#[N:14]
Reactant: N#CN
Reactant: N#Cc1cncc(CO)c1
Agent: Cl
Solvent: CCCO
Product: CCCOC(=NC#N)c1cncc(CO)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
After 3-cyano-5-hydroxymethylpyridine (0.79 g, 5.9 mmol) was dissolved in 1-propanol (30 ml) and hydrogen chloride gas was passed into the solution under ice-cooling for 30 minutes, the reactor was tight sealed for stirring the mixture at room temperature for 20 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was neutralized with a saturated aqueous sodium carbonate solution and extracted with chloroform (30 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in acetonitrile (20 ml), and an aqueous solution (30 ml) of cyanamide (0.50 g, 11.9 mmol), Na2HPO4 (0.84. g, 5.9 mmol) and NaH2PO4 ·2H2O (3.79 g, 23.7 mmol) was added to the solution. The mixture was stirred at room temperature for 10 hours. After the completion of the reaction, the mixture was extracted with chloroform (100 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl N-cyano-5-hydroxymethyl-3-pyridinecarboximidate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[CH3:12][C:13](OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:14].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:1]1[CH2:12][CH2:13][O:14][CH:2]1[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(CCO)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: OCCO
Product: N#Cc1ccc(CC2OCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a stirred solution of 4-(2-hydroxyethyl)benzonitrile (1.09 g, 7.41 mmol) in DCM (20 mL), was added Dess-Martin Periodinane (3.77 g, 8.84 mmol), and the reaction mixture stirred at room temperature for 1 hour. A 1:1 mixture of saturated aqueous sodium hydrogen carbonate and saturated sodium thiosulfate was added, and the bi-phasic mixture stirred for 1 hour. The organic phase was separated, and the aqueous phase extracted with further DCM (×3). The combined organic extracts were dried with anhydrous magnesium sulphate, and the solvent evaporated at reduced pressure. The crude material was dissolved in toluene (40 mL) and ethylene glycol (2.29 g, 37.05 mmol), and p-toluenesulfonic acid (0.14 g, 0.74 mmol) added. The mixture was heated under Dean and Stark conditions for 2 hours. The solvent was evaporated under reduced pressure, and the residue partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic phase was removed, and the aqueous phase was extracted with further ethyl acetate (×3). The combined organic phases were dried with anhydrous magnesium sulphate, and the solvent evaporated at reduced pressure to afford the title compound (1.40 g, 99%).