Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nn(Cc2ccc(OC)cc2)c2ccccc12
Temperature: 80 °C
Reaction time: 15 h
Yield: 24.8 %

Procedure:
Methyl 3-indazolylcarboxylate (2.0 g, 11.4 mmol) was dissolved in DMF (20 ml). To the resulting solution were added 4-methoxybenzyl chloride (1.7 ml, 12.5 mmol) and potassium carbonate (2.35 g, 17.0 mmol). The resulting mixture was stirred at 80° C. for 15 hours. After cooling, the reaction mixture was poured in water (50 ml), followed by extraction with ethyl acetate (200 ml). The extract was washed with saturated brine (2×100 ml), dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (4:1) eluate fractions, methyl 1-(4-methoxybenzyl)-3-indazolylcarboxylate (polar fractions, 838 mg, 25%) was obtained as a pale yellow oil and 2(4-methoxybenzyl) isomer (non-polar fractions, 500 mg, 15%) was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12](Cl)=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1.C1COCC1.Cl.[NH2:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:31][N:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[NH:25][C:12]([C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:5]=2)=[CH:8][CH:9]=1)=[O:13]
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)Cl)s1
Reactant: Cn1cccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cccc1NC(=O)c1ccc(-c2cc(C(F)(F)F)nn2C)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
5-(1-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonyl chloride (295 mg) and THF (3 ml) were added to a mixture of 2-amino-1-methylpyrrole hydrochloride (202 mg), potassium carbonate (553 mg), THF (2 ml) and water (4 ml), followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with 1 N hydrochloric acid, saturated sodium bicarbonate aqueous solution and water in that order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1-3:2) and then recrystallized from a mixed solvent of ethyl acetate and n-hexane to give N-(1-methyl-2-pyrrolyl)-5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxamide (126 mg) as light yellow powder crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:4][CH:3]1[OH:13].C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(Cl)Cl>[CH:7]1([N:5]2[CH2:4][C@@H:3]([OH:13])[C@H:2]([NH:1][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)[CH2:6]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NC1CN(C2CCCCC2)CC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(N[C@@H]1CN(C2CCCCC2)C[C@H]1O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.84 g (0.01 mole) of 4-amino-1-cyclohexyl-3-pyrrolidinol in 50 ml of methylene chloride was cooled to 5° C. and 2 g of powdered, anhydrous potassium carbonate was added. The mixture was stirred while a solution of 1.86 g of p-nitrobenzoyl chloride in 20 ml of methylene chloride was added dropwise. The mixture was then allowed to warm to room temperature and was stirred for one hour. The slurry was filtered, and the residue, after solvent evaporation, crystallized immediately and was recrystallized from acetone. Yield was 3.0 g (90%), m.p. 155.5°-157.0° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][CH:8]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[CH:5]([CH2:6][CH2:7]2)[CH2:4]1.ClC(Cl)(Cl)[C:25]([N:27]=C=O)=[O:26]>O1CCCC1>[C:21]([C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([N:10]2[CH:8]3[CH2:7][CH2:6][CH:5]2[CH2:4][CH:3]([NH:2][C:25]([NH2:27])=[O:26])[CH2:9]3)=[CH:12][CH:13]=1)#[N:22]
Reactant: N#Cc1ccc(N2C3CCC2CC(N)C3)c2ccccc12
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(N2C3CCC2CC(NC(N)=O)C3)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
The amine 165RL21 (40 mg, 0.144 mmol) was dissolved in tetrahydrofuran (1 mL) and cooled to 0° C. Trichloroacetyl isocyanate (0.019 mL) was added and the solution was left to warm to rt and stirring was continued for 30 minutes. The mixture was concentrated and the residue was dissolved in methanol (1 mL). 2 M NaOH (1 mL) was added, and the mixture was heated to 70° C. for 1 hour. Then, water (20 mL) was added and methanol was removed by evaporation in vacuo. The aqueous phase was extracted with dichloromethane (2×20 mL), and the combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC (0-5% methanol in dichloromethane) to give the title compound (24 mg, 52% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[C:8](Cl)(=[O:10])[CH3:9].O>N1C=CC=CC=1>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:8](=[O:10])[CH3:9])[S:3][CH:4]=1
Reactant: Cc1csc(N)n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc(C)cs1
Reaction time: 2 h

Procedure:
2-Amino-4-methylthiazole (10.0 g, 87.6 mmol) is dissolved in dry pyridine (75 ml) at room temperature. This solution is then treated dropwise with acetyl chloride (6.3 ml, 87.6 mmol). After 2 hours, the reaction mixture is poured into water (1000 ml), and extracted with ethyl acetate (3×250 ml). The combined organic layers are washed with water (2×200 ml), brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in toluene (200 ml) followed by the removal of the solvent in vacuo. The solid thus obtained is dried in vacuo to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]([CH3:12])[N:4]=1.[CH3:13][O:14][CH2:15][CH2:16][OH:17]>F[B-](F)(F)F.[Ag+]>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]([CH3:12])[N:4]=1
Reactant: Cn1nc(CBr)c([N+](=O)[O-])c1Cl
Reactant: COCCO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Product: COCCOCc1nn(C)c(Cl)c1[N+](=O)[O-]
Yield: 65 %

Procedure:
3-Bromomethyl-5-chloro-1-methyl-4-nitropyrazole (2.42 g, 9.5 mmoles), and silver tetrafluoroborate (2.22 g, 11.4 mmoles), were stirred at reflux in 2-methoxyethanol (25 ml) for 6 hours. The black solid was filtered off and the solvent removed under reduced pressure. The oil was dissolved in ethyl acetate (100 ml) and washed with water (100 ml). The organic phase was dried over magnesium sulphate and the solvent removed under reduced pressure. The product was purified by chromatography on silica eluting with 10% ethyl acetate in dichloromethane. Fractions containing product were evaporated yielding the title compound as a white solid (1.54 g, 65%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]=1[CH:25]=O.N1CCCCC1>C(O)C>[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]=1[CH:25]=[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=2)[NH:10][C:9]1=[O:14]
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(S(N)(=O)=O)cc32)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of 5-aminosulfonyl-2-oxindole (84 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 88 mg (71% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Nc1cnc(Cl)cn1
Agent: [Na+]
Solvent: CO
Product: COc1cnc(N)cn1
Temperature: 150 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
To a solution of 5-chloropyrazin-2-amine (0.2 g, 1.54 mmol) in MeOH (3 mL) was added Cu powder (0.13 g, 2.07 mmol), followed by a solution of sodium methoxide in MeOH (0.38 mL, 1.75 mmol). The reaction mixture was stirred at 150° C. in a sealed tube for 24 h. The reaction mixture was then filtered through Celite, and the filtrate was concentrated in vacuo. The crude product obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3%) to afford the title compound (0.13 g, 67%). LCMS (ES+) 126 (M+H)+, RT 1.06 minutes (method 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[H-].[Na+].I[CH3:19].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]([CH3:19])[C:7](=[O:12])[C:8]([F:10])([F:11])[F:9]
Reactant: CI
Reactant: O=C(NCc1cccc(F)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cccc(F)c1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 3-fluoro-N-(trifluoroacetyl)benzylamine (Intermediate 105, 0.508 g) in THF (5 mL) was added to a stirred suspension of sodium hydride (60% oil dispersion, 0.096 g) in THF (5 mL). The resultant mixture was stirred at room temperature for 30 minutes. Iodomethane (0.653 g) was added and the mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 3-fluoro-N-methyl-N-(trifluoroacetyl)benzylamine (0.497 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:33][C:30]1([CH3:34])[CH2:31][O:32][C:1]([C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[CH:11][C:12]4[O:16][C:15]([C:17]5[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=5)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=4[CH:28]=3)[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Reactant: CC(C)(N)CO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=NC(C)(C)CO4)c3)cc12
Temperature: 200 °C
Reaction time: 168 h
Yield: 14.6 %

Procedure:
Zinc chloride (1 mg) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and 2-amino-2-methylpropan-1-ol (10 mg, 0.108 mmol) in PhCl (3 mL) at 130° C. It was allowed to stir for 7 days. ˜20% conversion was observed. Additional amounts of ZnCl (8 mg) and 2-amino-2-methylpropan-1-ol (50 mg) were added and the reaction was heated in the microwave for 1 hr at 200° C. The reaction had progressed-50%. The mixture was concentrated and purified on silica gel (BIOTAGE®, EtOAc/hexanes gradient, Rf˜0.2 in 50% EtOAc/hexanes; fraction collection at λ=254 nm) followed by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (7 mg, 14%). 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (1H, s), 7.97 (2H, dd, J=8.09, 5.65 Hz), 7.93 (1H, s), 7.88 (2H, dd, J=11.44, 8.39 Hz), 7.68 (2H, s), 7.57 (1H, t, J=7.78 Hz), 7.27 (2H, t, J=8.55 Hz), 4.25 (2H, s), 2.99 (3H, s), 1.42 (6H, s). LC-MS retention time 1.60 min; m/z (MH+): 443. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=12.24 min, purity=95%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=10.02 min, purity=95%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][O:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:16](=[O:17])[CH2:15][O:14][CH3:13]
Reactant: OCCCBr
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)OCCCBr
Temperature: 0 °C
Reaction time: 17.5 h
Yield: 106.1 %

Procedure:
1-Bromopropan-3-ol (1.32 mL, 14.6 mmol) was dissolved in anhydrous methylene chloride and cooled to 0° C. under nitrogen atmosphere. The solution was treated with triethylamine (2.2 mL, 15.8 mmol) and methoxyacetyl chloride (1.42 mL, 15.5 mmol) then warmed to room temperature. The reaction mixture was stirred for 17.5 h. It was then diluted with methylene chloride (150 mL) and extracted with saturated sodium bicarbonate (2×50 mL). The aqueous phase was back extracted with methylene chloride (100 mL) and the organic phases were combined and concentrated in vacuo to yield a crude, pale yellow oil (3.27 g). 1H NMR δ 4.25 (t, 2H, J=6.1), 4.05 (s, 2H), 3.45 (s, 3H), 3.22 (t, 2H, I=6.9), 2.18 (quint, 2H, J=6.6). The product was used as such in the following reaction.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([NH:13][CH2:14][NH:15][C:16]([N:18]=[N+]=[N-])=[O:17])=[O:12])[CH2:10][CH:5]2[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[BH4-].[Na+].O>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:18][C:16]([NH:15][CH2:14][NH:13][C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2](=[O:1])[O:3][C:4]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:5]2[CH2:10]1)=[O:12])=[O:17]
Reactant: [N-]=[N+]=NC(=O)NCNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)NCNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
[[[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]amino]methyl]carbamic azide (68 mg, 0.16 mmol) was dissolved in methanol (3 mL). Nickel (II) chloride hexahydrate (77 mg, 0.32 mmol) and sodium borohydride (12 mg, 0.32 mmol) were added thereto, and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The precipitated powder was washed with diisopropyl ether and dried to obtain the title compound (52 mg, yield 81%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[NH:13]2)=[O:11])=[CH:5][CH:4]=1.[CH:32](N(C(C)C)CC)(C)[CH3:33].C(I)C>CN(C)C=O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:13]2[CH2:32][CH3:33])=[O:11])=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)N1
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1C(c2ccc(Cl)cc2)C(c2ccccc2)CN1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 60 °C

Procedure:
To 1.0 g (2.2 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-phenyl-2,3,4,5-tetrahydro-1H-pyrazole-1-carboxamide (Example 3) in 5 ml of dimethylformamide was added 0.5 ml (3.0 mmole) of diisopropylethylamine and 0.25 ml (3.0 mmole) of ethyl iodide. The mixture was heated at 60° C. for 18 hours and then partitioned between diethyl ether and water. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. Filtration, concentration in vacuo, and chromatography on silica gel using diethyl ether and hexanes gave the expected compound, a foam. NMR 1.3 t 3H, 3.1 q 2H, 4.1 dd 1H, 4.3 dd 1H, 4.4 t 1H, 6.7 d 2H, 6.9 m 2H, 7.1 m 5H, 7.5 s 4H, 8.4 s 1H.
Reaction SMILES: Br[C:2]1[C:3]([NH2:20])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.[C:21]([C:23]1[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=1)#[CH:22].C1CCN2C(=NCCC2)CC1>C(#N)C.[Pd]>[NH2:29][C:27]1[N:28]=[C:23]([C:21]#[C:22][C:2]2[C:3]([NH2:20])=[N:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=3)[N:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: C#Cc1cccc(N)n1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Agent: [Pd]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(N)n3)n2)cc1
Temperature: 100 °C
Yield: 25.4 %

Procedure:
3-bromo-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-amine (75 mg, 0.2105 mmol), 6-ethynylpyridin-2-amine (29.84 mg, 0.2526 mmol), Pd EnCat 30 (33.68 mg, 0.01347 mmol) and DBU (70.50 mg, 69.25 μL, 0.4631 mmol) were combined in acetonitrile (1.500 mL). The reaction mixture was heated at 100° C. under microwave conditions for 1.5 hours. After this time the solid residue was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 100% EtOAc/Petroleum Ether to 10% MeOH/DCM) to give the titled product as a beige solid (21 mg, 26% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, 6H), 3.45 (sept, 1H), 6.20 (s, 2H), 6.52 (d, 1H), 7.06 (d, 1H), 7.07 (br s, 2H), 7.45 (dd, 1H), 7.90 (d, 2H), 8.25 (d, 2H) and 8.78 (s, 1H) ppm; MS (ES+) 394.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:17])[NH:15][CH3:16])[CH:9]=1)[CH3:6])[CH3:2].[CH3:20][C:21]1[C:26]([CH2:27]OS(C)(=O)=O)=[CH:25][CH:24]=[C:23]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[N:22]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:17])[N:15]([CH3:16])[CH2:27][C:26]2[C:21]([CH3:20])=[N:22][C:23]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[CH:24][CH:25]=2)[CH:9]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1
Temperature: 0 °C
Yield: 46.1 %

Procedure:
0.28 g (1.05 mmol) of 2-methyl-2-(3-methylcarbamoyl-phenoxy)-propionic acid ethyl ester and 0.36 g (1.05 mmol) of methanesulfonic acid 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl ester (example 59E]) were dissolved in 15 ml of DMF. The reaction mixture was cooled down to 0° C. and 0.05 g (1.20 mmol) of sodium hydride (55% in mineral oil) was added. After stirring for sixteen hours at ambient temperature, the reaction mixture was poured into crashed ice and extracted twice with Et2O. The combined organic phases were washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to give 0.249 g of the title compound as yellow oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](OCC)=[O:12])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C>CCOCC.CCCCCC>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH2:11][OH:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: CCCCCC
Product: OC/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
(E)-Ethyl 3-(4-(trifluoromethyl)phenyl)acrylate (25.00 g, 102 mmol) in 100 mL ether was cooled in an ice-water bath. To this solution, di-iso-butylaluminum hydride (205 mL, 205 mmol) in hexane was added. After addition, the ice-water bath was removed. After 2 hours of stirring at room temperature, the reaction mixture was diluted with 200 mL diethyl ether, cooled to 0° C. and quenched with careful addition of 200 mL brine and 200 mL of 5.0 M HCl. The aqueous solution was extracted twice with diethyl ether (200 mL each time). The combined organic phases were washed with brine and dried over sodium sulfate. The product was chromatographed eluting with 20% EtOAc in hexane. After removing the solvent, a white solid was obtained as the desired product (15.3 g, yield=74%). 1H NMR (400 MHz, CD3OD) δ ppm 4.28 (dd, J=5.28, 1.57 Hz, 2H) 6.55 (dt, J=15.94, 5.23 Hz, 1H) 6.67-6.75 (m, 1H) 7.58-7.67 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C)C=O.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc2ncc(Br)cc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc2ncc(Br)cc2n1COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (3.0 g, 14.1 mmol) in a mixture of N,N-dimethylformamide and tetrahydrofuran (30 mL, 2:1) at 0° C. was added 60% sodium hydride in mineral oil (0.68 g, 17.0 mmol) and the reaction mixture was stirred for 30 minutes, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (2.7 mL, 14.9 mmol). The reaction mixture was stirred for 16 hours at room temperature then it was quenched by the careful addition of water and diluted with ethyl acetate (250 mL), washed with brine (3×150 mL), dried over sodium sulfate, filtered and concentrated. Gradient column chromatography (10% to 30% ethyl acetate in hexane) provided 6-bromo-2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridine (4.4 g, 92%). 1H NMR (400 MHz, CDCl3): 8.41 (s, 1H), 8.12 (s, 1H), 5.67 (s, 2H), 3.62 (m, 2H), 2.76 (s, 3H), 0.96 (m, 2H), 0.00 (s, 9H). MS (EI) for C13H20BrN3OSi: 342, 344 (MH+, Br iotope pattern).