Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[O:12][CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:13][O:12][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1)[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2ccncc2cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ccncc2cc1-c1cccnc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
7-Bromo-6-methoxyisoquinoline (100 mg), tetrakistriphenylphosphine palladium(0) (49 mg), and 3-pyridineboronic acid (155 mg) were suspended in a mixed solvent composed of N,N-dimethylformamide (1.5 ml) and a 2 N aqueous potassium carbonate solution (1.5 ml), and the mixture was stirred at 80° C. for 4.5 hr. The reaction was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 6-methoxy-7-pyridin-3-yl-isoquinoline (42 mg, yield 85%).
Reaction SMILES: NC(N)=[S:3].CO.Cl.[CH2:8]([O:15][C:16]1[C:17]([CH3:26])=[N:18][CH:19]=[C:20]([CH:24]=[CH2:25])[C:21]=1[CH2:22]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[CH3:26][C:17]1[C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:21]([CH2:22][SH:3])[C:20]([CH:24]=[CH2:25])=[CH:19][N:18]=1
Reactant: NC(N)=S
Reactant: C=Cc1cnc(C)c(OCc2ccccc2)c1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=Cc1cnc(C)c(OCc2ccccc2)c1CS

Procedure:
To a well stirred solution of 0.11 mole of thiourea in 250 ml. methanol, under N2 is added 0.1 mole of 3-benzyloxy-4-chloromethyl-2-methyl-5-vinylpyridine hydrochloride. The mixture is refluxed for 1 hour and then cooled. A solution of 0.4 mole of sodium hydroxide in 50 ml. of water is added, and the resulting mixture refluxed for 30 minutes. After concentration in vacuo the reaction mixture is taken up between benzene and water and enough acetic acid added to neutralize the mixture. The organic layer is separated, washed well with water, dried, and concentrated to give 2-methyl-3-benzyloxy-4-mercaptomethyl-5-vinylpyridine.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][CH2:8][CH2:9][N:4]2[C:3](=[O:10])[O:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[CH:15]=[N:14][N:13]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:12]([N:7]1[CH2:8][CH2:9][N:4]3[C:3](=[O:10])[O:2][CH2:1][C@H:5]3[CH2:6]1)=[N:13][N:14]=[CH:15]2
Reactant: Clc1ccc2c(Cl)nncc2c1
Reactant: O=C1OC[C@H]2CNCCN12
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC[C@H]2CN(c3nncc4cc(Cl)ccc34)CCN12
Temperature: 140 °C

Procedure:
The title compound was prepared by a method analogous to that described in Example 8 (Method A). A mixture of (R)-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (0.800 g, 5.63 mmol), 1,6-dichlorophthalazine (0.516 g, 2.59 mmol) and N,N-diisopropylethylamine(1.40 mL, 8.04 mmol) in 3 mL 1-methyl-2-pyrolidone was heated at 140° C. After 4.5 h the reaction was cooled to RT, quenched with H2O and extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, evaporated onto silica gel and purified by flash chromatography eluting with 2 M NH3 in MeOH/CH2Cl2 (0:1→1:39) to give 1.18 g of a brown liquid. MS m/z: 305.1 [M+1].
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:18])=[N:16][N:17]=2)=[CH:9][CH:8]=1)[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.COCCN(S(F)(F)F)CCOC.Cl.[CH3:42][NH:43][O:44][CH3:45]>C(Cl)Cl>[CH3:45][O:44][N:43]([CH3:42])[C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:18])=[N:16][N:17]=2)=[CH:9][CH:8]=1
Reactant: COC(C(=O)O)c1ccc(-c2nnc(C)o2)cc1
Reactant: CNOC
Agent: COCCN(CCOC)S(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 26 %

Procedure:
To an ice-cold solution of 2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid (6.8 g, 27.4 mmol) in anhydrous CH2Cl2 (270 mL) and diisopropylethylamine (17 mL, 97 mmol) under argon was added bis(2-methoxyethyl)aminosulfur trifluoride (5.6 mL, 30.3 mmol) dropwise. After stirring over an ice bath for 45 min, N,O-dimethylhydroxylamine hydrochloride (3.40 g, 34.8 mmol) was added in three aliquots over a period of 15 min. The mixture was stirred for 15 min then the ice bath was removed. After 3 hrs, saturated aqueous NaHCO3 was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaHCO3, H2O and brine, dried over MgSO4, filtered through Celite and concentrated in vacuo. Purification by chromatography (75-100% EtOAc-hexanes then 0-5% EtOH-EtOAc) gave N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide as an oil that solidified upon standing (2.06 g, 26% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([F:13])[CH:5]=1)[CH3:2].O.NN>CCO.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([F:13])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOc1ccc(N)c(F)c1
Temperature: 90 °C

Procedure:
To a solution of 4-ethoxy-2-fluoro-1-nitro benzene (1.0 g, 5.4 mmol) in absolute EtOH (25 mL) at rt was added 250 mg of Pd/C (Aldrich, 10 wt. % on activated carbon), followed by slow addition of hydrazine hydrate (2.5 mL). The resulting reaction mixture was refluxed at 90° C. for 30 min. It then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford 4-ethoxy-2-fluoro-phenyl amine as a pale yellow oil: MS (ESI) 156 (M+H)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C(OCC)C.[OH:10][CH2:11][C:12]1[N:24]2[C:15]([C:16]3[CH:17]=[C:18]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:19]([C:25]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=4)=[N:20][C:21]=3[CH:22]=[CH:23]2)=[N:14][N:13]=1.B(F)(F)F.CCOCC>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:30][C:29]1([C:28]2[CH:31]=[CH:32][C:25]([C:19]3[C:18]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:17][C:16]4[C:15]5=[N:14][N:13]=[C:12]([CH2:11][OH:10])[N:24]5[CH:23]=[CH:22][C:21]=4[N:20]=3)=[CH:26][CH:27]=2)[CH2:2][CH2:1]1
Reactant: N#Cc1ccc(-c2nc3ccn4c(CO)nnc4c3cc2-c2ccccc2)cc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1(c2ccc(-c3nc4ccn5c(CO)nnc5c4cc3-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethylmagnesium bromide in diethyl ether (0.4 mL, 1.2 mMol, 3M) was added at −70° C. to a solution of 15-1 (0.1 g, 0.3 mmol) and titanium (IV) isopropoxide (0.17 g, 0.6 mMol) in anhydrous THF (7 mL). After 10 min, the cold bath was removed and the reaction was warmed to room temperature. After stirring for 1 hour, more ethylmagnesium bromide in diethyl ether (0.18 mL, 0.5 mMol, 3M) was added and the reaction was cooled to 0° C. in an ice bath and was treated with boron trifluoride etherate (0.18 g, 1.2 mMol). The reaction was stirred at 0° C. for 30 minutes then warmed to room temperature for 1 hour. The reaction was quenched with 1N HCl followed by stirring for 3 hours. The solution was basified with 1M NaOH, extracted with chloroform, dried with Na2SO4, filtered and concentrated in vacuo. Crude residue was taken up in methanol and purified using a C18 reverse phase HPLC to give 15-2 as a solid. LC/MS (M+1) calculated: 408.4; observed: 408.0
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([C:25](=[O:27])[CH3:26])=[N:14][C:15]=2[C:16]2[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([C:25](=[O:27])[CH3:26])=[N:14][C:15]=2[C:16]2[CH:21]=[C:20]([S:22]([CH3:23])=[O:33])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Nc2ncc(C(C)=O)nc2-c2cc(SC)nc(C)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncc(C(C)=O)nc2-c2cc(S(C)=O)nc(C)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(5-(6-methoxypyridin-3-ylamino)-6-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-yl)ethanone (25 mg, 0.065 mmol) and 3-chloroperoxybenzoic acid (22.5 mg, 0.131 mmol, Aldrich) in dioxane (1 mL) was stirred at room temperature for 2 h. The reaction mixture was taken on directly to the next step without work-up.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1.[Cl:31]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:31][C:12]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][C:9]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[N:10][C:11]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1ccc(N2CCN(c3nc(N4CCOCC4)cc(N4CCOCC4)n3)CC2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Yield: 43.7 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. 4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine (300 mg, 0.73 mmol) was dissolved in chloroform solution (5 ml), benzoyl peroxide (0.3 mg, 0.0014 mmol) and N-chlorosuccinimide (117 mg, 0.87 mmol) was added, and refluxed under heating for 1 hour. Water was added, and extraction was done with dichloromethane. After washing the organic layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=4:1), and 142 mg of 5-chloro-4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained (yield 46%). The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 130 are shown below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:25]([O-])(O)=O.[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:25])=[O:12]
Reactant: O=C(O)c1cccnc1Nc1ccc(-c2cccc(O)c2)cc1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cccnc1Nc1ccc(-c2cccc(O)c2)cc1F
Yield: 38.4 %

Procedure:
To a mixture of 2-(3-fluoro-3′-hydroxybiphenyl-4-ylamino)nicotinic acid (1 g, 3.08 mmol) and NaHCO3 (0.5 g, 6.17 mmol) in acetone (20 ml) was added dropwise dimethyl sulphate (0.47 g, 3.70 mmol). The mixture was heated to reflux overnight and then concentrated. Ethyl acetate was added to the crude and washed twice with 4% solution of NaHCO3 and brine. The organic phase was then dried over MgSO4 and concentrated in vacuo to afford 0.4 g of solid beige pure enough for the next synthetic step. Yield=36%
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH:25]4[CH2:34][CH2:33][C:28]5([O:32][CH2:31][CH2:30][O:29]5)[CH2:27][CH2:26]4)[N:23]=[CH:24][C:10]=13)[CH2:2]2.C(N(CC)CC)C.Cl[C:43]([O:45][CH2:46][CH2:47][F:48])=[O:44]>ClCCl>[F:48][CH2:47][CH2:46][O:45][C:43](=[O:44])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH:25]4[CH2:34][CH2:33][C:28]5([O:29][CH2:30][CH2:31][O:32]5)[CH2:27][CH2:26]4)[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC5(CC4)OCCO5)c3n2)cc1
Reactant: O=C(Cl)OCCF
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC5(CC4)OCCO5)c3n2)cc1)OCCF
Reaction time: 0.5 h

Procedure:
was also prepared by an alternative route: 36 mg 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline was dissolved in dichloromethane (0.5 mL) containing triethylamine (100 uL). 93 uL 2-fluoroethyl chloroformate was added and the mixture was stirred for 30 minutes. The mixture was concentrated and the title compound was obtained after HPLC purification. MS: 553.2 [M+H], RT 2.42.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>[OH-].[Na+]>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:14][CH2:13]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2nc3ccccc3[nH]2)CC1
Temperature: 125 °C
Reaction time: 5 h
Yield: 49.5 %

Procedure:
A mixture of 2-chlorobenzimidazole (10.00 g) and N-mehylpiperazine (20.00 g) is stirred at 125° C. for 5 hours. A 10% aqueous sodium hydroxide (100 ml) is added to the reaction mixture, and the precipitated crystals are separated by filtration. The filtrate is extracted with chloroform, and the chloroform extract is evaporated to dryness to give the same crystals. The crystals are combined and recrystallized from water-methanol to give 2-(4-methyl-1-piperazinyl)benzimidazole (7.02 g) as colorless needles, m.p. 225°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14]C.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A mixture of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea (Compound 77, example 1.61) (0.270 g, 0.69 mmol) in anhydrous 1,2-dichloroethane (10 mL) was cooled to 0° C. on an ice bath and stirred for 10 minutes. Anhydrous aluminium chloride (0.368 g, 2.76 mmol) was added and the reaction mixture stirred at 0° C. for 20 minutes, then moved to an oil bath and stirred at 80° C. for 1 hour. Ethyl acetate was added and washed with potassium sodium tartrate (10%) twice. Organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product that was further purified via HPLC. The corresponding fractions were collected and lyophilized to afford Compound 120 as a white solid in 75.0% yield. LCMS m/z (%)=379 (M+H 35Cl, 100), 381 (M+H 37Cl, 40). 1H NMR (400 MHz. DMSO-d6) δ: 9.81 (s, 1H), 8.92 (s, 1H), 8.45 (s, 1H), 8.12-8.06 (m, 1H), 7.63 (s, 1H), 7.40-7.31 (m, 3H), 7.09-7.04 (m, 1H), 6.99 (d, J1=8.72 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C:6]1[CH:17]=[CH:16][CH2:15][C:14]2[C:7]=1[CH:8]=[C:9]1[C:13]=2[C:12](=[O:18])[NH:11][N:10]1[CH2:19][CH:20]([OH:22])[CH3:21]>C(OCC)C.CO>[CH3:3][O:18][C:12]1[C:13]2[C:9](=[CH:8][C:7]3[C:14]=2[CH2:15][CH:16]=[CH:17][C:6]=3[O:5][CH3:4])[N:10]([CH2:19][CH:20]([OH:22])[CH3:21])[N:11]=1
Reactant: COC1=C2C=c3c(c(=O)[nH]n3CC(C)O)=C2CC=C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC1=C2C=c3c(c(OC)nn3CC(C)O)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
A solution of 0.79 g (18.8 mmol) of diazomethane in 56 ml of anhydrous diethyl ether was added while stirring to a solution of 2.44 g (9.37 mmol) of (RS)-1-(7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazol-3-on-1-yl)-propan-2-ol in 80 ml of anhydrous diethyl ether and 50 ml of anhydrous methanol. The mixture was stirred at room temperature for a further 15 hours and subsequently concentrated in a vacuum. 2.08 g (81%) of (RS)-1-(3,7-dimethoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol were obtained as a brown solid which was used directly in the next reaction.
Reaction SMILES: [Na+].CS([CH2-])=O.[H-].[Na+].[CH3:8][N:9]1[CH2:14][CH2:13][C:12]([C:16]#[CH:17])([OH:15])[CH2:11][CH2:10]1.F[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CS(C)=O>[CH3:8][N:9]1[CH2:14][CH2:13][C:12]([C:16]#[CH:17])([O:15][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: C#CC1(O)CCN(C)CC1
Agent: [CH2-]S(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C)CC1
Yield: 53.6 %

Procedure:
To a stirred solution of dimsyl sodium prepared from 43.0 g of sodium hydride (50% in oil, washed three times with hexanes) and 1100 ml of dimethylsulfoxide was added, in aliquots, 125 g of N-methyl-4-ethynyl-4-piperidinol at a rate such that the temperature remained below 23°. When the addition was complete, 167 g of 2,5-difluoronitrobenzene was added slowly dropwise at a rate such that the temperature remained below 21°. When the addition was complete, the mixture was poured into ice, extracted twice with ether, washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was filtered through 800 g of silica gel (70-250 mesh) and eluted with 3 l of 10% methanol/dichloromethane. Evaporation of solvent provided an oil, which crystallized on standing to yield 134 g (54%) of product. Recrystallization from cyclohexane provided the analytical sample, mp 70°-73°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:16]1[CH:24]=[C:23]2[C:19]([C:20]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C:21]=3[N:22]2[CH3:25])=[CH:18][CH:17]=1>>[CH3:25][N:22]1[C:23]2[C:19](=[CH:18][CH:17]=[C:16]([N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=[O:14])[CH:24]=2)[C:20]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C:21]1=2
Reactant: Cc1ccc(-c2cc[nH]c(=O)c2)cn1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CN(C(=O)OC(C)(C)C)CC5)c(=O)c2)cn1
Yield: 54.9 %

Procedure:
4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one (150 mg, 0.81 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (294 mg, 0.805 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (208 mg, 55%) as a yellow/green solid: 1H NMR (300 MHz, CDCl3) δ 8.79 (d, J=8.2 Hz, 1H), 7.83 (dd, J=8.0, 2.3 Hz, 1H), 7.58-7.51 (m, 2H), 7.36 (s, 1H), 7.30 (1H, partially under solvent), 7.08 (dd, J=8.3, 1.8 Hz, 1H), 6.90 (d, J=1.7 Hz, 1H), 6.50 (dd, J=7.1, 2.0 Hz, 1H), 4.65 (br s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 2.64 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:22][O:23][CH2:24][CH2:25]OC>CN(C=O)C.O>[CH3:22][O:23][CH2:24][CH2:25][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reaction time: 1 h
Yield: 154.8 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.8 g, 4.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), and 1-(chloromethoxy)-2-methoxyethane (0.59 mL, 5.2 mmol) in DMF (14 mL) was heated in a microwave at 90° C. for 1 hr. After the initial heating, additional 1-(chloromethoxy)-2-methoxyethane (0.59 mL) and cesium carbonate (2 g) was added. Heating was repeated for an additional 1 hr. The crude reaction mixtures were then diluted with water (250 mL) and extracted with ethyl acetate (3×50 mL). The title compound was purified by silica gel column using DCM/EtOAc/MeOH (8/1.5/0.5) as eluent to give 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.6 g) as a light yellow oil. ESI-MS:m/z 283.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[O:24]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26]1>>[O:24]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH:27]([NH:30][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:26]1
Reactant: NC1CCS(=O)(=O)C1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCS(=O)(=O)C2)cn1
Yield: 54 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 1,1-dioxo-tetrahydro-thiophen-3-ylamine instead of methylamine, to the title compound (150 mg, 54%) which was obtained as a white solid. MS: m/e=428.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH:9]([N:6]2[C:5]3[CH:27]=[CH:28][C:2]([NH:1][S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc(N)ccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc(NS(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 3-(5-amino-1H-benzimidazol-1-yl)-3-(1,1′-biphenyl)-4-ylpropanoate (15 mg, 40 μmol) in dichloromethane (500 μL) was added benzenesulfonyl chloride (6.0 μL, 47 μmol) and N,N-diisopropylethylamine (8.0 μL, 46 μmol). The solution was stirred at room temperature for 48 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (96:4), to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=5.50 min, MH+ 513].