Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:20][C:21]([F:27])([F:26])[S:22](O)(=[O:24])=[O:23].N([O-])=O.[Na+]>CN(C)C=O>[F:20][C:21]([F:27])([F:26])[S:22]([C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:24])=[O:23]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: N#Cc1cccc(-c2nc(N)cc3cccnc23)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2nc(S(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-amino-8-(3-cyanophenyl)-1,7-naphthyridine (4.058 g) in dimethyl-formamide (DMF) (22 ml) under argon at 0° C. is added trifluoromethanesulfonic acid (11 ml). The mixture is stirred at 0° C. for 10 minutes and then sodium nitrite (2.26 g) is added slowly. The cooling bath is then removed and the mixture stirred at room temperature for 3 hours. The resulting mixture is diluted with ethyl acetate and washed with water, 2M NaOH and water again. The organic layer is dried over sodium sulfate, then concentrated in vacuo and purified by column chromatography, eluting with 10:0.5 toluene:acetone to yield the title compound. M.p. 102-104° C. MS (m/e)=380.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32])[CH:18]=1>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:17]1[N:22]=[CH:21][N:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32])[CH:18]=1)#[N:2]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 2-cyanophenol (12.6 g), potassium carbonate (8.28 g) and (E)-methyl 2-[2-(6-chloropyrimidin4-yloxy)phenyl]-3-methoxypropenoate (33.0 g) was heated at 120° C. for 3 hours. The mixture was then cooled to 100° C. after which methanol (40 ml) was added to help cooling to 65° C. The resulting mixture was cooled to 0-5° C. and kept at this temperature for 1 hour. The mixture was filtered to leave (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate as the residue (87.5%
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH:9][NH:10][C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[C:14]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]4([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=2)=[N:16]3)=O)[N:4]=[CH:3]1.C(O)(=O)C.O1CCOCC1>C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:20]3[C:11]([C:12]4[CH:13]=[C:14]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:15]([C:21]5[CH:22]=[CH:23][C:24]([C:27]6([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:28][CH2:29][CH2:30]6)=[CH:25][CH:26]=5)=[N:16][C:17]=4[CH:18]=[CH:19]3)=[N:10][N:9]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(C(=O)NNc2nccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)cc23)c1
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)nc4ccn23)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a round bottom flask was added tert-butyl {1-[4-(5-{2-[(1-methyl-1H-imidazol-4-yl)carbonyl]hydrazino}-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-7) (2.73 g, 4.63 mmol), acetic acid (5.30 mL, 93 mmol), and 1,4-dioxane (20 mL). The reaction mixture was heated to 80° C. while stirring open to the atmosphere (capped) in a hot oil bath. After 3 hours the reaction mixture was permitted to cool to room temperature, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography 1-15% IPA/DCM. The appropriate fractions were combined and the solvent was removed in vacuo. The resulting residue was repurified by reverse phase column chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were free based by suspending in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl (1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)carbamate (1-8) as an off-white solid. MS (M+H)+: observed=572.3, calculated=572.7.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[N:7][C:6]=12.C[C:26]([N:28](C)C)=O>O.ClCCl.[Zn].[C-]#N.[C-]#N.[Zn+2]>[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][N:5]3[N:4]=[CH:3][C:2]([C:26]#[N:28])=[C:6]3[N:7]=2)=[CH:18][CH:19]=1)=[O:22]
Reactant: CC(=O)N(C)C
Reactant: O=Cc1ccc(-c2nc3c(Br)cnn3cc2-c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: ClCCl
Solvent: O
Product: N#Cc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Temperature: 160 °C

Procedure:
400 mg 4-(3-bromo-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described under example 31), 7.0 mg zinc powder, 75.0 mg Zn(CN)2 and 39.0 mg dichloride[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct are suspended in 10 ml dimethylacetamide and the mixture is heated for 45 min under microwave irradiation to 160° C. The workup is performed by diluting the mixture with water and dichloromethane, extracting the aqueous layer twice and drying the combined organic layers over Na2SO4. The compound is isolated by evaporation of the solvent and chromatography on silica gel (dichloromethane/ethyl acetate).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:25])=[CH:19][C:20](OCC)=[O:21])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1>CCOCC>[CH:7]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]([CH3:25])=[CH:19][CH2:20][OH:21])=[CH:16][CH:17]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)C=C(C)c1ccc(C2CCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=CCO)c1ccc(C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To an ice cooled slurry of LiAlH4 (2.7 g) in dry ether (150 ml) was added a solution of ethyl 3-(4′-cyclopentylphenyl)-but-2-enoate (3a, 8.2 g) in dry ether (50 ml) dropwise. The mixture was stirred at 0° C. for 3 h. The reaction mixture was quenched with water (10 ml). A solution of 10% NaOH (5 ml) was added and then ether layer was decanted. The precipitate was washed with ether and combined organic layer was concentrated. The crude product was purified by column chromatography on silica gel to give 5.6 g (82.3% yield) of 3-(4′-cyclopentylphenyl)-2-butenol (4a, formula 4, R=cyclopentyl) as oil.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([NH:35][NH2:36])=O)[CH2:28][CH2:27]1)(=[O:25])[CH3:24].C[O-].[Na+]>CO>[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[NH:6][C:5]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[C:10]4[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:36][N:35]=2)[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCN(CC(=O)NN)CC1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCN(Cc2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)CC1
Yield: 5.2 %

Procedure:
The procedure described for Example 283 B was followed using ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (600 mg, 1.88 mmol), 2-(4-acetylpiperazinyl)-N-aminoacetamide (1.12 g, 5.64 mmol), sodium methoxide (1.3 mL, 5.64 mmol), and methanol (8 mL) to yield the title compound (41 mg, 5% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.6 (s, 1H), 8.0 (m, 5H), 7.6 (m, 2H), 7.4 (t, 3H), 4.6 (m, 2H), ES-MS (m/z) 420 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:31])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]([NH:29][OH:30])=[NH:28])=[N:19]3)[CH:12]([CH3:32])[CH2:11]2)=[C:4]([F:33])[CH:3]=1.[C:34]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:31])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]4[N:28]=[CH:34][O:30][N:29]=4)=[N:19]3)[C@@H:12]([CH3:32])[CH2:11]2)=[C:4]([F:33])[CH:3]=1
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(C(=N)NO)c4cccnc43)C(C)C2)c(F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncon4)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 248.1 %

Procedure:
A mixture of 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine (1.2 g), trimethyl orthoformate (20 ml) and para-toluene sulfonic acid (PTSA) (0.1 g) was stirred at 100° C. overnight. The reaction mixture was concentrated in vacuo to provide a crude residue which was purified by flash chromatography to provide 1-[(S)-4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(3-[1,2,4]oxadiazol-3-yl-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (0.7 g). LCMS Retention time: 2.61 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid /5% acetonitrile /94.9% water, B=0.1% formic acid /5% water/94.9% acetonitrile). LCMS observed for (M+H)+: 486.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11](CC=C)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C(=O)CC(=O)N(C)C1=O.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCN1CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: Cl
Solvent: ClCCl
Product: c1ccc(CN2C3CCC2CNC3)cc1

Procedure:
A mixture of 8-benzyl-3-(2-propenyl)-3,8-diazabicyclo[3.2.1]octane (22.2 g, 92.7 mmol), 1,3-dimethylbarbituric acid (21.5 g, 137.0 mmol), Pd2(dba)3 (5 g, 5 mmol) and P(C6H5)3 (5.2 g, 20.0 mmol) in methylene chloride (500 mL) was heated at reflux for 16 h. The reaction was poured into 1 N HCl (250 mL) at 0° C. The aqueous acidic layer was separated and made basic with 6 N NaOH, then extracted with ethyl acetate (2×150 mL).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:39])[CH2:30][CH:31]2[CH2:36][CH2:35][CH:34]([CH2:37][NH2:38])[CH2:33][CH2:32]2)[B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:26])[CH3:25])[O:16]2)[C:8]=1[O:40][CH3:41])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:49]([NH:56][CH2:57][CH2:58]Br)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].CN(C=O)C>CCOC(C)=O>[C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:39])[CH2:30][CH:31]2[CH2:32][CH2:33][CH:34]([CH2:37][NH:38][CH2:58][CH2:57][NH:56][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:35][CH2:36]2)[B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:25])[CH3:26])[O:16]2)[C:8]=1[O:40][CH3:41])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(CC(NC(=O)CC2CCC(CN)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(CC(NC(=O)CC2CCC(CNCCNC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 65 °C
Yield: 47 %

Procedure:
A sealable reaction tube was charged with 3-[2-[2-(4-Aminomethyl-cyclohexyl)-acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (0.205 g, 0.352 mmol), potassium carbonate (0.057 g, 0.412 mmol), 2-(Boc-amino)ethyl bromide (0.095 g, 0.424 mmol), and DMF (3.0 mL). The tube was sealed and the reaction heated at 65° C. for 24 hr. The reaction was cooled to RT. The reaction was diluted with EtOAc and washed with 5% aqueous LiCl (2×) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to afford 0.120 g of crude product which was carried to the next step without purification. ESI-MS m/z 726 (MH)+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)([OH:17])[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.N1C=CC=CC=1.[Cl:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[C:41](Cl)=[O:42]>O1CCCC1>[Cl:37][C:38]1[CH:39]=[C:40]([C:41]([N:14]2[CH2:15][CH2:16][CH:11]([C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:29])([F:1])[F:30])=[CH:9][CH:8]=3)([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)[OH:17])[CH2:12][CH2:13]2)=[O:42])[CH:44]=[CH:45][C:46]=1[O:47][CH3:48]
Reactant: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Reactant: COc1ccc(C(=O)Cl)cc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a separate reaction vessel, a solution of 0.5 gram (0.0012 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine (prepared in Step B of Example 7) and 0.09 gram (0.0012 mole) of pyridine in a small amount of tetrahydrofuran was stirred, and the solution of 3-chloro-4-methoxybenzoyl chloride in tetrahydrofuran, prepared above, was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 15 minutes and then filtered to remove a white solid. The filtrate was stirred for about 18 hours and then was partitioned between ethyl acetate and an aqueous solution saturated with sodium chloride. The organic layer was separated and passed through a column of silica gel. Elution was accomplished with 50% ethyl acetate in hexane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.62 gram of N-(3-chloro-4-methoxyphenylcarbonyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=2)[N:6]([CH2:21][C:22]([O:24]C)=[O:23])[N:5]=1)(=[O:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[N:16]=[CH:17][CH:18]=[CH:19][N:20]=3)[CH:11]=2)[N:6]([CH2:21][C:22]([OH:24])=[O:23])[N:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cn1nc(C(C)=O)c2cc(OCc3ncccn3)ccc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1nn(CC(=O)O)c2ccc(OCc3ncccn3)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To methyl 2-(3-acetyl-5-(pyrimidin-2-ylmethoxy)-1H-indazol-1-yl)acetate (1.93 g, 5.67 mmol) in THF (15 mL) and water (15 mL) was added LiOH.H2O (0.25 g, 5.95 mmol). The reaction mixture was stirred at RT for 1.5 h. Volatiles were evaporated and the residue was freeze-dried overnight to give the title compound. MS (LC/MS): 327.0 [M+H]+, 325.1 [M+H]+; tR (HPLC conditions c): 3.24 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[O:14]1CCC[CH2:16][CH:15]1OCCBr.[NH4+].[Cl-]>CN(C=O)C>[OH:14][CH2:15][CH2:16][N:9]1[C:10]2[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: COc1cccc2[nH]ccc12
Reactant: BrCCOC1CCCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cccc2c1ccn2CCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
Under argon atmosphere, NaH (283 mg) was added to 4-methoxyindole (516 mg) in DMF (10 ml) and the mixture was stirred at 0° C. for 15 minutes. To this mixture, 2-tetrahydropyranyloxy-1-bromoethane (890 mg) was added and the mixture was gradually heated to room temperature, followed by stirring the mixture at room temperature for 90 minutes. The reaction mixture was added to saturated aqueous NH4Cl solution (5 ml) cooled at 0° C. to stop the reaction, and the resultant was extracted with ethyl acetate (3×10 ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure. The obtained oil was transferred to a reaction vessel and dissolved in methanol (10 ml), followed by cooling the obtained solution to 0° C. To this solution, 1N hydrochloric acid (1 ml) was added and the solution was stirred at 0° C. for 2 hours. After removing the solvent under reduced pressure, water (5 ml) was added and the resultant was extracted with ethyl acetate (3×20 ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (547 mg, yield: 82%).
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:20][O-:21].[Na+]>O1CCCC1>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([O:21][CH3:20])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: C[O-]
Reactant: NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cncc(Nc2ccc(I)cc2F)c1C(N)=O
Temperature: 80 °C
Reaction time: 72 h

Procedure:
140 mg of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (0.340 mmol, 1 eq.) were dissolved in 3 mL of tetrahydrofurane and cooled to −75° C. bath temperature upon which 18 mg sodium methoxide (0.340 mmol, 1 eq.) were added and the mixture allowed to come to room temperature. Then the mixture was stirred at 80° C. bath temperature for 3 days. Since the reaction was not completed another 18 mg sodium methoxide (0.340 mmol, 1 eq.) were added and the mixture stirred at 80° C. bath temperature for 1 more day. The reaction mixture was concentrated in vacuo and the residue was partitioned between 20 ml each of water and dichloromethane. The aqueouse layer was separated and reextracted twice with dichloromethane (20 ml each). The combined organic layers were washed with brine (30 ml), dried over a silicone filter and concentrated. The residue was purified by flash chromatography to afford 67 mg (0.17 mmol, 51%) of the analytically pure target compound.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Li+].[H-].[Na+].Cl[C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=1.O>CN(C)C=O>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:3][CH:2]([CH3:4])[C:1]([OH:6])=[O:5])[CH:16]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: CC(O)C(=O)[O-]
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1cc(C(F)(F)F)ccn1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of lithium lactate (7.8 g, 81 mmol) in 100 mL of anhydrous dimethylformamide was added sodium hydride (60% dispersion in mineral oil, 3.2 g, 80 mmol). After stirring at room temperature for 30 min, 2-chloro-4-trifluromethylpyridine (10 g, 55 mmol) was added, and the mixture was heated at 100° C. overnight. The reaction was cooled to room temperature, poured into 500 mL of water, and was washed with hexane (200 mL). The aqueous solution was acidified with concentrated hydrochloric acid (pH>2), and was extracted with ether (2×500 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:32])[C:21]#[C:22][CH2:23][O:24][Si](C(C)(C)C)(C)C)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:33]#[N:34])[CH:5]=[CH:6][CH:7]=1>C(O)(=O)C.O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:32])[C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:33]#[N:34])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnc2ccc(NC(=O)C#CCO)cc2c1Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
N-[4-[(3-Bromophenyl)amino]-3-cyano-6-quinolinyl]-4-t-butyldimethylsiloxy-2-butynamide (60 mg, 0.122 mmol) was dissolved in a solution of acetic acid, tetrahydrofuran and water (3:1:1) and stirred overnight at room temperature. The solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The ethyl acetate was concentrated to give 42.2 mg (90%) of yellow solid; : mass spectrum (electrospray, m/e,): 421.0311 (M+.).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.Br[CH2:11][C:12]#[N:13].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([CH2:11][C:12]#[N:13])[N:3]=1
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn(CC#N)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
A mixture of 3-methyl-4-nitro-1H-pyrazole (7 g, 0.055 mol), bromoacetonitrile (13.2 g, 0.11 mol) and K2CO3 (23 g, 0.165 mol) in DMF (120 mL) was stirred at 80° C. for 2 hrs. TLC (petroleum ether:EtOAc=2:1) showed the reaction was complete. The mixture was filtered, concentrated and the residue purified by flash chromatography (petroleum ether:EtOAc=4:1) to give the title compound (3.5 g, 38% yield) as light yellow oil.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]([O-])([CH3:30])[CH3:29].[K+].ClCC(CCl)=C>CN(C=O)C>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:30][C:28](=[CH2:27])[CH2:29]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Agent: C=C(CCl)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (prepared as described in International patent application WO2006/046030) (0.12 M) in DMF was treated with KOtBu (2.1 eq) in one portion; the resulting mixture was stirred for 30 min at RT then treated dropwise with 3-chloro-2-(chloromethyl)prop-1-ene (1.1 eq). The resulting solution was stirred at RT overnight before being quenched by addition of HCl (1N) and extracted into EtOAc. The combined organic layers were washed with sat. aq. NaHCO3 and brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 85:15) affording the product as a yellow oil (97%). (ES+) m/z 402 (M+H)+.