Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([CH3:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:17].[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:9]1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:11][C:2]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)=[C:3]2[C:8]=1[C:7](=[O:17])[NH:6][CH:5]=[CH:4]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1c(OC(C)C)cc(Br)c2cc[nH]c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(OC(C)C)cc(-c2cnn(C)c2)c2cc[nH]c(=O)c12
Temperature: 140 °C
Reaction time: 0.58 h
Yield: 92.9 %

Procedure:
A mixture of 5-bromo-8-methyl-7-(propan-2-yloxy)isoquinolin-1(2H)-one (108h, 150 mg, 0.507 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (210 mg, 1.01 mmol) and Pd(Ph3P)4 (29 mg, 0.025 mmol) in 1M aq. Na2CO3 (1 mL) and DME (5 mL) was degassed with N2 for 3 minutes. The reaction mixture was stirred at 140° C. in the microwave for 35 minutes. The reaction mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (EtOAc) to give 8-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7-(propan-2-yloxy)isoquinolin-1(2H)-one (108i, 0.14 g, 92.9%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>>[NH:21]1[CH:22]=[CH:23][C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[N:20]1
Reactant: Nc1cc[nH]n1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: FC(F)(F)c1cc(Nc2cc[nH]n2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (75 mg, 0.289 mmol) and 3-amino pyrazole (31 mg, 0.373 mmol) similar to Example 166 and was isolated as a white solid (mp 230° C. decompose, 31 mg, 0.101 mmol, 35%). 1H NMR (DMSO-d6) 9.62 (d, J=1.2 Hz, 1H), 8.77 (m, 3H), 7.71 (s, 1H), 7.62 (dd, J=4.5, 7.5 Hz, 1H), 6.09 (d, J=3 Hz, 1H), 5.89 (s, 1H).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:12][C:11]=1[O:23][CH3:24])=[O:8].[CH:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH2:28]>O1CCOCC1>[F:26][C:6]([F:5])([F:25])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:28][CH2:27][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:19][CH2:18]2)=[CH:12][C:11]=1[O:23][CH3:24])=[O:8]
Reactant: COc1cc(C2CCNCC2)c(C)cc1NC(=O)C(F)(F)F
Reactant: C=CS(C)(=O)=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1NC(=O)C(F)(F)F
Temperature: 90 °C
Yield: 28.4 %

Procedure:
To 2,2,2-trifluoro-N-[5-methyl-2-(methyloxy)-4-(4-piperidinyl)phenyl]acetamide acetate (1.5 g, 4.0 mmol) in 30 mL of dioxane was added, TEA (2 g, 20 mmol), and methyl vinyl sulfone (1.06 g, 10 mmol). The mixture was heated to 90° C. for 72 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give 480 mg of 2,2,2-trifluoro-N-(5-methyl-2-(methyloxy)-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}phenyl)acetamide and the title compound of step D (0.40 g, 1.2 mmol, 31%). 1H NMR (400 MHz, CDCl3) δ ppm 6.62 (s, 1H), 6.51 (s, 1H), 5.22 (s, 2H), 3.80 (bs, 3H), 3.29 (t, J=6.87 Hz, 2H), 3.13 (d, J=11.17 Hz, 2H), 3.04 (s, 3H), 2.98 (t, J=6.96 Hz, 2H), 2.61-2.70 (m, 1H), 2.24-2.31 (m, 2H), 2.17 (s, 3H), 1.73-1.81 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][CH:16]=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:26]=[C:25]([CH2:24][OH:27])[N:12]4[CH:11]=2)[CH:15]=[CH:16][CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cccc2c1O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CO)cc3cccc(c1=O)c32
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-3-quinolinecarboxamide (prepared according to the general procedure in WO 9932450, 0.53 g), copper iodide (0.11 g), bis(triphenylphosphine)palladium(II) chloride (0.043 g) and propargyl alcohol (0.085 mL) in 20 mL diethylamine is stirred at room temperature for 18 h. The solid in the reaction mixture is filtered, washed with hexanes and dried. The solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (gradient from CH2Cl2 to 3% MeOH/CH2Cl2) affords N-(4-chlorobenzyl)-2-(hydroxymethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a white solid (0.23 g, 52%), m.p. 211-213° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4.C(N(CC)CC)C.[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>C1C=CC=CC=1>[CH:29]1([C:33]([N:19]2[CH2:18][CH2:17][C@@:14]34[C:15]5[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[CH2:7][C@@H:8]2[C@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)=[O:34])[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(O)CCC(=O)C3
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc2c(c1)[C@]13CCN(C(=O)C4CCC4)[C@H](C2)[C@]1(O)CCC(=O)C3

Procedure:
In an anhydrous system 32 g of 3-methoxy-14-hydroxy-6-ketomorphinan, 16 ml triethylamine and 300 ml of benzene are stirred together and, over a 30 minute period, a solution of 13 g of cyclobutylcarbonylchloride in 100 ml of benzene is added. The internal temperature is kept below 25° by means of an ice bath, after which stirring is continued for four more hours at room temperature. In the isolation, triethylaminehydrochloride is removed by filtration, the solvent evaporated, and the residue solidified by stirring in 200 ml of petroleum ether to give crude N-cyclobutylcarbonyl-3-methoxy-14-hydroxy-6-ketomorphinan.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CN(C=O)C.[Br:23][C:24]1[CH:29]=[C:28](Cl)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1>CCOCC>[Br:23][C:24]1[CH:29]=[C:28]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2cc(Br)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
N-Boc-4-piperidinemethanol (860 mg, 4.0 mmol) was added to a suspension of 60% sodium hydride (160 mg, 4.0 mmol) in DMF (40 mmol) at room temperature. After 20 minutes, 2-bromo-4-chloro-5-nitropyridine (949 mg, 4.0 mmol) was added in one portion, and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with ether and washed with water. The aqueous phase was extracted with ether. The combined organic phases were washed with water and brine, then dried (Na2SO4) and concentrated. Silica column chromatography, eluting with 20% ethyl acetate-hexane, gave tert-butyl 4-((2-bromo-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate (789 mg, 62%) as a viscous, pale yellow oil which solidified on standing.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[C:24]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1C(O)=O)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:23])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:7])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(Cl)cc1
Yield: 59.2 %

Procedure:
By the same procedure as in Example 26-D), while using (2S)-1-(tert-butoxycarbonyl)-2-[2-(4-chlorophenoxy)-1-hydroxyethyl]pyrrolidine (2.80 g) and N-(tert-butoxycarbonyl)-L-proline (1.94 g), there was obtained 2.13 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)(=[O:3])[CH3:2].[NH2:12][C@@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([NH:12][C@@H:13]([CH3:29])[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=3)=[N:16]2)=[O:11])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Yield: 30.5 %

Procedure:
(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from 5-acetylisoxazole-3-carboxylic acid (2.142 g, 13.81 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (3 g, 2.142 g). The product was purified by Flash-chromatography with yield of 30.5%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.66 (s, 3H), 4.26 (dd, 1H), 4.47 (dd, 1H), 4.56-4.66 (m, 1H), 4.65 (d, 1H), 7.30 (s, 1H), 7.50 (d, 1H), 7.71 (d, 1H), 7.84 (dd, 1H), 7.08 (d, 1H), 7.17 (d, 1H).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([CH3:14])[CH2:8]2)(=[NH:4])[NH2:3].C([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)O[CH:22]([CH3:27])[CH2:21]2)(O)=O.C[O-].[Na+]>CO>[CH3:14][CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:2]3[N:3]=[CH:13][C:5]([C:26]4[CH:18]=[CH:19][C:20]([CH2:21][CH2:22][CH2:27][CH2:9][CH2:8][CH2:7][CH2:11][CH3:12])=[CH:24][CH:25]=4)=[CH:2][N:4]=3)[CH:6]=2)[O:10]1
Reactant: CC1Cc2cc(C(=O)O)ccc2O1
Reactant: CC1Cc2cc(C(=N)N)ccc2O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCc1ccc(-c2cnc(-c3ccc4c(c3)CC(C)O4)nc2)cc1
Yield: 58.4 %

Procedure:
0.40 g (1.88 mM) of 5-amidino-2-methylcoumaran hydrochloride (M5) as an intermediate product prepared in Example 1, 0.79 g (1.90 mM) of 3-dimethylamino-2-(4-octylphenyl)-N,N-dimethylpropene-(2)-ammonium perchlorate 0.41 g (7.59 mM) of sodium methylate and 15 ml of methanol were placed in a 50 ml-round bottomed flask and refluxed for 5 hours and 10 minutes under stirring. After the reaction, the reaction mixture was cooled on an ice-common salt bath to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water. The resultant crystal was dissolved in toluene and dried with mirabilite. After distilling-off of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent:toluene/ethyl acetate=100/1) and recrystallized from a mixture solvent of toluene and methanol to obtain 0.44 of 2 (-2methylcoumaran-5-yl)-5-(4-octylphenyl)pyrimidine (Ex. Comp. No. I-235) (Yield: 58.4%). The product showed the following phase transition temperatures (°C.). ##STR92##
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][C:11]=1[F:41].C(N(CC)CC)C>ClCCl>[F:41][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:32]([F:33])([F:34])[F:35])[C:36]([F:38])([F:39])[F:37])=[CH:27][CH:26]=3)[CH2:22][CH2:23]2)=[O:17])[CH:14]=[CH:15][C:10]=1[NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH3:8])[CH3:1]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: CC(C)CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Yield: 9 %

Procedure:
4-Methylvaleric acid (4.30 mmol, 0.543 mL, 0.5 g) was stirred in dichloromethane (5 mL) at 0° C. Oxalyl chloride (21.52 mmol, 1.848 mL, 2.73 g) was added. The reaction mixture allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated under vacuum to give the intermediate 4-methylpentanoyl chloride. A mixture of 4-methylpentanoyl chloride (1.564 mmol, 0.211 g), (4-amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (1.043 mmol, 0.5 g) and triethylamine (2.086 mmol, 0.290 mL, 0.211 g) were stirred in dichloromethane at 0° C. for 1 hour. The reaction mixture was washed with water, dried over sodium sulfate, concentrated under vacuum and purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol/dichloromethane) to afford the title compound (54 mg).
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9])=[CH:19][CH:18]=1
Reactant: OCCO
Reactant: Clc1ccc(C(=CCBr)c2ccc(Cl)cc2)cc1
Agent: [Li]CCCC
Solvent: O
Product: OCCOCC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of n-butyllithium in hexanes (15.0 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to ethylene glycol (30 ml) at 10° C. When addition was complete the mixture was stirred for 0.5 h at room temperature. 3-Bromo- 1,1-bis(4-chlorophenyl)-1-propene (13.0 g, 38 mmol, prepared similarly to the method described in Example 23) was added and the reaction mixture was stirred at room temperature for 72 h. The mixture was poured into water (100 ml) and extracted with ethyl acetate (2×75 ml). The combined organic extracts was dried over sodium sulphate and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (200 g) using a mixture of n-heptane and ethyl acetate (3:2) as eluent provided 8.1 g (66%) of 2-(3,3-bis(4-chlorophenyl)-2-propen-1-yloxy)ethanol, M.P. 93°-95° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[I:10]I.[OH-].[K+]>CN(C=O)C>[I:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: c1cnc2[nH]ncc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 1H-pyrazolo[3,4-b]pyridine (500.0 mg, 4.2 mmol, 1 equiv) in DMF (10 mL) at 0° C., was added iodine (2.13 g, 8.4 mmol, 2 equiv) and potassium hydroxide (943 mg, 16.8 mmol, 4 equiv). The resultant mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction solution was slowly quenched with saturated sodium thiosulfate (Na2S2O5) solution (10 mL), and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (3×50 mL), brined (50 mL), dried over sodium sulfate and concentrated in vacuo to give 3-Iodo-1H-pyrazolo[3,4-b]pyridine (1.02 g) as a yellow powder which was used without further purification: LCMS (ES) M+H 246.2, Rf 2.17 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[CH:20]=[CH:19][S:18][CH:17]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:24][N:25]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[N:27]=[CH:26]1.C(N(CC)CC)C>>[CH3:24][N:25]1[CH:29]=[C:28]([S:30]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]5[CH:20]=[CH:19][S:18][CH:17]=5)[CH:14]=4)[NH:9][CH:8]=3)[CH2:3][CH2:2]2)(=[O:32])=[O:31])[N:27]=[CH:26]1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Product: Cn1cnc(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccsc5)cc34)CC2)c1

Procedure:
Following the general procedure in example 267, 3-(4-piperidinyl)-5-(3-thienyl)-1H-indole-7-carboxamide (40 mg, 0.12 mmol), 1-methyl-1H-imidazole-4-sulfonyl chloride (29.7 mg, 0.18 mmol) and triethylamine (0.05 mL, 0.36 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (20 mg, 34%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([O:33][C:34]([F:37])([F:36])[F:35])[CH:27]=1)([CH3:25])=[O:24].[OH-].[Na+]>COCCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:27][C:28]=2[O:33][C:34]([F:37])([F:35])[F:36])=[N:3][CH:4]=1
Reactant: CP(C)(=O)c1ccc(N)c(OC(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2OC(F)(F)F)ncc1Cl
Temperature: 90 °C
Yield: 8.6 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as prepared in Example 17: 0.040 g, 0.12 mmol) in 1 mL of 2-methoxyethanol was added 4-(dimethylphosphoryl)-2-(trifluoromethoxy)aniline (0.035 g, 0.12 mmol) as its hydrochloride salt. The mixture was heated in a sealed tube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by prep-HPLC to afford the final compound (5.8 mg, 9% yield). MS/ES+: m/z=563.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.O.[C:43](#[N:45])C>[C-]#N.[Zn+2].[C-]#N>[C:43]([C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])#[N:45]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(C#N)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 90 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
4-Trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (300 mg, 0.505 mmol) was dissolved in acetonitrile (15 mL), and the solution was added with zinc cyanide (178 mg, 1.52 mmol) and [bis(diphenylphosphino)ferrocene]dichloropalladium (33 mg, 0.0404 mmol), followed by stirring at 90° C. for 17 hours under argon atmosphere. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=8/1) to obtain 4-cyano-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (198 mg, yield 83%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1)([O-])=O>C(O)C.C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2cnccc2[N+](=O)[O-])C1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCCN(c2cnccc2N)C1
Yield: 79 %

Procedure:
The method of Example 90 (Method 5) was followed using 1 eq of tert-butyl 1-(4-nitropyridin-3-yl)piperidin-3-ylcarbamate in 1:1 ethanol/ethyl acetate at 30 psi for 72 hours, yielding tert-butyl 1-(4-aminopyridin-3-yl)piperidin-3-ylcarbamate (79%). LCMS (m/z): 293.1 (MH+); LC Rt=2.14 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:11]2[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)(=[O:7])=[O:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Yield: 20.6 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide (Example 38a) (0.222 mmol) in DMF (4 mL) was reacted with K2CO3 (61 mg, 0.444 mmol) and pyrrolidine (92 uL, 1.11 mmol) to afford the title compound (23.5 mg, 21% for 2 steps).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C(N(CC)CC)C.[CH2:28]([CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])=[O:38])[CH2:33][CH2:32]1)[C:29]#[CH:30]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[Cl:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[O:39][C:37]([N:34]1[CH2:33][CH2:32][CH:31]([CH2:28][C:29]#[C:30][C@@:9]2([N:8]3[C:18]4[N:19]=[CH:2][N:3]=[C:4]([NH2:20])[C:5]=4[N:6]=[CH:7]3)[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:36][CH2:35]1)=[O:38]
Reactant: C#CCC1CCN(C(=O)Oc2ccccc2Cl)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2[C@]1(C#CCC2CCN(C(=O)Oc3ccccc3Cl)CC2)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-iodoadenosine (0.602 g, 1.531 mmol) in freshly degassed DMF (20 mL) was added degassed triethylamine (1.20 mL, 8.54 mmol), Pd(PPh3)4 (85 mg, 0.074 mmol), CuI (catalytic), and 2-chlorophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.588 g, 2.117 mmol). The mixture was stirred at room temperature under and inert atmosphere for 20 h. Silica bound Pd(II) scavenger Si-thiol (400 mg) and Pd(0) scavenger Si-TAAcOH (619 mg) were added and stirring continued a further 72 h. The suspension was filtered through celite and the resulting solution evaporated to dryness. The crude was purified by column chromatography, eluting with a gradient of DCM/MeOH (0-4%) to afford the pure product as a white solid: yield 0.733 g, 88%.