Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26](O)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][C:39]2[CH:40]=[C:41]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51]N)[CH:46]=3)[CH:42]=[CH:43][CH:44]=2)[CH2:34][CH2:33]1.C[N:54]1CCC(CC2C=C(C3C=CC=C(CN)C=3)C=CC=2)CC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][N:20]([CH2:51][C:47]3[CH:46]=[C:45]([C:41]4[CH:42]=[CH:43][CH:44]=[C:39]([CH2:38][CH:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)[CH:40]=4)[CH:50]=[CH:49][CH:48]=3)[C:21]([C:23]3([C:26]([NH2:54])=[O:27])[CH2:24][CH2:25]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1cccc(-c2cccc(CC3CCN(C)CC3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
A mixture of 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid (100 mg, 0.241 mmol), ({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amine 1-{3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methanamine (92 mg, 0.241 mmol), HBTU (110 mg, 0.289 mmol) and Et3N (0.101 mL, 0.722 mmol) in DCM was stirred at room temperature overnight. The crude mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give crude residue. The crude product was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (18 mg, 10.8%). LC-MS m/z 692 (M+H)+, 0.75 min (ret time).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][N:17]([CH3:31])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([O:29][CH3:30])[CH:23]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.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]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:31])[CH3:16])=[CH:23][C:24]=2[O:29][CH3:30])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: COc1cc(OCCCN(C)C)ccc1N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(OCCCN(C)C)cc2OC)c1C(=O)OC
Yield: 46 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 4-(3-dimethylaminopropoxy)-2-methoxyphenylamine (0.70 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.6 g of the product at 94:6 methylene chloride-methanol, in 46% yield: 1H NMR (CDCl3) δ 1.98 (p, J=6.8 Hz, 2H), 2.30 (s, 6H), 2.51 (t, J=7.3 Hz, 2H), 3.81 (s, 3H), 3.87 (s, 6H), 4.02 (t, J=6.4 Hz, 2H), 6.45 (dd, J=8.6 Hz, J=2.6 Hz, 1H), 6.54 (d, J=2.6 Hz, 1H), 6.97 (dd, J=7.3 Hz, J=1.0 Hz, 1H), 7.09 (dd, J=8.5 Hz, J=1.0 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.92 (br, 1H).
Reaction SMILES: NS(C1C=CC(C2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])N=2)=CC=1)(=O)=O.[CH3:19][C:20]([CH3:34])([O:22][C:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([NH2:33])[CH:26]=1)=[O:24])[CH3:21].S.BrCC(=O)C(OCC)=O>>[C:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:30]=2)=[C:27]([NH2:33])[CH:26]=1)([O:22][C:20]([CH3:34])([CH3:19])[CH3:21])=[O:24]
Reactant: NS(=O)(=O)c1ccc(-c2nc(C(=O)O)cs2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)c(N)c1
Agent: CCOC(=O)C(=O)CBr
Agent: S
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C(=O)O)cs2)c(N)c1

Procedure:
In a manner similar to that described for the preparation of 2-(4-aminosulfonylphenyl)thiazole-4-carboxylic acid, 4-[(1,1-dimethylethoxy)carbonyl]-aminobenzonitrile was treated with H2S, ethyl bromopyruvate, and LIOH successively to give the title compound. MS m/z: 321 (M+H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([NH:17][CH:18]=[N:19]2)=[C:15]([Cl:22])[N:14]=1.[CH:23]([O:26][C:27]([O:36][CH:37]([CH3:39])[CH3:38])([P:32]([OH:35])([OH:34])=[O:33])[O:28][CH2:29][CH2:30]Cl)([CH3:25])[CH3:24]>CN(C=O)C>[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH2:30][CH2:29][O:28][C:27]([O:26][CH:23]([CH3:24])[CH3:25])([O:36][CH:37]([CH3:38])[CH3:39])[P:32]([OH:35])([OH:34])=[O:33])=[C:15]([Cl:22])[N:14]=1
Reactant: CC(C)OC(OCCCl)(OC(C)C)P(=O)(O)O
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)OC(OCCn1cnc2c(Cl)nc(N)nc21)(OC(C)C)P(=O)(O)O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
In 120 ml DMF, 29.3 g of DBU, 32.45 g (0.191 mol) of 2-amino-6-chloropurine were added, stirred at 80° C. for 30 min, then 50 g (0.193 mol) of 2-(diisopropyloxy-phosphonomethoxy)-ethyl chloride was added, the reaction was performed at 100° C. for 8 h, cooled, distilled at a reduced pressure to remove DMF, added with water and ethyl acetate, layered, the water phase was extracted twice with ethyl acetate, the organic phases were combined, dried, separated by silica gel column chromatography, eluted with MeOH:CH2Cl2=1:30, yield 46 g of II1.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[C:6]([C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:19])[CH:3]=1.C[O:21]C(O)C>P(=O)(O)(O)O.O>[CH3:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][C:3]1=[O:21]
Reactant: COC(C)O
Reactant: Cn1cc(Cl)c2cccc(C(=O)c3ccccc3)c21
Agent: O=P(O)(O)O
Solvent: O
Product: CN1C(=O)Cc2cccc(C(=O)c3ccccc3)c21

Procedure:
A solution of 46 grams (0.17 mol) of 3-chloro-1-methyl-7-benzoylindole in 250 ml of methoxy-ethanol and 60 ml of 70% phosphoric acid was heated at reflux under a nitrogen atmosphere for 5 hours. The solution was then cooled and diluted with 1.5 liters of water. The organic materials were extracted with methylene chloride and concentrated. The concentrated extract was chromatographed on silica gel and the product eluted with isopropyl ether. The residue obtained crystallized upon standing and was recrystallized from isopropyl alcohol to give 8.9 grams of 1-methyl-7-benzoylindolin-2-one, having a m.p. of 89°-90.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:18])[C:12]#[C:13][C:14]([O:16]C)=[O:15])=[CH:5][CH:4]=1.[OH-].[K+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11](=[O:18])[C:12]#[C:13][C:14]([OH:16])=[O:15])=[CH:7][CH:8]=1
Reactant: COC(=O)C#CC(=O)/C=C/c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(/C=C/C(=O)C#CC(=O)O)cc1
Reaction time: 0.17 h

Procedure:
A solution of 5.3 g (21.7 mmol) of methyl (E)-6-(4-methoxyphenyl)-4-oxo-5-hexen-2-ynoate in 70 ml of tetrahydrofuran was treated at 0° within 15 minutes with 48.6 ml (26 mmol) of a 3% aqueous potassium hydroxide solution. The reaction mixture was stirred at 0° for 10 minutes, then diluted with 100 ml of water and extracted once with 100 ml of ether. The organic phase was discarded. The aqueous phase was adjusted to pH 1 by the careful addition of 1N hydrochloric acid and extracted twice with ether. The combined organic phases were washed with water, dried over sodium sulphate and concentrated. Crystallization of the residue from ether/hexane yielded (E)-6-(4-methoxy-phenyl)-4-oxo-5-hexen-2-ynoic acid of melting point 98°-100°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:14]#[C:15][Si](C)(C)C)=[N:10][CH:11]=[CH:12][CH:13]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)C>[NH:7]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:14]=[CH:15]1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1cnc2cc[nH]c2c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A mixture of (2-trimethylsilanylethynylpyridin-3-yl)carbamic acid tert-butyl ester (500 mg, 1.72 mmol) in 5 mL of THF was treated with TBAF (1 M in THF, 10.3 mL) at room temperature. The mixture was heated at reflux for 8 hours, cooled to room temperature, diluted with 100 mL of diethyl ether, and quenched with 100 mL of water. The aqueous layer was extracted with three 50 mL portions of diethyl ether, and the combined organic layers were washed with 500 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (100% CH2Cl2 to 10% MeOH in CH2Cl2, gradient) gave 160 mg of the title product as tan solid (79% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=2)=[O:19])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)=[O:19])[CH2:14][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C(=O)N2CCN(c3ccc(Cl)cc3C(C)(C)C)CC2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Cl)ccc1N1CCN(C(=O)c2ccc(OCC(=O)O)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A mixture of methyl [(6-{[4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl]carbonyl}pyridin-3-yl)oxy]acetate (Example 209, 0.25 g, 0.56 mmol) and 1 M LiOH solution (5 mL, 5.0 mmol) in tetrahydrofuran (5 mL) was stirred at 0° C. for 2 h. The reaction mixture was acidified with 1 M HCl solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.21 g, 87%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:44])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:35])[C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[CH3:22])=[C:17]([CH2:36][O:37]CC[Si](C)(C)C)[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:44])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:35])[C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[CH3:22])=[C:17]([CH2:36][OH:37])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:45][CH:46]=1
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1COCC[Si](C)(C)C)CC(O)c1ccc2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CO)CC(O)c1ccc2ccccc2n1
Yield: 98.5 %

Procedure:
A solution of 174 mg of N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-quinolin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 2.5 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is extracted with 4 portions of CH2Cl2, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 3% MeOH in CH2Cl2 provides 146 mg of the title compound as a white solid. Recrystallization from EtOAc-hexane affords white solid.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=O)(=[O:5])=[O:4])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[OH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][C:32]=1[O:40][CH3:41].Cl>O1CCCC1>[OH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][C:8](=[O:10])[C@@H:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:11]([CH3:13])[CH3:12])=[CH:33][C:32]=1[O:40][CH3:41]
Reactant: CCS(=O)(=O)N[C@H](C(=O)O)C(C)C
Reactant: COc1cc(CCN)ccc1O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
5.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid and 5.7 ml of N-methylmorpholine are cooled in 200 ml of tetrahydrofuran, with stirring, to −20° C. 3.15 ml of chloroformic acid isobutyl ester are added dropwise thereto. Stirring is then carried out for 30 min, during which the reaction temperature is increased to −10° C. Cooling is then carried out to −20° C. again and 5.0 g of 2-(4-hydroxy-3-methoxyphenyl)-ethylamine hydrochloride are introduced. The reaction mixture is allowed to warm to room temperature and is stirred for a further 24 hours. The reaction mixture is introduced into 300 ml of 2N hydrochloric acid. It is extracted twice with 500 ml of ethyl acetate each time. The organic phases are washed twice with 100 ml of saturated sodium chloride solution each time, combined, dried over magnesium sulfate and concentrated. The residue is purified by flash-chromatography on silica gel using a mixture of ethyl acetate/n-hexane 3:1, yielding (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-amide in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[N:10][NH:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19].[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[K+].Br/[CH:29]=[CH:30]\[C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[F:38].ClOC(C)(C)C>ClCCl>[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH+:9]1[CH:29]=[C:30]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[N:11]([C:12]2[C:13]([F:19])=[CH:14][CH:15]=[CH:16][C:17]=2[F:18])[NH:10]1
Reactant: Fc1cccc(F)c1N=NNc1c(F)cccc1F
Reactant: Fc1cccc(F)c1/C=C\Br
Agent: CC(C)(C)OCl
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Product: Fc1cccc(F)c1C1=C[NH+](c2c(F)cccc2F)NN1c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of triazene 8d (808 mg, 3 mmol) and anhydrous potassium hexafluorophosphate (750 mg, 4 mmol) and (Z)-1-Bromo-2-(2,6-difluorophenyl)ethene 11q (1.32 g, 6 mmol) in dry dichloromethane (20 mL) in the dark at −78° C. is added tert-butyl hypochlorite (500 μL, 4.4 mmol), upon which the mixture instantly darkens. The mixture is stirred overnight as it is slowly allowed to warm to room temperature. The contents are then filtered, and the solid residue is washed with dichloromethane. The filtrate is collected, and volatiles are evaporated under reduced pressure. Diethyl ether is then added, and the mixture is vigorously triturated for ca. 1 hour, with occasional scratching of the glass surfaces to ensure efficient mixing. Filtration and washing with copious quantities of diethyl ether afford, after drying under vacuum, triazolium salt 10dq as an off-white solid (1.45 g, 88%). Analytical samples were obtained after recrystallization by vapor diffusion of diethyl ether in an acetonitrile solution of 10dq. 1H-NMR ((CD3)2SO, 300 MHz): δ=10.37 (s, 1H), 8.05-7.90 (m, 2H), 7.89-7.81 (m, 1H), 7.69 (t, J=8.9 Hz, 2H), 7.61 (t, J=8.9 Hz, 2H), 7.44 (t, J=8.9 Hz, 2H). 13C-NMR (((CD3)2SO, 75 MHz): δ=159.4 (dd, J=253, 4 Hz), 155.7 (d, J=257 Hz), 155.3 (d, J=257 Hz), 137.1 (2t, J=10 Hz), 136.2, 135.9 (t, J=10 Hz), 134.6, 114.0 (d, J=18 Hz), 113.8 (d, J=18 Hz), 113.0 (d, J=20 Hz), 112.6 (t, J=14 Hz), 110.3 (t, J=15 Hz), 99.1 (t, J=18 Hz). 19F-NMR (CD3CN, 282 MHz): δ=−71.9 (d, J=705 Hz, 6F), −110.3 (2F), −118.8 (2F), −119.0 (2F). HR-MS (ESI): Calcd. for C20H10F6N3 [M+]: 406.0773. found 406.0784.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]1([C:35]2[NH:36][C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:36]1[C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=[C:35]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[N:3][C:4]=2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(-c4ccccc4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-phenylbenzimidazole were reacted to give 207. LCMS m/z: 567.3 (MH+)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][CH2:14]Br>>[Cl:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])[CH:16]=[CH:17][CH:18]=1
Reactant: CCc1ccncc1
Reactant: Clc1cccc(CCBr)c1
Product: CC(CCc1cccc(Cl)c1)c1ccncc1
Yield: 28.3 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.05 g (9.35 mmol) of 3-chlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 0.65 g of the desired compound (yield: 28.2%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:21])[CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20]>N1C=CC=CC=1>[S:7]([O:21][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC#CC=CCCCO
Solvent: c1ccncc1
Product: CCC#CC=CCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a mixture of p-toluenesulfonyl chloride (22.4 g., 0.12 moles) and50 ml. of anhydrous pyridine is added 14 g. of non-4-en-6-yn-1-ol (0.107 moles) with ice bath cooling. The mixture is stirred for 1 hour and then is stored at 0° overnight. Ice is added to the mixture which is extracted with several portions of 50:50 ether/hexane. The combined organic phase is washed with 5% HCl, water, saturated sodium bicarbonate and dried over sodium sulfate. Removal of solvent at reduced pressure and subsequent solvent removal at 0.15 mm. for 1 hour gives 1-tosyloxy-non-4-en-6-yne (28 g.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:12]=1)(C)(C)C.[ClH:20].O1CCOCC1>>[ClH:20].[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[C:11]1[CH:12]=[C:8]([NH2:7])[S:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2ncccn2)cs1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(-c2ncccn2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4 N hydrochloric acid-dioxane solution (20 mL) was added to tert-butyl(4-(pyrimidin-2-yl)thiophen-2-yl)carbamate obtained in the above-described Step 3, and the reaction solution was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum, and then isopropyl ether was added. The deposited precipitate was filtrated to obtain 4-(pyrimidin-2-yl)thiophen-2-amine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][NH:29][CH:30]([CH3:32])[CH3:31])=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Br:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][N:29]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=1)[CH:30]([CH3:32])[CH3:31])=[O:27]
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1cccc(Br)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (100 mg, 0.35 mmol), 3-bromo-N′-isopropylbenzohydrazide (134.24 mg, 0.52 mmol) and HATU (198.5 mg, 0.52 mmol) dissolved in DMF (4.0 ml), N,N-diisopropylethylamine (DIPEA)(0.09094 ml, 0.52 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) and dried so that ivory (E)-tert-butyl 3-(3-(2-(3-bromobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (53.6 mg, 29.3%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:14])[NH2:13]>>[CH3:8][C:7]1[C:2]([C:19]2[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH2:13])=[O:14])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: NC(=O)c1cccc(B(O)O)c1
Product: Cc1cc([N+](=O)[O-])cnc1-c1cccc(C(N)=O)c1
Yield: 95 %

Procedure:
Obtained (0.225 g, yield 95%) following the procedure described in Intermediate 27, starting with 2-bromo-3-methyl-5-nitropyridine (0.92 mmol, 0.200 g), 3-carbamoylphenyl boronic acid (0.92 mmol, 0.152 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:13])[CH3:12])[C:5]([OH:7])=O.[O:14]=[C:15]1[O:19][CH:18]([O:20][CH2:21][CH2:22][C:23]2C=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]([NH:29][C:30]([CH:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:37](=[O:51])[CH:38]([NH:40]C(=O)C2C=CC(N)=C(Cl)C=2)[CH3:39])=[O:31])[CH2:16]1>>[CH2:21]([O:20][CH:18]1[CH:17]([NH:29][C:30]([CH:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:37](=[O:51])[CH:38]([NH:40][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([N:11]([CH3:13])[CH3:12])=[C:2]([Cl:1])[CH:3]=2)[CH3:39])=[O:31])[CH2:16][C:15](=[O:14])[O:19]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: CN(C)c1ccc(C(=O)O)cc1Cl
Product: CC(NC(=O)c1ccc(N(C)C)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 44 %

Procedure:
Prepared from {2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbmoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert-butyl ester and 3-chloro-4-dimethylamino-benzoic acid according to the procedure used to prepare 98a to afford 82 mg of title compound (44% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.18-1.53 (m, 3H), 1.70-2.40 (m, 4H), 2.55-3.10 (m, 2H), 2.84 (s, 6H), 3.45-3.94 (m, 2H), 4.25-4.95 (m, 5H), 5.46 (s, 0.3H), 5.51 (s, 0.2H), 5.63 (d, 0.4H), 5.73 (d, 0.1H), 7.05 (d, 1H), 7.15-7.95 (m, 7H). Analytical HPLC: 11.85, 12.19 min. LC-MS (ES+): m/e=557.3 (M+H+).