Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]#[C:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1>[Pd].CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#CCCN3C(=O)c4ccccc4C3=O)ccc21
Agent: [Pd]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCN3C(=O)c4ccccc4C3=O)ccc21
Yield: 86.9 %

Procedure:
10% Palladium on carbon (0.52 g) was added to a methanol solution (50 ml) of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)but-1-ynyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.2 g). The mixture was subjected to catalytic reduction at room temperature under normal pressure. The catalyst was removed by celite filtration, followed by concentration under reduced pressure to give the title compound (1.93 g) as a brown solid.
Reaction SMILES: [C:1](Cl)(=O)C.[N+:5]([C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]=1[C:17]([OH:19])=[O:18])([O-:7])=[O:6]>CO>[CH3:1][O:12][C:11](=[O:13])[C:10]1[C:9](=[C:8]([N+:5]([O-:7])=[O:6])[CH:16]=[CH:15][CH:14]=1)[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To MeOH (100 ml) at 0° C. was added acetyl chloride (14.5 mL, 203.4 mmol) and the solution stirred at rt for 1 h. 3-Nitrophthalic acid (25.7 g, 121.7 mmol) was added and the mixture heated at reflux for 22 h. The reaction was cooled to rt and partitioned between water (80 mL) and EtOAc (3×80 mL). The combined organic phase was dried (MgSO4) and solvent removed in vacuo to give the title compound: Data in agreement with previous reports (Roger, M. E.; Averill, B. A. J. Org. Chem. 1986, 51, 3308-3314).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18](Cl)=[O:19].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]([C:10]2[O:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1cc2ccccc2o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)cc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To 1.72 g of 4-bromoaniline was added to 1.89 g of benzofuran-2-carboxylic acid chloride in 35 mL of dichloromethane cooled in ice bath, followed by the addition of 4.9 mL of triethylamine. The reaction was stirred at room temperature overnight and then diluted with dichloromethane. The dichloromethane layer was washed with water, 1N HCl, water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide 2.61 g of N-(4-bromophenyl)-1-benzofuran-2-carboxamide as a yellow solid. Yield 72%. m.p. 178-180° C.; MS: 314.1(M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:18]([O-])=O)[CH:4]=1.[H][H]>CO.O=[Pt]=O>[NH2:18][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: COCCOc1cc(C(=O)OC)c(N)cc1OC
Yield: 82.8 %

Procedure:
A solution of methyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate (3.39 g, 11.88 mmol) in methanol (40 mL) was hydrogenated at 50 psi hydrogen gas in the presence of PtO2 (0.050 g) using a Parr hydrogenator for 24 h. The reaction mixture was filtered and concentrated to give the title compound as an oil (2.51 g, 83%).
Reaction SMILES: [CH2:1]=O.Cl.[I:4][C:5]1[CH:16]=[CH:15][C:8]2[C:9]([CH2:12][CH2:13][NH2:14])=[CH:10][O:11][C:7]=2[CH:6]=1>Cl.C=O>[I:4][C:5]1[CH:16]=[CH:15][C:8]2[C:9]3[CH2:12][CH2:13][NH:14][CH2:1][C:10]=3[O:11][C:7]=2[CH:6]=1
Reactant: C=O
Reactant: NCCc1coc2cc(I)ccc12
Agent: Cl
Product: Ic1ccc2c3c(oc2c1)CNCC3
Temperature: 70 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
Paraformaldehyde (8.9 g, 0.297 mol) was added to a solution of 2-(6-iodo-1-benzofuran-3-yl)ethanamine hydrochloride (80 g; 0.247 mol) in 1N HCl (500 mL) under N2. After 2 h stirring at 70° C., another portion of paraformaldehyde (740 mg) was added. The reaction mixture was cooled down to r.t., filtered, the resulting solid was washed with 1N HCl (100 mL), dried overnight under house vacuum to afford 76.7 g of the title product as a hydrochloric acid salt. 1H-NMR (400 MHz, CDCl3): δ 2.06 (bt, 2H), 2.92 (bt, 2H), 4.37 (s, 2H), 7.45 (d, 1H) 7.62 (dd, 1H), 8.05 (d, 1H), 10.04 (bs, 2H).
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(O[C:4]1[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[C:6](=[O:10])[CH2:7][CH2:8][CH:9]=1)=O.[CH2:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O)[CH3:38].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.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>[CH2:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:4]1[N:5]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=2)[C:6](=[O:10])[CH2:7][CH2:8][CH:9]=1)[CH3:38]
Reactant: O=C1CCC=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccccc1C1=CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 40 °C

Procedure:
A mixture of 6-oxo-1-(4-(trifluoromethoxy)benzyl)-1,4,5,6-tetrahydropyridin-2-yl diphenyl phosphate (140 mg; 0.13 mmol; 1.0 equiv.), (2-ethoxyphenyl)boronic acid (34 mg; 0.20 mmol; 1.5 equiv.), PdCl2(PPh3)2 (5 mg; 0.007 mmol; 0.05 equiv.), Na2CO3 (188 mg; 1.78 mmol; 13.2 equiv.) in THF (2 ml) and water (0.9 ml) was heated to 40° C., under nitrogen, for 1.5 h. After cooling to rt, water was added, and the mixture was extracted with Et2O (3×). The mixed organic layers were dried over anh. K2CO3, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded 6-(2-ethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)-3,4-dihydropyridin-2(1H)-one. LC-MS (conditions E): tR=0.83 min.; [M+H]+: 392.2 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13].C(N(CC)C(C)C)(C)C.[CH3:23][O:24][CH2:25]Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][O:13][CH2:23][O:24][CH3:25])[NH2:8]
Reactant: O=[N+]([O-])c1ccc(CCO)c(Cl)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCCc1ccc(N)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(2-chloro-4-nitrophenyl)ethanol (2.9 g) in dichloromethane (20 ml) were added N,N-diisopropyl-ethylamine (3.0 ml) and chloromethyl methyl ether (1.2 ml) under ice-cooling, and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (20 ml), 3% platinum sulfide on activated carbon (wet) (842 mg) was added, and the mixture was stirred for 10 hours under a hydrogen atmosphere. After the catalyst was removed by filtration, the solvent was removed under reduced pressure to give 3-chloro-4-[2-(methoxy-methoxy)ethyl]aniline (2.0 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[C:15]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:15]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[N:7]3)[CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2c(N3CCN(CCCCn4nnc5ccccc54)CC3)cccc2c1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-naphthyl)piperazine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.9 g compound (I-47) with a yield of 60.1%. ESI-MS [M+H]+: m/z 385.2.
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19][CH2:20][CH3:21])=[CH2:18])CCC>>[CH2:20]([O:19][C:17]([C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[CH2:18])[CH3:21]
Reactant: CCOC(=O)c1coc(Cl)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Product: C=C(OCC)c1nc(C(=O)OCC)co1

Procedure:
Ethyl 2-(1-ethoxyvinyl)oxazole-4-carboxylate was prepared using the procedure described in Example 33(a), starting from ethyl 2-chlorooxazole-4-carboxylate (10.5 g, 59.8 mmol) and tributyl(1-ethoxyvinyl)stannane (24 ml, 65.8 mmol), The product was purified with flash-chromatography. Yield 10.3 g. 1H-NMR (400 MHz; CDCl3): δ ppm 1.23-1.46 (m, 6H), 3.94-3.99 (m, 2H), 4.36-4.42 (m, 2H), 4.8 (d, 1H), 5.33 (s, 1H), 8.19 (s, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated at 160° C. After 2 h reaction time, the phenol conversion was 11.9%, wherein 0.6 g of phenyl chloroformate and 18.6 g of diphenyl carbonate were formed. The selectivity to give the carbonate and phenyl chloroformate was greater than 99%.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][NH:44][C:43]1=[O:47].OS([O-])(=O)=O.[Na+]>CCO>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][N:42]2[CH2:46][CH2:45][NH:44][C:43]2=[O:47])=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCCN1CCNC1=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Product: NCCn1c(=O)c(C(=O)NCCN2CCNC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 1-(2-aminoethyl)-2-imidazolidinone (0.0078 g, 0.03 mmol, 50% W/W in IPA) for 30 min. (150° C. The reaction was further microwaved for 30 min.@150° C. after the addition of an additional 0.6 equivalents (0.015 mL) of the amine, cooled to ambient temperature, and treated with 1N NaHSO4. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The filtrate residue was purified by reversed phase HPLC. Pure fractions were combined and concentrated to afford the title compound as an off-white solid: ES+ MS: 469 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([Cl:20])[C:6]([Cl:19])=[C:7]([O:17]C)[CH:8]=2)[C:3]1=[O:21].Cl.N1C=CC=CC=1>O>[CH3:1][C:2]1([CH3:22])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([Cl:20])[C:6]([Cl:19])=[C:7]([OH:17])[CH:8]=2)[C:3]1=[O:21]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)C(=O)c2c(cc(O)c(Cl)c2Cl)C1c1ccccc1
Temperature: 180 °C

Procedure:
A stirred mixture of 2,2-dimethyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone (6.5 g., 0.02 mole) and pyridine hydrochloride (60 g.) is heated at 180° C. for two hours, then poured into water (800 ml.). The 2,2-dimethyl-3-phenyl-5-hydroxy-6,7-dichloro-1-indanone which separate (5.10 g.) melts at 259°-262° C. after recrystallization from ethanol:water, 2:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:5][CH:4]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:20](=[O:21])[CH2:19][Cl:18]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(Nc2c(Cl)cccc2Cl)cc1
Product: COc1ccc(N(C(=O)CCl)c2c(Cl)cccc2Cl)cc1
Yield: 64 %

Procedure:
Under anhydrous conditions, a mixture of N-(4-methoxyphenyl)-2,6-dichloroaniline (20.2 g, 75.4 mmmol) in 175 mL of chloroacetyl chloride is heated at reflux for 1 hour. The excess acid chloride is evaporated in vacuo and the residue partitioned between saturated NaHCO3 solution and ethyl acetate (30 mL each). The organic phase is washed with brine (30 mL) and dried (Na2SO4). Removal of solvent affords an amber oil. Crystallization of the crude oil from methanol affords the title product (16.63 g, 64%, white needles, m.p. 105°-106° C., lit: 127°-128° C. from methanol) as a 1:1 mixture of rotamers.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCNC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(C2=CCNC2)cc1
Yield: 18 %

Procedure:
To a suspension of 0.43 mmol rac-3-(4-Trifluoromethyl-phenyl)-pyrrolidin-3-ol in 0.4 ml dichloromethane under argon, was added 0.4 ml TFA. The reaction mixture was stirred at reflux for 5 days and concentrated. The residue was dissolved in ethyl acetate and NaOH 2N was added until pH 9-10. The organic phases were dried over Na2SO4 and evaporated to yield the title compound (18%) as an oil MS (m/e): 214.2 ([M+1], 100%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]OC1C=CC=CC=1.B(Br)(Br)[Br:24]>C(Cl)Cl>[Br:24][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccccc1CCCCCCCOc1ccccc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1CCCCCCCBr

Procedure:
7-Bromo-1-(2-hydroxy-phenyl)-heptane (9.3) was synthesized as in 9.1 using 8.3 (0.30 g, 1.01 mmol) in anhydrous CH2Cl2 (10 mL), and BBr3 (1M solution in CH2Cl2, 2.2 mL, 2.2 mmol). The title compound (9.3) was isolated as a viscous liquid after purification by flash column chromatography (0.247 g, 90% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+]>>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][C:25]#[N:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Product: N#CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
That is, 2,4-dihydroxybenzaldehyde [IV] is benzylated with benzyl chloride to produce 2,4-dibenzyloxybenzaldehyde [V], then [V] is reduced with sodium borohydride to produce 2,4-dibenzyloxybenzyl alcohol [VI] and then, [VI] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxybenzyl chloride [VII]. Then, [VII] is allowed to react with sodium cyanide to obtain 2,4-dibenzyloxyphenyl acetonitrile [VIII], thereafter [VIII] is hydrolyzed with an alkali to produce 2,4-dibenzyloxyphenylacetic acid [IX], then this [IX] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxyphenylacetyl chloride [X] and further, this [X] is allowed to react with L-asparagine or glutamine p-nitrophenyl ester to obtain [IIa].
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[C:6]3[CH:12]=[N:11][NH:10][C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[K+].[I:28]I>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[C:6]3[C:12]([I:28])=[N:11][NH:10][C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C3CC3)cnc3[nH]ncc23)CC1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(C3CC3)cnc3[nH]nc(I)c23)CC1
Temperature: 60 °C
Yield: 102.1 %

Procedure:
A mixture of tert-butyl 4-(5-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.44 g, 4.19 mmol) and powdered potassium hydroxide (0.692 g, 10.5 mmol) in DMF (20 mL) was treated with iodine (2.13 g, 8.39 mmol), and the mixture was heated at 60° C. for 5 hours. The mixture was diluted with EtOAc (200 mL) and successively washed with saturated Na2S2O3 solution (2×20 mL) and water (2×50 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo to provide the crude tert-butyl 4-(5-cyclopropyl-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (2.01 g, 4.28 mmol, 100%) yield) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].Cl[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[N:12]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2c(C#N)cccc21
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C#N)cccc21

Procedure:
(S)-tert-butyl (4-cyano-2,3-dihydro-1H-inden-1-yl)(2-(dimethylamino)-2-oxoethyl)carbamate INT-60 was prepared analogously to INT-59 from (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate INT-53 and 2-chloro-N,N-dimethylacetamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:33]=[CH:32][C:26]([CH2:27][P:28]([CH3:31])(=[O:30])[OH:29])=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1(O)[CH2:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH:34]1([O:30][P:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:21](=[O:22])[NH:20][C:10]3[CH:11]=[C:12]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)[CH:13]=[CH:14][C:9]=3[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:33][CH:32]=2)([CH3:31])=[O:29])[CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CP(C)(=O)O)cc1
Reactant: OC1CCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CP(C)(=O)OC2CCC2)cc1
Reaction time: 18 h

Procedure:
To a solution of [4-(2-tert-butoxycarbonylamino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-methyl-phosphinic acid (57 mg, 0.117 mmol), cyclobutanol (0.038 mL, 0.703 mmol), and Hunig's Base (0.031 mL, 0.176 mmol) in DMF (2 mL) was added BOP (78 mg, 0.176 mmol). After 18 h, the reaction was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water plus 0.025% TFA (40-100%) to give material after extraction of fractions with EtOAc. 1H NMR (DMSO-d6) δ 9.88 (s, 1H), 8.74 (br s, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.79 (br s, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.52-7.47 (m, 2H), 7.44-7.39 (m, 3H), 7.12-7.09 (m, 1H), 4.64 (m, 1H), 3.27 (dd, J=23.2, 17.6 Hz, 1H), 3.25 (dd, J=23.2, 17.6 Hz, 1H), 2.25-21.4 (m, 2H), 2.05-1.94 (m, 2H), 1.67-1.60 (m, 1H), 1.49-1.42 (m, 1H), 1.43 (s, 9H), 1.31 (d, J=14.1 Hz, 3H). MS: cal'd 441 (MH+; -Boc), exp 441 (MH+; -Boc).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:3]=1.[C:22]([C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])([OH:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][NH:11][C:4]1[N:5]=[C:6]([CH2:8][O:9][CH3:10])[N:7]=[C:2]([C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])[CH:33]=[CH:32][CH:31]=2)[CH:3]=1
Reactant: COCc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COCc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
Argon is bubbled through a mixture of (6-chloro-2-methoxymethyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (200 mg, 0.58 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [266 mg, 1.28 mmol, see Example 49(b) step 2], Cs2CO3 (1.56 g, 2.52 mmol), and tetrakis(triphenylphosphine)palladium (0) (69 mg, 0.06 mmol) in ethylene glycol dimethyl ether (4 mL) and water (1 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 16 hours the mixture is diluted with water (40 mL) and extracted twice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with 40% ethyl acetate:heptane to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxymethyl-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [165 mg, 60%, Example 85] as a solid. LCMS RT=2.59 minutes, MS: 474 (M+H). IC50=2.7 nM
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][N:15]=[C:14]4[CH:21]=[CH:22][S:23][C:13]=34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O.[OH-].[Na+]>CC(C)=O>[N+:18]([C:17]1[C:12]([NH:11][CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[C:13]2[S:23][CH:22]=[CH:21][C:14]2=[N:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1NC1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
A mixture of N-1,4-dioxaspiro[4.5]dec-8-yl-6-nitrothieno[3,2-b]pyridin-7-amine (0.45 g, 1.3 mmol) and 3.0 M hydrogen chloride in water (9 mL, 30 mmol) in acetone (20 mL) was stirred at room temperature for 20 min and then at 60° C. for 1 h. The mixture was basified with aq. 5M NaOH solution at 0° C., then extracted with EtOAc. The combined organic layers were dried over sodium sulfate, concentrated and purified on silica gel column (eluting with 0-30% of EtOAc in methylene chloride) to give the desired product (0.2 g, 51% in 2 steps). LCMS calculated for C13H14N3O3S (M+H)+: m/z=292.1. Found: 292.0.