Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(#N)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:49])=[C:34]([C:36]([CH3:48])([CH3:47])[CH2:37][C:38]([C:43]([F:46])([F:45])[F:44])([OH:42])[CH2:39][C:40]#[CH:41])[CH:35]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.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.[Cu]I.O1CCCC1>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:49])=[C:34]([C:36]([CH3:47])([CH3:48])[CH2:37][C:38]([C:43]([F:44])([F:45])[F:46])([OH:42])[CH2:39][C:40]#[C:41][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[N+:16]([O-:18])=[O:17])[CH:35]=1
Reactant: C#CCC(O)(CC(C)(C)c1cc(F)ccc1C)C(F)(F)F
Reactant: O=[N+]([O-])c1c(F)cccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(F)cc1C(C)(C)CC(O)(CC#Cc1cccc(F)c1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A mixture of trifluoromethanesulfonic acid 3-fluoro-2-nitrophenyl ester (149 mg, 0.52 mmol), dichlorobis(triphenylphosphine)palladium (II) (20 mg, 0.028 mmol), copper (I) iodide (14 mg, 0.074 mmol), tetrabutyl ammonium iodide (200 mg, 0.54 mmol), 0.25 mL of anhydrous triethylamine, 0.5 mL of anhydrous acetonitrile, and 0.5 mL of anhydrous tetrahydrofuran was stirred at room temperature for 30 minutes. The resulting mixture was treated with 6-(5-fluoro-2-methylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (145 mg, 0.48 mmol) and stirred at room temperature for 18 hours. The crude product was purified by chromatography on SiO2 (50% hexanes in dichloromethane) to give 96 mg of the title product as light yellow oil, (45% yield).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[N:11][C:12]2[C:13](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:7][CH:8]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:10]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=4)[CH:18]([CH2:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:13]4[N:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:38][CH2:37]2)=[CH:34][CH:35]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1ncccc1N=C=Nc1cccc(C(F)(F)F)c1
Product: CC(C)(C)OC(=O)CC1c2ncccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting from 53 mg (0.14 mmol) of the carbodiimide from Example 14A and 24 mg (0.14 mmol) of 4-fluorophenylpiperazine, general procedure [C] and purification on preparative HPLC result in 38 mg (48% of theory) of product.
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:23]([NH:25][N:26]1[C:30](=[O:31])[CH2:29][N:28]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:27]1=[O:37])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:23]([NH:25][N:26]1[C:30](=[O:31])[CH2:29][N:28]([CH2:32][CH2:33][N:34]([CH3:35])[CH3:36])[C:27]1=[O:37])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:11]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CN(CCN(C)C)C1=O)[C@H](CCCc1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(CCN(C)C)C1=O)[C@H](CCCc1ccccc1)C(=O)NO
Yield: 93.6 %

Procedure:
A solution of 0.061 g of 2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenylbutyl]-N-[3-[2-(dimethylamino)ethyl]-2,5-dioxo-1-imidazolidinyl]-4-methylvaleramide in 10 ml of methanol was hydrogenated in the presence of 0.005 g of 10% palladium-on-carbon for 3 hours. The catalyst was removed by filtration and evaporation gave 0.048 g of 2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenylbutyl]-N-[3-[2-(dimethylamino)ethyl]-2,5-dioxo-1-imidazolidinyl]-4-methylvaleramide in the form of 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.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][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
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ccc(Cl)c(N)c1
Product: Cc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5-methylaniline (41 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (15 mg, 21%). 1H NMR (CDCl3): 9.62–9.61 (m, 1H), 8.73–8.69 (m, 2H), 7.89 (s, 1H), 7.44–7.40 (m, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.00 (dd, J=0.9, 8.4 Hz, 1H), 6.88 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:8](=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[C:7](=[O:19])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:4][N:3]1[CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]1[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=1)=[O:28].B(Br)(Br)Br.CO>ClCCl>[O:1]=[C:2]1[C:8](=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[C:7](=[O:19])[N:6]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]1[CH2:26][C:27]([N:29]([C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1)[CH:38]([CH3:40])[CH3:39])=[O:28]
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=Cc3n[nH]c4ccccc34)C2=O)C(C)C)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)N(C(=O)CN1C=CN(c2ccccc2)C(=O)C(=Cc2n[nH]c3ccccc23)C1=O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To the solution of 2-[2,4-dioxo-3-(1H-indazol-3-ylmethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (Example 1) (1 g, 1.86 mM) in 50 ml of dichloromethane was cooled to 0° C. and 10 fold excess of BBr3 was added. The reaction mixture was stirred for 3 hrs at room temp., cooled to 0° C. and methanol was added dropwise. Organic solvents were evaporated under reduced pressure and residue was purified using column chromatography on silica gel using mixture of Hexane-Ethyl Acetate (1:3) as an eluent providing 700 mg of pure racemic product.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=C)=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[O:23][CH3:24].CC(C)=[O:27].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=[O:27])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(F)c(OC)c2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(F)c(OC)c2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of methyl 5-(4-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-vinylbenzoate (0.39 g) in a mixed solvent of acetone (9.00 mL)-acetonitrile (9.00 mL)-water (9.00 mL) were added osmium oxide (fixed catalyst I) (0.15 g) and sodium periodate (1.27 g), and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate to give the title compound (0.39 g). This compound was used in the next step without an additional purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=1>>[CH:9]1([O:8][C:6]2[N:5]=[C:4]3[CH2:14][CH2:15][CH2:16][C:3]3=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=3)[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1cc(OC2CCCC2)nc2c1CCC2
Product: CCOC(=O)Cc1ccc(Nc2cc(OC3CCCC3)nc3c2CCC3)cc1
Yield: 79.8 %

Procedure:
Following general procedure B2, 4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.070 g, 0.29 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.080 g, 0.44 mmol) to afford the title compound (0.088 g, 78%) as a yellow foam. MW=380.48. APCI MS m/z 381 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C(Cl)(Cl)Cl.CO>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1ccc(C(=O)O)cn1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(N)nc1

Procedure:
To a solution of 6-aminonicotinic acid (2.00 g, 14.48 mmol) dissolved in chloroform/MeOH (90 mL: 30 mL) was added (trimethylsilyl)diazomethane (2.0M in hexanes, 25 mL). After 15 minutes acetic acid (0.1 mL) was added and the solution was concentrated in vacuo to a residue. Trituration with EtOAc/Hex (2:1) provided methyl-6-aminonicotinate as a pale yellow solid after filtration. This material was used directly in the next step. To a solution of methyl-6-aminonicotinate (1.86 g, 12.22 mmol) dissolved in methylene chloride (90 mL) was added di-t-butyl dicarbonate (2.69 g, 12.34 mmol), 4-dimethylaminopyridine (0.15 g, 1.22 mmol) and triethylamine (2.00 mL, 14.66 mmol). After 14 h the reaction was diluted with EtOAc (400 mL) and washed with citric acid (1×50 mL, 10%), water (1×50 mL) and brine (1×50 mL) and was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (40×150 mm column of SiO2, EtOAc/Hex gradient elution 1:6, 1:5, 1:3) to to give the title compound as a white solid:
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.O>CS(C)=O>[C:1]1([S:7]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 120 °C
Yield: 79.6 %

Procedure:
Sodium phenylsulfinate (16.4 g, 0.1 mol) and 4-fluorobenzaldehyde (12.4 g, 0.1 mol) were combined in dimethylsulfoxide (100 mL) and heated at 120° C. for 4 days. The cooled reaction was poured into water. The resulting crystals were filtered off and washed with water, then dissolved in ethyl acetate/dichloromethane, dried and concentrated in vacuo until crystallisation ensued. The mixture was diluted with isohexane and the crystals filtered off and washed with further isohexane to yield 4-(phenylsulfonyl)benzaldehyde (19.6 g, 80%). δH (500 MHz, d6 DMSO): 10.06 (1H, s), 8.16 (2H, d, J=8.3 Hz), 8.09 (2H, d, J=8.3 Hz), 7.99 (2H, d, J=7.7 Hz), 7.71 (1H, t, J=6.9 Hz), 7.63 (2H, t, J=7.7 Hz).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][CH2:31][CH2:32]Br>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:32][CH2:31][O:30][CH3:29])[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Product: COCCn1ccc2c(-c3ccc(Cl)cc3)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 2-bromoethyl methyl ether. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.59-7.65 (m, 1H) 7.45-7.51 (m, 2H) 7.39-7.45 (m, 1H) 7.10-7.16 (m, 1H) 5.91-5.99 (m, 1H) 5.30-5.38 (m, 1H) 4.67-4.87 (m, 2H) 3.72-3.86 (m, 2H) 3.67 (s, 3H)) 3.34 (s, 3H) 1.01 (s, 9H); LCMS (m/z) ES+=447 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][CH3:28])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:27][CH3:28])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)OCC)ccc1OC
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: 2-(2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-propionic acid ethyl ester and benzyl chloroformate.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16]C)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A methanol solution of methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate was mixed with 1 M sodium hydroxide aqueous solution and stirred at room temperature for 2Hours. After completion of the reaction, this was neutralized with 1 M hydrochloric acid, and methanol was evaporated. The thus formed crystals were collected by filtration to obtain 1-benzyl-5-oxo-3-pyrrolidine-carboxylic acid. FN: 218.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][Si](C(C)C)(C(C)C)C(C)C)[CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:41][C:42](=[O:44])[CH3:43].CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH2:41][C:42](=[O:44])[CH3:43])[CH:5]=1
Reactant: CC(=O)CCl
Reactant: COC(=O)c1ccnc(S[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(SCC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Triisopropylsilanylsulfanyl-isonicotinic acid methyl ester (1.5 g, 4.6 mmol) was dissolved in THF (50 mL) and tetrabutylammonium fluoride (1 M in THF, 6.9 mL, 6.9 mmol) was added. After 15 minutes TLC indicated complete cleavage of the protecting group and chloroacetone (0.440 mL, 5.52 mmol) and Hünig's base (2.8 mL, 16.1 mmol) were added. After 1 hour additional portions of chloroacetone (1.2 eq.) and Hünig's base (3.5 eq.) were added. After stirring at room temperature for 2 hours the reaction was diluted with EtOAc and washed with H2O/brine with back-extraction. The combined organic portions were dried over MgSO4 and concentrated then purified on silica gel (0-100% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(Cl)Cl>O.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Cl)cc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)Nc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(tert-butoxycarbonyl)-N-methylglycine (10 g), 4-chloroaniline (8.8 g), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 25.7 g) and methylene chloride (150 ml) is added dropwise triethylamine (5.9 g) while the temperature of the mixture is kept at 0-5° C. After addition, the mixture is stirred at room temperature for 8 hours, and thereto is added water. The methylene chloride layer is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from diethyl ether to give 2-[N'-(tert-butoxycarbonyl)-N'-methylamino]-N-(4-chlorophenyl)acetamide, m.p. 126-128° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.CO.[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>CC(O)=O>[Br:1][CH2:2][CH2:3][C:4](=[N:14][NH:15][C:16]([NH2:18])=[S:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CCBr)c1ccccc1
Reactant: NNC(N)=S
Solvent: CC(=O)O
Solvent: CO
Product: NC(=S)NN=C(CCBr)c1ccccc1
Yield: 42.8 %

Procedure:
(Du, X.; Guo, C.; Hansell, E.; Doyle, P. S.; Caffrey, C. R.; Holler, T. P.; McKerrow, J. H.; Cohen, F. E. J. Med. Chem. 2002, 45, 2695-2707) Into a round bottom flask containing 3-bromopropiophenone (0.508 g, 2.34 mmol), 20 mL of anhydrous methanol were added and the solution was refluxed for 15 minutes. To the warm ketone solution, thiosemicarbazide (0.184 g, 2.04 mmol) and 1% solution of HOAc (0.2 mL) were added. The reaction mixture was refluxed under nitrogen atmosphere for 17 h, at which point, the solvent was evaporated and, the crude reaction mixture was purified by flash chromatography (30% EtOAc/70% hex) to obtain 0.2498 g (0.873 mmol) of the product in a 37% yield.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:6]([C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:8])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)[C@H]1CCCO1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccccc2)CC1)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A solution of (R)-tetrahydro-2-furoic acid (58.5 g, 504 mmol) and oxalyl chloride (86 mL, 1.0 mol) in 100 mL CH2Cl2 were refluxed for 2 hours in a flask equipped with a CaCl2 guard tube. After the solution was cooled to room temperature the solvents and excess oxalyl chloride were removed by evaporation under reduced pressure. The resulting acid chloride was dissolved in 200 mL CH2Cl2 and added dropwise to a solution of 1-benzyl-4-amino piperidine dihydrochloride (142 g, 539 mmol) and triethylamine (240 mL, 1.7 mol) in 300 mL CH2Cl2 cooled in an ice bath. The resulting mixture was stirred for 2 hours at room temperature and subsequently washed twice with 300 mL portions of 5% aq. NaHCO3 and 300 mL saturated aq. NaCl solution, dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure. The solid residue was triturated with 500 mL heptanes, collected by filtration, and washed twice with 200 mL portions of heptanes. The solid was air-dried at 45° C. to yield (R)-tetrahydrofuran-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide (128 g, 88%) as an off-white solid. 1H-NMR (300 MHz, CDCl3): δ 7.35-7.20 (m, 5H), 6.58 (bs, 1H), 4.29 (dd, J=5.9, 8.4 Hz, 1H), 3.92-3.77 (m, 2H), 3.48 (s, 2H), 2.82-2.74 (m, 2H), 2.32-2.21 (m, 1H), 2.19-1.95 (m, 3H), 1.94-1.78 (m, 4H), 1.58-1.40 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[OH:27][CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 28 using 5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.78 min, m/z=445.0 [M+H]+, m/z=443.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.78-1.90 (m, 1H) 2.88 (d, J=11.25 Hz, 1H) 3.13-3.28 (m, 2H) 3.35-3.45 (m, 1H) 4.20 (br. s, 1H) 4.85 (d, J=3.42 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.50 (dd, J=7.82, 4.89 Hz, 1H) 7.82 (d, J=8.07 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H) 8.04 (d, J=2.20 Hz, 1H) 8.59 (dd, J=4.77, 1.34 Hz, 1H) 8.65 (d, J=1.96 Hz, 1H) 8.78 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[C:22]([Cl:24])[C:21]([N+:25]([O-])=O)=[CH:20][C:19]=4[F:28])=[C:11]3[C:10]([I:29])=[N:9]2)=[CH:5][CH:4]=1.CCO>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[C:19]([F:28])=[CH:20][C:21]([NH2:25])=[C:22]([Cl:24])[CH:23]=4)=[C:11]3[C:10]([I:29])=[N:9]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4F)ccnc32)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c(N)cc4F)ccnc32)cc1
Temperature: 70 °C
Yield: 74.9 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-4-(5-chloro-2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrazolo[3,4-b]pyridine (2.85 g, 5.14 mmol), SnCl2 dihydrate (4.64 g, 20.6 mmol) and EtOH (70 mL) was heated to 70° C. for 8 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with saturated aqueous Na2CO3, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (2.02 g, 64% yield) as a light yellow solid. LRMS (APCI pos) m/e 524.9 (M+H).