Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:48]=[CH:47][C:46]([O:49]CC4C=CC=CC=4)=[CH:45][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:24]([CH2:36][O:37][Si](C(C)(C)C)(C)C)[CH:23]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[OH2:57]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:24]([CH2:36][OH:37])[CH:23]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:11][CH2:12][O:57][CH2:13][CH2:14]1
Reactant: O
Reactant: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(CO[Si](C)(C)C(C)(C)C)c3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(CO)c3)sc3cc(O)ccc23)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
The (30.8 mg, 0.0381 mmol) 6-benzyloxy-2-[3-t-butyldimethylsilyloxymethyl-4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 3-methoxy-4-(1-pyrrolidinylmethyl)phenyl ketone (Part C) was dissolved in 0.5 mL of 1N tetrabutylammonium fluoride in THF. The solution was stirred at room temperature for 1 h. To the reaction mixture was added 1.0 mL of water and diluted with 15 mL of EtOAc. The layers were separated and the aqueous layer was extracted (1×10 mL) with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 80:17:3 THF-Hexanes-Et3N) afforded 5.7 mg (0.0082 mmol, 22%) of a yellow oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].C(N(CC)CC)C.[CH3:14][O:15][CH2:16]Cl>C(Cl)Cl>[CH3:14][O:15][CH2:16][O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: COCCl
Reactant: COC(=O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOCC(=O)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of methyl glycolate (18.02 g) and triethylamine (20.24 g) in anhydrous methylene chloride (100 ml.) is added dropwise over 40 minutes to an ice-cold, stirring solution of chloromethyl methyl ether (17.7 g) in methylene chloride (200 ml.). The resulting mixture is allowed to stand overnight in a flask protected from moisture by a drying tube. The mixture is washed with water, 5% aqueous sodium bicarbonate, water, and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Distillation of the residue yields methyl methoxymethyloxyacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:37][C:36]([F:39])([F:38])[CH2:35]1)(=[O:33])=[O:32]>>[F:39][C:36]1([F:38])[CH2:35][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:37]1
Reactant: O=S(=O)(c1ccccc1Br)N1CC(F)(F)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CC(F)(F)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-3,3-difluoroazetidine. MS (ESI): mass calcd. for C19H15F3N4O2S, 420.09; m/z found, 421.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37-8.26 (m, 2H), 8.14-8.07 (m, 1H), 8.02-7.95 (m, 1H), 7.77-7.69 (m, 1H), 7.66-7.57 (m, 1H), 7.48-7.40 (m, 1H), 7.35-7.24 (m, 2H), 4.02-3.92 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Br:20][C:21]1[CH:29]=[C:28]([C:30](Cl)=[O:31])[C:24]2[O:25][CH2:26][CH2:27][C:23]=2[CH:22]=1>C1COCC1>[Br:20][C:21]1[CH:29]=[C:28]([C:30](/[N:12]=[C:6]2\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\2[CH2:4][CH2:3][O:2][CH3:1])=[O:31])[C:24]2[O:25][CH2:26][CH2:27][C:23]=2[CH:22]=1
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1cc(Br)cc2c1OCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Br)cc2c1OCC2
Yield: 35.5 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and 5-bromo-2,3-dihydrobenzo[b]-furan-7-carbonyl chloride (Maybridge, 0.42 g, 1.6 mmol) in 35 mL THF were processed as in Example 126B. The resulting crude material was purified via flash column chromatography (SiO2, 7:3 hexanes:EtOAc) to afford the title compound (0.16 g, 0.39 mmol, 36% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.24 (s, 3H), 2.28 (s, 3H), 3.23 (t, J=8.5 Hz, 2H), 3.33 (s, 3H), 3.78-3.87 (m, 2H), 4.45-4.56 (m, 2H), 4.70-4.81 (m, 2H), 7.35-7.39 (m, 1H), 8.09 (d, J=20 Hz, 1H); MS (DCI/NH3) m/z 411, 413 (M+H)+; Anal. calculated for C17H19BrN2O3S.0.3H2O: C, 49.00; H, 4.74; N, 6.72. Found: C, 48.91; H, 4.36; N, 6.57.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=3[F:32])[C:13]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:12]2[C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[N:9][NH:8]3)=[C:26]([F:32])[CH:27]=1
Reactant: CC(C)(C)OC(=O)c1ccc2c(cnn2C(=O)OC(C)(C)C)c1Nc1ccc(Br)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
To a solution of 4-(4-bromo-2-fluorophenylamino)-indazole-1,5-dicarboxylic acid di-tert-butyl ester (420 mg, 0.83 mmol) in DCM (5 ml) was added TFA (1.2 mL, 16.2 mmol). The reaction mixture was stirred at room temperature for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (232 mg, 80%). LCMS (Method B): RT=3.22 min, [M+H]+=350/352.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:23])=[C:4]([O:24][CH3:25])[CH:3]=1.ClCCl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[N:30]=1.N1C=CC=CC=1>CO.CCOC(C)=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:35][C:31]4[N:30]=[N:29][CH:34]=[CH:33][CH:32]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:23])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1cccnn1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3cccnn3)ccc21
Reaction time: 8 h
Yield: 22.2 %

Procedure:
A RBF was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonyl chloride (527.2 mg, 1.060 mmol), dichloromethane (1767 μl), and pyridazin-3-amine (151 mg, 1.590 mmol) to give a thick suspension. Pyridine (3533 μl) was added relatively quickly, and the mixture was stirred overnight. In the morning, the mixture was concentrated in vacuo, then taken up in 2N aq. HCl and MeOH/EtOAc. A solid formed that was slowly dissolved in the MeOH/EtOAc by repeated exposure. The layers were separated, and the aq. layer was extracted with MeOH/EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 0-50% 3:1 EtOAc/EtOH in heptane with 10% DCM). The main peak was collected with a slightly lower-Rf peak to give 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoxaline-6-sulfonamide (119 mg, 0.235 mmol, 22.18% yield) as a yellow solid. m/z (ESI) 506.0 (M+H)+.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9]1[N:10]=[C:11]([O:31][CH2:32][CH2:33][CH3:34])[C:12]2[N:17]=[C:16]([C:18]3[CH:28]=[C:27]([CH3:29])[C:21]([O:22][CH2:23][C:24](O)=[O:25])=[C:20]([CH3:30])[CH:19]=3)[O:15][C:13]=2[N:14]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:66]1[CH2:77][CH2:76][CH2:75][C@H:67]1[C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69].Cl>O.CN(C)C=O>[F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9]1[N:10]=[C:11]([O:31][CH2:32][CH2:33][CH3:34])[C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:30])[C:21]([O:22][CH2:23][C:24]([N:66]4[CH2:77][CH2:76][CH2:75][C@H:67]4[C:68]([O:70][C:71]([CH3:73])([CH3:74])[CH3:72])=[O:69])=[O:25])=[C:27]([CH3:29])[CH:28]=3)[O:15][C:13]=2[N:14]=1
Reactant: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)c(C)c3)nc12
Reaction time: 16 h

Procedure:
82 mg of {4-[5-(trans-2-fluorocyclohexyloxy)-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetic acid were added to 1.5 ml of N,N-dimethylformamide, and 48 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 10 mg of 1-hydroxy-7-azabenzotriazole and 195 μl of N,N-diisopropylethylamine were added, and after 5 min 24 mg of tert-butyl L-prolinate were added. After 16 h at room temperature, 10 ml of water were added, after which the mixture was adjusted to pH 3 by addition of 2 M aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution and sodium chloride solution, dried and concentrated under reduced pressure. This gave 79 mg of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:15])[N:10]1[CH2:14][CH2:13][S:12][CH2:11]1)(C)(C)C.[ClH:17].O1CCOCC1>>[ClH:17].[NH2:7][CH2:8][CH:9]([N:10]1[CH2:14][CH2:13][S:12][CH2:11]1)[OH:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCSC1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(O)N1CCSC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Oxo-2-thiazolidin-3-yl-ethyl)-carbamic acid tert-butyl ester (5.41 g, 22 mmol) was dissolved in 4M HCl-dioxane (80 mL) at 0° C. The resulting solution was stirred at 25° C. for 2 hours, concentrated and the residue triturated with ether. Yield, 3.9 g, 97%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:17][N:18]1[C:22]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=2[C:33]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:34]=2[CH:35]=[CH:36][C:37]([S:43](Cl)(=[O:45])=[O:44])=[CH:38]3)=[CH:21][CH:20]=[N:19]1.[NH4+].[Cl-]>C1COCC1>[CH3:17][N:18]1[C:22]([C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=2[C:33]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:34]=2[CH:35]=[CH:36][C:37]([S:43]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:45])=[O:44])=[CH:38]3)=[CH:21][CH:20]=[N:19]1
Reactant: Nc1nccs1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)Cl)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
A round bottom flask was charged with 2-aminothiazole (20.26 mg, 0.202 mmol) and sealed with septum. THF (1686 μl) was added and the solution was cooled to 0° C. A THF solution of lithium bis(trimethylsilyl)amide (253 μl, 0.253 mmol, 1 M) was added and the solution was maintained at 0° C. for 5 min To this solution was added 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonyl chloride (76.0 mg, 0.169 mmol) as a solution in THF (3 mL total). After 15 minutes at 0° C., saturated aqueous NH4Cl (1 mL) was added to the reaction mixture. The reaction mixture was partitioned between saturated aqueous NH4Cl (10 mL) and EtOAc (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under a vacuum. The residue was taken up in minimal DMSO and purified by preparative HPLC (column: Phenomenex C18 150×30 mm, 5 μm (Phenomenex, Torrance, Calif.): 20 to 90% CH3CN:H2O (1% TFA modifier) over 15 min). Fractions were combined and concentrated to afford 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (50.0 mg, 0.097 mmol) as a white amorphous solid. 1H NMR (400 MHz, d6-acetone) δ ppm 3.50 (s, 3H) 5.84 (d, J=1.86 Hz, 1H) 6.74 (d, J=4.69 Hz, 1H) 7.02 (d, J=1.96 Hz, 1H) 7.19 (d, J=4.70 Hz, 1H) 7.46 (d, J=7.04 Hz, 1H) 7.51-7.59 (m, 1H) 7.64 (d, J=8.90 Hz, 1H) 7.72 (d, J=8.02 Hz, 1H) 7.75-7.82 (m, 1H) 7.87 (s, 1H) 7.94 (d, J=8.12 Hz, 1H) 8.05 (d, J=8.31 Hz, 1H) 8.44 (s, 1H); m/z (ESI, +ve ion) 515.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:30][N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:33]4[CH2:34][CH2:35][N:31]([CH3:30])[C:32]4=[O:36])=[CH:7][C:6]=3[N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N(C)S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3N(C)S(C)(=O)=O)CC2)c(C)c1
Yield: 70.4 %

Procedure:
Using N-{5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-N-methylmethanesulfonamide (130 mg) described in Preparation Example 227 and 1-methylimidazolidin-2-one (27 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (95 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.Cl>CCOCC.[Cl-].[Cd+2].[Cl-]>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([C:13]([CH:10]2[CH2:12][CH2:11]2)=[O:14])[CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cccc(Br)c1
Agent: Cl
Agent: [Cd+2]
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1cccc(C(=O)C2CC2)c1
Reaction time: 1 h

Procedure:
m-Bromotoluene (34.2 g) in dry ether (120 ml) was added dropwise to magnesium turnings (4.8 g) in dry ether (100 ml). The heat of reaction maintained the mixture to boiling under reflux during the addition and the mixture was heated under reflux for a further hour. The mixture was cooled to 0°, dry cadmium chloride (19.6 g) was added and the temperature allowed to rise to 20° C. After 1 hour, cyclopropanecarbonyl chloride (20.8 g) in dry ether (50 ml) was added dropwise and the mixture was heated under reflux for 4 hours, cooled to 0° and treated with 2 N hydrochloric acid. The ether layer was separated, washed with aqueous sodium bicarbonate (3× 100 ml., 8%) and with water, dried over magnesium sulphate, filtered and evaporated. The residue was distilled under reduced pressure and the fraction b.p. 86°-90°/0.4 mm was collected.
Reaction SMILES: Cl.I[CH:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:16].[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[O:25][CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: COc1ccc(O)c(Cl)c1
Reactant: CCCCCCC(I)Cn1ccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OC(C)CCCCCCn2ccnc2)c(Cl)c1

Procedure:
Combine the product of step (b) (2.5 g) with 2-chloro-4-methoxyphenol (5.2 g) and potassium carbonate (10 g) in acetone (100 ml) and relux for 48 hours. Evaporate the solvent, extract the resultant residue with dichloromethane and purify on a silica gel column, eluting with 100% CH2Cl2 →10% CH3OH/CH2Cl2.
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)(=O)=O.O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:8]12([CH2:7][O:6][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:25][CH:26]=3)[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: O=S(=O)(OCC12CC3CC(CC(C3)C1)C2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(OCC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
To a solution of Intermediate 34 (4.2 g, 14.07 mmol) in anhydrous dimethylformamide (12 mL) and a solution of Intermediate 20 (0.98 g, 4.14 mmol) in anhydrous dimethylformamide (2 mL) was added cesium carbonate (1.8 g, 5.62 mmol). The reaction mixture was stirred at 65° C. for 72 hours. The crude was poured into water and extracted with ether. The organic layer was washed with a solution of sodium hydroxide 2N, water and brine. The solvent was removed under reduced pressure and the title compound was obtained as an oil (1.3 g, 67%) and used in the next step without further purification. MS (M+): 386.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([O:29]CC)=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Li+].[OH-]>>[C:34]1([S:40]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5]3)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccc(Cn2ccc3cc(NS(=O)(=O)c4ccccc4)ccc32)cc1

Procedure:
Treatment of ethyl N-{4-[(5-amino-1H-indol-1-yl)methyl]benzoyl}phenylalaninate with benzenesulfonyl chloride followed by LiOH hydrolysis as described in the procedure of Example 1 gave the title compound: MS (ESI) m/z 554; MS (ESI) m/z 552.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][OH:41])[CH:35]=2)=[O:33])=[CH:26][C:25]=1[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]2[CH2:54][CH2:53][N:52](C(OC(C)(C)C)=O)[CH2:51][CH2:50]2)[CH:43]=1>CN(C=O)C>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][O:41][CH2:40][C:36]3[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=3)[C:32]([NH:31][CH2:30][C:27]3[CH:26]=[C:25]([C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]5[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]5)[CH:43]=4)[C:24]([F:23])=[CH:29][CH:28]=3)=[O:33])[C:4]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CO)c4)ccc3F)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CCl
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1COCc1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 5.8 %

Procedure:
To a solution of 5-(chloromethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (73.9 mg, 0.229 mmol) in DMF (0.5 mL) was added 1,1-dimethylethyl 4-({2′-fluoro-5′-[({[3-(hydroxymethyl)phenyl]carbonyl}-amino)methyl]-3-biphenylyl}methyl)-1-piperazinecarboxylate (122 mg, 0.229 mmol). The mixture was stirred at room temperature for 15 h then more 5-(chloro-methyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-amine (73.9 mg, 0.229 mmol) was added. The mixture was stirred for another 24 h. The reaction was quenched with H2O (1 drop), diluted with MeOH (0.5 mL), purified using a Gilson HPLC (with TFA). To the Fractions containing the product was added TFA (1 drop in each tube ˜12 mL) and solvent was concentrated on a GeneVav EZ-2 evaporator. The compound was purified again with a Gilson HPLC (with TFA) and concentrated on GeneVav EZ-2 evaporator. Residue was basified with an amine cartridge to afford 0.0095 g (6%) of the title compound. LC-MS m/z 720 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.29 (t, J=7.65 Hz, 3 H) 1.50 (t, J=7.28 Hz, 3 H) 1.62-1.75 (m, 2 H) 1.97-2.06 (m, 2 H) 2.96 (q, J=7.53 Hz, 2 H) 3.38-3.47 (m, 4 H) 3.47-3.54 (m, J=4.52 Hz, 4 H) 3.56-3.64 (m, 2 H) 3.85-3.93 (m, 2 H) 4.25-4.33 (m, 1 H) 4.36 (s, 2 H) 4.47 (q, J=7.28 Hz, 2 H) 4.60 (s, 2 H) 4.70 (s, 2 H) 4.83 (s, 2 H) 7.19 (dd, J=10.67, 8.41 Hz, 1H) 7.37-7.43 (m, 1 H) 7.46-7.59 (m, 5 H) 7.65 (d, J=6.78 Hz, 1 H) 7.72 (s, 1 H) 7.81 (d, J=7.78 Hz, 1 H) 7.89 (s, 1 H) 8.27 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1>CC#N>[Br:19][C:5]1[C:6]([C:8]([F:11])([F:9])[F:10])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(Br)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 86 %

Procedure:
To a solution of 2-amino-4-trifluoromethylpyrimidine (25 g, 0.15 mol) in CH3CN (800 mL) was added dropwise (over 2.5 hours) NBS (34.8 g, 0.195 mol) dissolved in 200 mL of CH3CN in the dark. The mixture was stirred 4.5 h at RT in the dark and then the solvent was evaporated. The residue was dissolved in EtOAc and H2O and the binary mixture was transferred into a separating funnel. The aqueous layer was separated and extracted with EtOAc. The organic layers were washed with H2O and brine, dried with Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel using a gradient of hexane/EtOAc 9:1 to 3:2. The combined pure fractions were evaporated and the residue suspended in 40 mL hexane, stirred for 10 min., filtered and washed with 2×20 mL of hexane to give the title product as a beige solid (31.2 g, 85%). tR: 0.82 min (LC-MS 1).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:24]=[C:25]1[NH:29][C@H:28]([CH2:30][O:31]C(=O)C2C=CC=CC=2)[CH2:27][O:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:29]4[C@H:28]([CH2:30][OH:31])[CH2:27][O:26][C:25]4=[O:24])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)nc3)CC2)c(C)c1
Yield: 64 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (940 mg) described in Preparation Example 73 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (814 mg), the title compound (660 mg) was obtained.