Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH3:20])[C:12]([O:15][CH2:16][C:17]([OH:19])=O)=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]([CH3:35])[C:17](=[O:19])[CH2:16][O:15][C:12]2[N:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][C:11]=2[CH3:20])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cnc1OCC(=O)O
Reactant: CNC1CCN(Cc2ccccc2)CC1
Product: Cc1cc(NC(=O)OC(C)(C)C)cnc1OCC(=O)N(C)C1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was synthesized from Compound 21 and 1-benzyl-N-methylpiperidine-4-amine in the same manner as in Example 49.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]1([OH:20])[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14][CH2:13][CH2:12]1.[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22].[NH4+].[Cl-]>O1CCCC1>[C:21]([Si:25]([CH3:27])([CH3:26])[O:19][CH:15]1[CH2:16][CH2:17][CH2:18][CH:11]([OH:20])[CH2:12][CH2:13][CH2:14]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: OC1CCCC(O)CCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCCC(O)CCC1
Temperature: 25 °C

Procedure:
Sodium bis(trimethylsilyl)amide (76.27 mL, 1 M in tetrahydrofuran, 76.27 mmol) was added drop wise to a stirred and cooled (0° C.) solution of cyclooctane-1,5-diol (10 g, 69.34 mmol) in dry tetrahydrofuran (120 mL). After the addition, the resulting solution was warmed to room temperature and stirred for another thirty minutes. The solution was re-cooled (0° C.) and a solution of tert-butyl-chloro-dimethyl-silane (10.45 g, 69.34 mmol) in tetrahydrofuran (20 mL) was added drop wise. The solution was then warmed to room temperature and stirred overnight before an NH4Cl solution was added. The mixture was partitioned with diethyl ether, and the organic phase was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 2-40% ethyl acetate in hexanes to provide the title compound as an oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].N1C=CC=CC=1.[CH:30]([N:33]=[C:34]=[O:35])([CH3:32])[CH3:31].O>ClCCl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:34]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:35])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CC(C)N=C=O
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)NC(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
A solution of 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.19 mmol) in dichloromethane (1 mL) was treated with pyridine (0.39 mmol) and isopropyl isocyanate (0.39 mmol). The reaction mixture was stirred for 18 h at room temperature and poured into water (1 mL), followed by extraction with (3×3 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC provided the title product as a white powder (45%). ESMS [M+H]+: 389.2
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2.[CH3:21][CH:22]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH3:23].C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([O:13][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:23])[CH3:21])[CH:6]=[CH:5]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc2cc(O)ccc2c(-c2ccc(Cl)cc2)c1Br
Agent: CN(C)c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2c(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
6-Bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2-ol (4.5 g, 12.9 mmol) was taken up in DCM (65 mL). Added to this solution were TIPSCl (4.1 mL, 19.4 mmol), DBU (3.5 mL, 23.2 mmol), and DMAP (0.16 g, 1.3 mmol). After stirring at room temperature overnight, the DCM was removed in vacuo and the residue taken up in hexane (200 mL). This solution was washed with 1 M HCl (100 mL) and the layers separated. Following extraction of the aqueous layer with hexanes, the combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (2-5% DCM/Hex) to afford 5.12 g (79%) of the title compound as a colorless syrup. 1H-NMR: 400 MHz, (CDCl3) δ: 7.61 (s, 1H); 7.49 (br d, J=8.4 Hz, 2H); 7.23 (br d, J=8.4 Hz, 2H); 7.17 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H); 6.95 (dd, J=8.8, 2.4 Hz; 1H); 2.60 (s, 3H); 1.30 (hep, J=7.2 Hz, 3H); 1.12 (d, J=7.2 Hz, 18H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:36])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH:34]=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[CH:34]=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:36])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-(isobutyl-amino)-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M127) (0.22 g, 0.42 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (90 mg, 53%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.[CH3:26][O:27][C:28](=[O:40])[C@H:29](O)[CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CO>C(OCC)(=O)C>[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH2:30][O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:34])[CH3:33]
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: COC(=O)[C@H](O)CO[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H](CO[Si](C)(C)C(C)(C)C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2

Procedure:
Following the procedures of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol and (R)-3-(tert-butyl-dimethyl-silanyloxy)-2-hydroxy-propionic acid methyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid methyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=4.48 min, [M+H]+=568
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([O:13][CH3:14])=[CH:6][CH:5]=2.Cl([O-])=[O:22].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[N:3]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4]2[C:9]([C:10]=1[C:11]([OH:22])=[O:12])=[CH:8][C:7]([O:13][CH3:14])=[CH:6][CH:5]=2
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc2c(c1)c(C=O)c(Cl)n2-c1ccccc1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc2c(c1)c(C(=O)O)c(Cl)n2-c1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 125.5 %

Procedure:
The compound of step 3 (456 mg, 1.59 mmol) was dissolved in tert-butanol (15 ml) and 2-methyl-2-butene (3 ml), and a solution of sodium chlorite (1.32 g, 14.6 mmol) and sodium dihydrogenphosphate (1.32 g, 11.0 mmol) in water (6 ml) was added. The reaction mixture was stirred at room temperature for 48 h and afterwards at 80° C. for 2.5 h. The mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give 602 mg of the crude title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(OC(C)C)(C)C.[Cl:38][C:39]1[CH:40]=[C:41](O)[CH:42]=[CH:43][C:44]=1[Cl:45].[OH-].[Na+].N1(O)CCC1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:38][C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][C:44]=1[Cl:45])[O:12][CH:10]1[CH2:11][N:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: ON1CCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1Cl
Reaction time: 18 h
Yield: 59.7 %

Procedure:
A mixture of 48 g (0.2 mole) of 1-(diphenylmethyl)-3-azetidinol and 22 g (0.22 mole) of triethylamine in 800 mL of toluene was stirred in a tap water bath while 27.5 g (0.22 mole) of methanesulfonyl chloride was added dropwise and stirring was continued for 18 h. The reaction mixture was treated with 400 mL of isopropyl ether then filtered. The filter cake was washed with 2×150 mL of 50/50 isopropyl ether and toluene. The combined filtrates were treated with 32.6 g (0.2 mole) of 3,4-dichlorophenol, 100 mg of tetra-n-butylammonium bromide and 24 g (0.6 mole) of sodium hydroxide in 100 mL of water. This mixture was stirred vigorously at reflux for 16 h. The basic aqueous portion was separated and the organic portion washed with water, dried over magnesium sulfate then concentrated to a solid residue, 74.5 g. Several recrystallizations from ethanol-water gave a product which was contaminated with starting azetidinol. Therefore, the material (57.4 g) was dissolved in toluene and treated with silica gel. After stirring for 6 h, the silica gel was removed by filtration and washed with 50/50 ethyl acetate and toluene. The filtrates were concentrated to yield 45.9 g (59.7%) of pure product. A sample for elemental analysis was recrystallized from 190 ethanol, mp. 114°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29]Cl)=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:32]([CH3:34])[CH3:33])[NH:11]1.[NH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O>CN(C=O)C.C1COCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([CH2:29][N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[O:31])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:32]([CH3:34])[CH3:33])[NH:11]1
Reactant: C1CNCCN1
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NC(=O)CCl)cc3)nc(=O)c1-2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NC(=O)CN4CCNCC4)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Part B: To a stirred solution of 300 mg (0.55 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(chloroacetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 6 mL of 1:1 DMF-THF was added 1 g of piperazine. The solution was stirred overnight at ambient temperature and poured into water. The mixture was extracted twice with EtOAc, and the combined organic extracts were washed (brine), dried (MgSO4), and concentrated under reduced pressure to afford 230 mg (71%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(piperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. Mass spec. (ESI+): 588 ((M+H)+).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:38]([OH:42])[CH:39]([CH3:41])[CH3:40]>>[CH2:38]([O:42][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)[CH:39]([CH3:41])[CH3:40]
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CC(C)CO
Agent: [Li]CCCC
Product: CC(C)COc1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (100 mg, 0.2 mmol) with 2 equivalents each of n-butyl lithium and iso-butyl alcohol by the procedure described in Reference Examples 6 and 7 to afford the title compound: HPLC/MS: m/e=500 (M++1); Rt=4.31 min. 1H-NMR 500 MHz (CDCl3): δ 0.96 (d, J=6 Hz, 6H), 2.02-2.10 (m, 1H), 4.01 (d, J=7 Hz, 2H), 7.18-7.30 (m, 6H), 7.39 (s, 1H), 7.40-7.43 (m, 1H), 7.58-7.60 (m, 1H), 8.55 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[C:6]1=[O:15].[N+:20]([CH3:23])([O-:22])=[O:21]>O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])([CH2:23][N+:20]([O-:22])=[O:21])[C:6]1=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: O=C1C(=O)N(Cc2ccccc2Cl)c2ccccc21
Solvent: O
Product: O=C1N(Cc2ccccc2Cl)c2ccccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 9 h

Procedure:
1-(2-chlorobenzyl)indoline-2,3-dione (0.135 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 9 hours. The obtained product was extracted with ethyl acetate and the solvent was removed to give pure product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[C:17]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=1)(=[O:33])=[O:32])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2c(C(=O)c3ccccc3)[nH]c3cc(Cl)ccc23)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 33 from ethyl 3-amino-2-benzoyl-6-chloro-1H-indole-1-carboxylate (Example 1, step 2) and p-toluenesulfonyl chloride.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C@@H:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:22]([NH:24][N:25]2[C:29](=[O:30])[CH2:28][NH:27][C:26]2=[O:31])=[O:23])[C:11](=[O:20])[NH:12][O:13]C2CCCCO2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C@@H:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:22]([NH:24][N:25]2[C:29](=[O:30])[CH2:28][NH:27][C:26]2=[O:31])=[O:23])[C:11](=[O:20])[NH:12][OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](CCCC1CCCCC1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](CCCC1CCCCC1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.7 %

Procedure:
A solution of 0.280 g of 2(R)-[4-cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]butyl]-4-methyl-N-(2,5-dioxo-1-imidazolidinyl)valeramide in 10 ml of methanol was treated with 0.028 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2 hours at room temperature and evaporated. The residue was dissolved in ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica gel using methanol/dichloromethane (1:9) for the elution to give 0.069 g of 2(R)-[4-cyclohexyl-1(S)-(hydroxycarbamoyl)butyl]-4-methyl-N-(2,5-dioxo-1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: [C:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[NH:16]C(=O)C(F)(F)F)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].FC(F)(F)S(O[C:29]1[C:38]2[C:33](=[C:34]([O:39][CH3:40])[CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH:30]=1)(=O)=O>>[CH2:3]([C:2]1[NH:16][C:8]2[C:7]([C:1]=1[C:29]1[C:38]3[C:33](=[C:34]([O:39][CH3:40])[CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31][CH:30]=1)=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1ccc(C(=O)O)cc1NC(=O)C(F)(F)F
Reactant: COc1cccc2c1CCC=C2OS(=O)(=O)C(F)(F)F
Product: CCCCc1[nH]c2cc(C(=O)O)ccc2c1C1=CCCc2c(OC)cccc21

Procedure:
The title compound was prepared according to the procedure outlined in Example 7, employing 4-(1-hexynyl)-3-trifluoroacetamidobenzoic acid on Wang resin (prepared according to Example 1) and 5-methoxy-3,4-dihydro-naphthalen-1-yl trifluoromethanesulfonate; 1H NMR (DMSO-d6) δ 0.80 (t, 3 H), 1.22 (m, 2 H), 1.60 (m, 2 H), 2.39 (m, 2 H), 2.70 (m, 4 H), 3.80 (s, 3 H), 6.02 (t, 1 H), 6.32 (d, 1 H), 6.85 (d, 1 H), 6.98 (m, 1 H), 7.08 (d, 1 H), 7.50 (d, 1 H), 7.95 (s, 1 H), 11.40 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:23]4[O:22][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[CH:24]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Reactant: OB(O)c1cc2ccccc2o1
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 2-benzofuranboronic acid (278 mg, 1.71 mmol) the subtitle compound was obtained (342 mg, 61%). The product was used directly in the next step without purification
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.COC(C1C=NC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2)=CN=1)=O>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=1
Reactant: CCOC(=O)c1conc1-c1ccccn1
Agent: COC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Product: O=C(O)c1conc1-c1ccccn1
Yield: 77.7 %

Procedure:
As described for example 17a, 3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester (9.6 g, 44 mmol), instead of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester, was converted to the title compound (6.5 g, 79%) which was obtained as an off-white solid. MS: m/e=189.3 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(O)COc1ccc(F)cc1Br
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Yield: 69.7 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (2.00 g, 8.03 mmol) and benzoic acid N′-isopropyl-hydrazide (1.72 g, 9.63 mmol) in DMF (20 mL) was treated with diisopropylethyl amine (3.5 mL, 20.07 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 5.62 g, 12.04 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white crystalline solid (2.29 g, 70%).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:75][CH2:76]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 26.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propan-2-ol (25 mg, 0.037 mmol) was hydrolyzed by lithium hydroxide (7 mg, 0.188 mmol) in THF/methanol/water (2/2/1 ml) to afford 5 mg (26.31% yield) of the titled compound after purification by preparative TLC (Silicagel-1000 micron) using 3% methanol in DCM as eluent. 1H NMR (CD3OD, 400 MHz): δ 8.45 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.65-7.55 (m, 3H), 7.45-7.35 (q, 1H), 7.15-7.00 (m, 4H), 5.45 (s, 2H), 4.05-3.95 (m, 1H), 3.70-3.45 (m, 2H), 2.85-2.35 (m, 6H), 1.22-1.98 (d, 3H). MS: m/z=511.6 (M+1), HPLC: 91.71% in method A.