Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH2:27][C@H:26]5[OH:34])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Temperature: 130 °C
Yield: 3.7 %

Procedure:
A stirred mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole from Example 29 (210 mg, 0.3 mmol), (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (92 mg, 0.6 mmol), and DIEA (267 μL, 1.5 mmol) in DMA (3 mL) was heated at 130° C. for 120 h in a sealed tube. The mixture was cooled to rt and subjected to purification by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (5.4 mg, 4%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.36-8.54 (m, 3H), 7.71 (s, 1H), 7.35 (m, 1H), 7.11-7.30 (m, 5H), 5.51 (s, 2H), 5.18 (t, J=7.0 Hz, 1H), 4.30 (m, 1H), 3.16 (dd, J=7.2, 15.8 Hz, 1H), 2.74 (dd, J=7.3, 15.4 Hz, 1H). LCMS (ESI) m/z 492 and 494 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCNc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Aminobenzophenone (75 g.) is heated with undecyl bromide (200 g.) in dry hexamethyl phosphoramide (300 ml.) containing anhydrous potassium carbonate (90 g.) for 16 hours at 100° C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water. The solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloro methane provides the product of the Example.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])=[O:5])[CH3:3]>O.CO.[Pd]>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[NH2:11])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
3.50 Grams of Z-Ala-Gln-OH was dissolved in 50 ml of water and 30 ml of methanol, and the mixture was catalytically reduced by using palladium as a catalyst to obtain H-Ala-Gln-OH.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([C:13]([OH:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.N1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>CN(C)C=O>[CH2:27]([O:26][C:23](=[O:25])[C:24]1[CH:10]=[CH:11][C:2]([O:14][C:13]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:16])([CH3:1])[CH2:11][CH2:10][C:9](=[O:12])[C:8]=3[CH:7]=2)=[O:15])=[CH:3][CH:8]=1)[C:28]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)CCC(=O)c2cc(C(=O)O)ccc21
Reactant: c1ccncc1
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CCC(=O)c2cc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Reaction time: 0.17 h

Procedure:
To a solution of 5,5-dimethyl-5,6,7,8-tetrahydro-8-oxo-naphthalen-2-carboxylic acid (Compound E3, 386 mg, 1.77 mmol) in dimethylformamide (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarboimide hydrochlorde (440 mg, 2.3 mmol) followed by dimethylaniino pyridine (DMAP) (280 mg, 2.3 mmol). The mixture was stirred for 10 minutes, and benzyl 4-hydroxy benzoate (426 mg, 1.9 mmol) was added and stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with water (10 mL), brine (10 mL), dried and solvent distilled off. The title compound was obtained as a pale yellow solid after chromatographic purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3O)[N:4]=1.[C-:23]#[N:24].[K+].Cl.[OH2:27]>>[C:23]([CH:17]1[C:16]2[C:21](=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[CH:13]=[CH:14][CH:15]=2)[C:19](=[O:20])[O:18]1)(=[O:27])[NH2:24]
Reactant: O
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3C(N)=O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxy-phthalide (see Example 84) is introduced into a solution of 2.1 g of potassium cyanide in 15 ml of water and the whole is treated dropwise at from -7° to -3° C., with cooling, over a period of 10 minutes, with 10 ml of concentrated hydrochloric acid. It is subsequently stirred at room temperature for approximately 16 hours and the crystals which have separated are then filtered off. They are washed with water and recrystallised from acetone/n-hexane to yield 0.2 g of 3-carbamoyl-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide (see also Example 17).
Reaction SMILES: [OH-].[Na+].[CH3:3]N(N=O)C(N[N+]([O-])=O)=N.[Cl:13][C:14]1[CH:22]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[C:20]2[C:16](=[CH:17][N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:19]=2)[CH:15]=1>C(OCC)C>[Cl:13][C:14]1[CH:22]=[C:21]([CH2:23][C:24]([O:26][CH3:3])=[O:25])[C:20]2[C:16](=[CH:17][N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[N:19]=2)[CH:15]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(CC(=O)O)c2n1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COC(=O)Cc1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 0.25 h

Procedure:
To a heterogeneous mixture of sodium hydroxide (4M in water, 25 mL) and diethyl ether (75 mL) at 0° C. was added N-methyl-N′-nitro-N-nitrosoguanidine (2.24 g, 15.3 mmol) with swirling (no stirbar). After addition was complete, the mixture was allowed to stand at 0° C. for 15 min with occasional swirling. The ethereal was transferred in portions to a suspension of 2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetic acid (2.6 g, 7.63 mmol) in diethyl ether (50 mL) until the yellow color persisted and all of the starting material had gone into solution. The reaction was allowed to rest at room temperature for 5 min before bubbling nitrogen through the solution to remove most of the unreacted diazomethane. Column chromatography (25% ethyl acetate/n-hexane) gave 2.28 g (84%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 8.02 (s, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.14 (d, J=0.9 Hz, 1H), 5.67 (s, 2H), 4.01 (s, 2H), 3.70 (s, 3H), 3.61 (t, J=8.2 Hz, 2H), 0.92 (t, J=8.3 Hz, 2H), −0.04 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 171.3, 146.9, 127.7, 127.5, 126.0, 122.61, 122.57, 118.3, 82.0, 67.7, 52.1, 36.1, 17.9, −1.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9](O)=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:29][Si](C)(C)C>C(Cl)Cl.CN(C)C=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([NH2:29])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
A mixture of 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (450 mg, 1.51 mmol) in methylene chloride (4 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0° C. The reaction mixture was then slowly treated with oxalyl chloride (145 μL, 1.66 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 1 h. The resulting reaction mixture was then treated dropwise with 1,1,1,3,3,3-hexamethyldisilazane (960 μL, 4.53 mmol) and subsequently stirred at 25° C. for 15 h. The resulting reaction mixture was diluted with methylene chloride (10 L) and methanol (10 mL). The organic layer was washed with a 5% aqueous sulfuric acid solution and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionamide (295 mg, 67%) as a yellow oil which solidified upon sitting to a yellow solid. The yellow solid was used without further purification: mp 112-114° C.; EI-HRMS m/e calcd for C14H17ClN2O3 (M+) 296.0927, found 296.0931.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][NH:25][C:26](=[O:32])[CH:27]([CH3:31])[C:28](O)=[O:29])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][NH:25][C:26](=[O:32])[CH:27]([CH3:31])[C:28]([NH:1][CH:2]2[C:8](=[O:9])[N:7]([CH3:10])[C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]2=3)=[O:29])=[CH:22][CH:21]=1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1ccc(F)cc1
Product: CC(C(=O)NCc1ccc(F)cc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=446.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(4-fluoro-benzyl)-2-methyl-malonamic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28]CC2C=CC=CC=2)[CH:23]=1)[C@@H:9]([OH:20])[CH2:10][C@H:11]([C:13](=[O:19])[NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:12])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)[C@@H:9]([OH:20])[CH2:10][C@H:11]([C:13](=[O:19])[NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:12])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](Cc1cccc(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Yield: 93.8 %

Procedure:
[(1S*,2S*,4R*)-1-(3-Benzyloxy-benzyl)-4-butylcarbamoyl-2-hydroxy-pentyl]-carbamic acid tert-butyl ester (240 mg, 0.48 mmol) is hydrogenated (5 atm H2) at rt with 10% Pd/C (Engelhard 4505, 60 mg) for 2 h. The catalyst is filtered off and after evaporation the residue is purified by chromatography on silica (Flashmaster, DCM to DCM/methanol 85/15) to give a white foam (184 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[CH:15]=3)[N:10]([C:24](=[O:32])[NH:25][C:26]3[S:27][C:28]([Cl:31])=[CH:29][N:30]=3)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[CH3:34][NH2:35]>>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][C:21]([NH:35][CH3:34])=[O:22])[CH:15]=3)[N:10]([C:24]([NH:25][C:26]3[S:27][C:28]([Cl:31])=[CH:29][N:30]=3)=[O:32])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(OCCCC(=O)O)cc12
Reactant: CN
Agent: Cl
Product: CNC(=O)CCCOc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)Nc1ncc(Cl)s1

Procedure:
4-((1′-Acetyl-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)oxy)butanoic acid and methylamine hydrochloride
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([Mg]Cl)[CH:2]=1.[CH:10]1[CH:15]=[C:14]2[CH:16]=[CH:17][C:18]3[C:23]([C:24](=[O:25])[C:13]2=[CH:12][CH:11]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3>>[CH3:9][C:1]1[CH:2]=[C:3]([C:24]2([OH:25])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:15][C:14]=3[CH:16]=[CH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]2=3)[CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: Cc1cccc([Mg]Cl)c1
Product: Cc1cccc(C2(O)c3ccccc3C=Cc3ccccc32)c1

Procedure:
m-tolylmagnesium chloride and dibenzosuberenone;
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.C(Cl)(=O)[C:11](Cl)=[O:12].[Cl:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1.N1C=CC=CC=1>ClCCCl.C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:11]([NH:9][C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])=[O:12])=[N:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: NC(=O)C1CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NC(=O)C1CCOCC1)Nc1ccc(Oc2ccnc(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.3 %

Procedure:
A mixture of Example B5 (0.568 g, 4.40 mmol) and oxalyl chloride (0.400 mL, 4.66 mmol) in DCE (10 mL) was heated at 100° C. for 1 h, cooled to RT, added to a solution of Example A9 (0.650 g, 2.93 mmol) and pyridine (0.400 mL, 4.96 mmol) in DCM (10 mL) and stirred at RT for 2 days. The mixture was treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN, sonicated, the solid collected via filtration and purified via silica gel chromatography (MeOH/DCM) to afford N-((5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)tetrahydro-2H-pyran-4-carboxamide (335 mg, 30%) as a white solid. MS (ESI) m/z: 377.1 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[NH:10]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:11]1=[O:12]>ClCCl>[Cl:1][CH2:2][C:3]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[NH:10][C:11](=[O:12])[CH:13]=[CH:14]2)=[O:4]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc2[nH]c(=O)ccc2c1
Yield: 50.1 %

Procedure:
To a solution containing 467 g of chloroacetyl chloride in 400 ml of dichloromethan, 735 g of aluminium chloride was added by 1/3 each at a temperature below 30° C. with stirring condition. Next 200 g of carbostyril was added thereto at the same temperature under stirring condition. The reaction mixture was refluxed for 6 hours, then the reaction mixture was poured into a mixture of ice-concentrated hydrochloric acid and the crystals formed were collected by filtration. The crystals were washed with methanol, then with hot-methanol to obtain 153 g of 6-chloroacetylcarbostyril. The mother liquor was concentrated to dryness, and the residue obtained was purified by a silica gel column chromatography, then recrystallized from methanol to obtain 35.41 g of 8-chloroacetylcarbostyril in the form of light yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[C:25]([CH3:35])=[N:26][C:27]([N:30]5[CH:34]=[N:33][CH:32]=[N:31]5)=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC(OC(C)C)=O.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[C:25]([CH3:35])=[N:26][C:27]([N:30]5[CH:34]=[N:33][CH:32]=[N:31]5)=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])[CH3:2]
Reactant: Cc1nc(-n2cncn2)ccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-n2cncn2)ccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A mixture of 4-[4-(2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 101; 50 mg, 0.105 mmol), trifluoroacetic acid (428 μL) and dichloromethane (2 mL) was stirred at room temperature for 30 min. The volatiles were evaporated under high vacuum and the residue was dissolved in dichloromethane (3 mL). Isopropyl chloroformate (1 M in toluene; 158 μL, 0.16 mmol) and triethylamine (95 μL, 0.68 mmol) were added and the mixture was stirred overnight at room temperature. 1 M aqueous sodium carbonate (6 mL) and dichloromethane (3 mL) were added, and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were evaporated and the residue was purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted three times with dichloromethane and the solvent was evaporated to give 4-[4-(2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (35 mg, 72%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.28 (d, 6H, J=6.0 Hz), 1.97-2.10 (m, 2H, J=10.9 Hz), 2.20-2.35 (m, 2H), 2.46 (s, 3H), 2.89-3.14 (m, 2H), 4.32-4.48 (m, 2H), 4.84-5.08 (m, 2H), 7.68 (d, 1H, J=8.8 Hz), 7.86 (d, 1H, J=8.8 Hz), 8.11 (s, 1H), 8.17 (s, 1H), 8.48 (s, 1H), 9.19 (s, 1H). Mass spectrum (ES) MH+=464. HRMS Calcd. for C22H26N9O3 (MH+): 464.2153. Found: 464.2151.
Reaction SMILES: C(C1C=C(C2O[N:12]=[C:11]([C:14]3[CH:29]=[C:28]([CH3:30])[C:17]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23](=[O:26])[CH2:24][OH:25])=[C:16]([CH3:31])[CH:15]=3)[N:10]=2)C=CC=1)=O.[CH3:32][N:33]([CH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([OH:42])=O)=[CH:38][C:37]=1[O:45][CH3:46])[CH3:34].OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O.C([O-])=O>>[CH3:34][N:33]([CH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]2[O:42][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([CH3:31])[C:17]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23](=[O:26])[CH2:24][OH:25])=[C:28]([CH3:30])[CH:29]=3)[N:10]=2)=[CH:38][C:37]=1[O:45][CH3:46])[CH3:32]
Reactant: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Reactant: COc1cc(C(=O)O)ccc1CN(C)C
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Agent: O=C[O-]
Product: COc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)ccc1CN(C)C

Procedure:
The title compound was prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 4-dimethylaminomethyl-3-methoxy-benzoic acid and rac-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide. LC-MS: tR=0.71 min; [M+1]+=485.27; 1H NMR (CDCl3): δ2.36 (s, 6H), 2.54 (s, 6H), 3.45-3.54 (m, 1H), 3.74-3.91 (m, 3H), 3.92 (s, 2H), 4.01 (s, 3H), 4.15-4.20 (m, 3H), 7.13 (t, J=5.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.81-7.86 (m, 3H), 8.50 (s, 1H) (as formate salt).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.[O:27]1C[CH:28]1[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([C:41]3[O:45][N:44]=[C:43]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:42]=3[C:52]([F:55])([F:54])[F:53])[O:38][N:37]=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[OH:27][CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([C:41]3[O:45][N:44]=[C:43]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:42]=3[C:52]([F:55])([F:54])[F:53])[O:38][N:37]=2)=[CH:32][CH:31]=1)[CH2:6][N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)CCO1
Temperature: 80 °C

Procedure:
4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid (69.5 mg, 0.301 mmol) was treated with TFA/DCM for 1 hour. Solvents were removed in vacuo and the resulting material was dried. The solids were dissolved in 2-propanol (2 mL) and DMSO (1 mL). 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (30 mg, 0.075 mmol) and cesium carbonate (98 mg, 0.301 mmol) were added. The reaction mixture was heated at 80° C. overnight. LCMS indicated almost complete conversion to desired product and no starting material. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 21 mg of 4-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)morpholine-2-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.23 (2H, d, J=7.91 Hz), 7.69 (4H, dd, J=12.08, 7.69 Hz), 7.54-7.65 (3H, m), 5.29 (1H, td, J=6.81, 4.39 Hz), 4.41-4.65 (1H, m), 4.08-4.37 (1H, m), 3.92-4.05 (2H, m), 3.56-3.91 (1H, m), 3.44 (3H, t, J=6.81 Hz), 3.12-3.38 (1H, m). MS (m+1)=531. HPLC Peak RT=3.24 minutes (Analytical Method A). Purity=85%.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH:7]([C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:28][O:27][C:26]1[CH:25]=[CH:24][C:11]([CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])=[CH:10][C:9]=1[CH:7]=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cc(CN2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
3.99 g of potassium-t-butoxide was added to 80 ml solution of 12.7 g methyltriphenyl phosphonium bromide in tetrahydrofuran at 0° C., 7 g of N-(3-formyl-4-methoxybenzyl)phthalimide was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction solution was filtered through Celite, and then evaporated. The resulting residue was purified by silica gel column chromatography to give 2.75 g of N-(4-methoxy-3-vinylbenzyl)phthalimide.