Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[H-].[Na+].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1>CN(C)C=O.C1C=CC=CC=1>[CH3:1][CH:2]([N:9]1[CH2:12][CH:11]([O:13][C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:28])([F:27])[F:18])=[CH:21][CH:22]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(c1ccccc1)N1CC(O)C1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(c1ccccc1)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 90 °C
Yield: 39.8 %

Procedure:
The maleate salt of 1-(α-methylbenzyl)-3-hydroxyazetidine (78.6 g., 0.20 mole) was partitioned between benzene and dilute sodium hydroxide, the benzene layer dried, filtered, and concentrated at reduced pressure. The residue was dissolved in 100 ml. of dry dimethylformamide and added at a rapid dropwise rate, to a stirring suspension of 10.1 g. (0.22 mole) of sodium hydride (50% in mineral oil) in 150 ml. of dry dimethylformamide at 90° C. The solution was heated at 90° C. for one hour and then treated dropwise with 32.0 g. (0.20 mole) of 4-trifluoromethylfluorobenzene. The solution was refluxed for three hours. The cooled solution was partitioned between water and isopropyl ether, and the ether layer extracted with dilute hydrochloric acid. The aqueous acid layer was made basic with concentrated sodium hydroxide and ice, and extracted with isopropyl ether. The ether layer was concentrated and the residue distilled at 150°-160° C./0.2 mm. to give 25.6 g of product.
Reaction SMILES: C([C@@H:4]1[C:13](=[O:14])[C:12]2[CH:11]=[CH:10][N:9]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:8]3[C:7]=2[N:6]([C:20](=[O:22])[CH3:21])[C@H:5]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)C.[BH4-].[Na+].C(=O)([O-])[O-:32].[K+].[K+]>CO>[C:20]([N:6]1[C:7]2[C:8]3=[N:17][C:16]([CH3:18])=[C:15]([CH3:19])[N:9]3[CH:10]=[CH:11][C:12]=2[C@@H:13]([OH:14])[C@H:4]([OH:32])[C@H:5]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)[C@@H]1C(=O)c2ccn3c(C)c(C)nc3c2N(C(C)=O)[C@H]1c1ccccc1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)[C@H](O)[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
64 g of (8R,9R)-8,10-diacetyl-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one (crude product) are dissolved in 250 ml of methanol. 12.3 g of sodium borohydride are introduced with ice cooling. After stirring for 1 h, 23 g of potassium carbonate are added to the reaction mixture and it is stirred for a further 2 h at room temperature. It is then added to ice water and the precipitate is filtered off with suction. After washing the precipitate with acetone and ether, 37 g of the title compound are isolated.
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH2:11])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36]>CC#N.C([O-])(O)=O.[Na+]>[CH2:35]([O:34][C:33](=[O:37])[NH:11][C@@H:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:22])([F:2])[F:23])=[CH:9][CH:8]=1)[C:12]1[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methanamine (Intermediate 1) (0.0610 g, 0.190 mmol) and DIPEA (0.066 mL, 0.381 mmol) in MeCN (1 mL) was added ethyl carbonochloridate (0.027 mL, 0.286 mmol). The mixture was then stirred at rt overnight. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting product was purified by silica gel chromatography: 5-50% EtOAc-hexanes to give the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (d, J=4.30 Hz, 1H), 7.99 (d, J=7.24 Hz, 1H), 7.46-7.60 (m, 4H), 7.40 (dd, J=7.73, 4.79 Hz, 1H), 6.54 (d, J=7.43 Hz, 1H), 6.41 (d, J=8.22 Hz, 1H), 4.11 (q, J=7.17 Hz, 2H), 1.17-1.30 (m, 3H). MS (ESI pos. ion) m/z: 393.0 (M+H).
Reaction SMILES: C([O-])C.Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.C(N(CC)CC)C.[CH3:30][N:31]=[C:32]=[O:33]>ClCCl>[CH3:30][NH:31][C:32]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:33]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CN=C=O
Agent: CC[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
To a solution of 2.0 gm (5.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride monoethanolate and 5.0 mL (36 mMol) triethylamine in 100 mL dichloromethane were added 0.74 mL (12.6 mMol) methyl isocyanate. The reaction mixture was stirred for 15 minutes and was then washed with 100 mL of water. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was crystallized from acetonitrile to give 1.05 gm (64%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Yield: 92.6 %

Procedure:
Dissolve 5-(R)-[1-(S)-benzyloxy-2-(S)-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester (187.7 mg, 0.263 mmol) in methanol (10 mL). Add 20% palladium hydroxide on carbon 100 mg) and hydrogenate at one atmosphere hydrogen gas for 18 hours. Add more 20% palladium hydroxide on carbon (100 mg) and further hydrogenate at one atmosphere hydrogen gas for 5 hours. Filter and concentrate to give the desired compound (107.8 mg, 93%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 5 h
Yield: 68.3 %

Procedure:
4-Hydroxybenzaldehyde (24.4 g) and sodium hydride (4.8 g) in dry dimethylformamide (400 ml) were stirred at room temperature for 3 h. N-(3-Bromopropyl)phthalimide (55.0 g) was added and the reaction was stirred for a further 5 h. The mixture was poured onto ice and the resulting white solid was recrystallised from a mixture of dichloromethane and cyclohexane to yield the title compound (42.2 g) m.p. 120°-1°. TLC silica, ethyl acetate, Rf 0.7.
Reaction SMILES: [O:1]([CH3:3])[K].CO.C1(C)C=CC=CC=1.F[C:14]1[CH:19]=[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:21]=2)[CH:17]=[CH:16][N:15]=1>>[CH3:3][O:1][C:14]1[CH:19]=[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:21]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CO[K]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccn1
Temperature: 70 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
In a 250 ml pressure vessel, 3-(2-Fluoro-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole 3BV (5.005 g, 10.0 mmole) was dissolved in 0.1N KOCH3/MeOH/Toluene (Acros, 150 mL, 15.0 mmole) under dry N2 gas. The pressure vessel was tightly sealed and heated under stirring at 70° C. for 24 hours. The pressure vessel was cooled to 0° C. in ice-bath before opening. The contents of the pressure vessel were transferred to 500 ml RBF and evaporated to dryness. The resulting solid was dissolved in CH2Cl2 and washed with saturated NaCl solution and dried over MgSO4. The solvent was evaporated to dryness and dried under high vacuum to yield 4BV as a brown solid (5.12 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]Cl)[CH:3]=1.[I-:22].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14][I:22])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cl)cc1O[C@H](CCCI)c1ccccc1
Yield: 89.5 %

Procedure:
A solution of the product from step (b) (2.80 g) and sodium iodide (20 g) in acetone (100 ml) was heated under reflux for 20 h. The mixture was filtered, evaporated, dissolved in water (50 ml) and extracted with ethyl acetate (three times). The organic extracts were washed with water, dried (magnesium sulphate) and evaporated to give the title compound (3.22 g).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:14]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[O:13][C:8]([OH:12])([C:9](=[O:11])[OH:10])[CH2:7][C@@H:6]1[OH:21])(=[O:3])[CH3:2].[C:22](Cl)(=O)[CH3:23]>C(O)C>[C:1]([NH:4][C@H:5]1[C@H:14]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[O:13][C:8]([OH:12])([C:9](=[O:10])[O:11][CH2:22][CH3:23])[CH2:7][C@@H:6]1[OH:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Solvent: CCO
Product: CCOC(=O)C1(O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a suspension of N-acetyl-neuraminic acid (1 g, 3.23 mmole) in anhydrous ethanol (75 ml) was added 1.5 ml acetyl chloride. The mixture was sealed and stirred at room temperature for 16 hrs. to form a clear solution. The resulting solution was vacuum evaporated to dryness. The white solid was washed with ethyl acetate and vacuum dried to afford the title compound as a white solid (1 g, 91.7%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CN(C=O)C.[CH:38]1[CH:39]=[CH:40][C:41]2[N:46](O)N=[N:44][C:42]=2[CH:43]=1.C1(N)C=CC=CC=1N>O>[NH2:44][C:42]1[CH:43]=[CH:38][CH:39]=[CH:40][C:41]=1[NH:46][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([CH2:22][NH:21][C:18]2[CH:17]=[CH:16][C:15]([C:6]([C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:32])=[CH:7][C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)=[CH:20][CH:19]=2)=[CH:24][CH:25]=1
Reactant: O=C(NC1CC1)C(=Cc1ccc(F)cc1)c1ccc(NCc2ccc(C(=O)O)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: Nc1ccccc1N
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(CNc2ccc(C(=Cc3ccc(F)cc3)C(=O)NC3CC3)cc2)cc1
Reaction time: 4 h
Yield: 7.7 %

Procedure:
To a suspension of 4-((4-(3-(cyclopropylamino)-1-(4-fluorophenyl)-3-oxoprop-1-en-2-yl)phenylamino)methyl)benzoic acid (0.215 g, 0.5 mmol) in DMF (3 mL) EDCl (0.23 g, 1.1 mmol), HOBt (0.08 g, 0.55 mmol), o-phenylene diamine (0.086 g, 0.7 mmol), were added followed by TEA (0.2 mL, 1.5 mmol). The reaction mixture was stirred for 4 hours after which the mixture was added to cold water (100 mL) and kept at 0° C. for 1 hour. The pale yellow solid formed was filtered and washed with ethyl acetate (15 mL) dried under vacuum to afford the title compound (0.020 g, 8% yield). 1H NMR (DMSO-d6) δ (ppm): 0.46-0.47 (2H, m, —CH2), 0.60-0.62 (2H, m, —CH2), 2.70-2.71 (1H, m, —CH), 4.36-4.37 (2H, d, —CH2), 4.88 (2H, s, —NH2), 6.55-6.61 (4H, m, Ar—H and —NH), 6.76-6.82 (3H, m, Ar—H), 6.93-6.94 (1H, t, Ar—H), 6.98-7.04 (3H, m, Ar—H), 7.06-7.17 (3H, m, Ar—H), 7.48-7.50 (3H, m, Ar—H and ═CH), 7.93-7.95 (2H, d, Ar—H and —NH), 9.61 (1H, s, —NH), MS m/z: 521.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:27][O:28][NH2:29]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:29][O:28][CH3:27])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: CON
Product: CONC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3OC)nc12
Yield: 67 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K) and O-methylhydroxylamine. The combined organic extracts were concentrated and the residue was purified by reverse phase HPLC (0-80% acetonitrile/water) to yield the title compound (29 mg, 67% yield). MS (apci) m/z=387.0 (M+H).
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][NH:2]1.[C:13](C1CC(=O)NC1=O)([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14]>ClCCl>[N:2]1([C:13]([O:15][CH2:16][CH:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:14])[CH2:3][CH2:4][CH2:5][N:1]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: O=C1CC(C(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Reactant: CC(C)(C)OC(=O)N1CCCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 94 %

Procedure:
Tert-butyl pyrazolidine-1-carboxylate (39) (1.39 g, 8.08 mmoles) was acylated with Fmoc succinimide (3.27 g, 9.69 mmoles, 1.2 eq.) in dry dichloromethane (20 mL). The reactive mixture was left stirring overnight. The volatiles were removed using a rotary evaporator and the residue was dissolved in EtOAc. The organic layer was extracted three times, respectively, with 5% citric acid, 5% NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to a white foam which was purified by column chromatography using 7:3 EtOAc:Hexane as eluant. Evaporation of the collected fractions afforded 1-(9H-fluoren-9-yl)methyl 2-tert-butyl pyrazolidine-1,2-dicarboxylate as a white solid in a 94% yield. Pyrazolidine-1,2-dicarboxylate (1.34 g, 3.4 mmoles) was treated with 25 mL of a 1:1 TFA:DCM solution and stirred for one hour. Removal of the volatiles by rotary evaporation gave a residue that was dissolved in 1N HCl, stirred for 1 hour and freeze-dryed to yield hydrochloride (9H-fluoren-9-yl)methyl-1-carboxylate: mp (143.2-148.1° C.), 1H NMR (DMSO) δ 7.89 (d, J=7.32 Hz, 2H), 7.72 (d, J=7.33 Hz, 2H), 7.43 (ddd, J=7.36 Hz, 0.57 Hz, 2H), 7.33 (ddd, J=7.42 Hz, 1.14 Hz, 2H), 4.44 (d, J=6.90 Hz, 2H), 4.33 (t, J=6.56 Hz, 1H), 3.58 (t, J=6.96 Hz, 2H), 3.43 (t, J=6.96 Hz, 2H), 2.20 (m, 2H). 13C (DMSO) δ 154.57, 144.64, 142.11, 129.26, 126.54, 121.67, 69.89, 47.50, 25.50.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:25][CH:24]=2)[N:13]=1.[H][H]>CN(C=O)C.[OH-].[OH-].[Pd+2].CCOC(C)=O>[NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:27][CH:28]=2)[N:13]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.5 %

Procedure:
tert-Butyl 2-(4-((4-((2-(2-amino-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I40) (0.120 g, 0.207 mmol) was dissolved in dry DMF (5 mL) under an atmosphere of nitrogen. 20% Pearlman's catalyst (0.060 g) in EtOAc (5 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 20 hours at room temperature. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×10 mL). The solvent was removed in vacuo to give a pale yellow gum which was purified by silica gel chromatography (Biotage, Isolera 12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I41) (0.090 g, 74% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1H), 8.67 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.43 (s, 1H), 7.26-7.21 (m, 1H), 7.20-7.09 (m, 5H), 6.89 (s, 1H), 5.31-5.19 (m, 1H), 3.92 (d, J=13.2 Hz, 1H), 3.49 (s, 2H), 3.16-2.98 (m, 4H), 2.71 (t, J=11.8 Hz, 1H), 2.29 (d, J=13.2 Hz, 1H), 1.75 (t, J=11.0 Hz, 1H), 1.58-1.50 (m, 2H), 1.46-1.23 (m, 11H). LCMS Method C: rt 6.59 min; m/z 584.3 [M+H]+.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3c(C)nc4sccn34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.30 min; [M+H]+=496.1.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[S:13][C:12]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][CH:10]=1.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>C(Cl)Cl>[Br:8][C:9]1[S:13][C:12]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])=[CH:11][CH:10]=1
Reactant: OCCCCCCOCc1ccc(Br)s1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Triethylamine (2.10 g, 20.8 mmol) is added dropwise to a solution of 6-(5-bromothiophen-2-yl)methoxyhexanol (3.10 g, 10.62 mmol) and methacryloyl chloride (1.20 g, 11.54 mmol) in DCM (30 mL) at −10° C. This mixture is allowed to warm to room temperature and stirred overnight before it is quenched by the addition water (50 mL) The organic layer is separated and the liquid phase is extracted with DCM (2×30 mL). The organic layers is combined, washed with brine (50 mL), dried (Na2SO4) and evaporated under reduced pressure. The product is purified by column chromatography on silica, eluting with petroleum ether (40-60° C.)/ethyl acetate (90:10) to afford the product as a pale yellow oil (3.27 g, 86%). NMR and MS showed the expected signals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH2:8])=[CH:2]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:9]([NH:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCc1ccoc1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(CNCCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the above crude 2-(3-furyl)ethylamine and 4.24 g (39.9 mmol) of benzaldehyde in 50 ml of methanol was stirred at room temperature for 0.5 hours. The reaction mixture was cooled with ice-water; 1.89 g (49.9 mmol) of sodium borohydride was added portionwise followed by stirring at room temperature for 1 hour. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to ethyl acetate) to yield the desired product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][CH2:8][O:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[N:16][C:17]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[C:22]([Cl:35])[CH:21]=2)[NH:12][N:11]=1>C(O)C>[Cl:35][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][N:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:18]=23)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: C1CCNC1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)c1
Solvent: CCO
Product: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCN5CCCC5)c34)cc2Cl)c1
Temperature: 120 °C
Yield: 31 %

Procedure:
Pyrrolidine (0.5 ml) was added to a suspension of 3-(2-chloroethoxy)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 12/0.2 g, 0.44 mmol) in ethanol (2 ml) and the reaction mixture was heated at 120° C. for 10 minutes in a microwave reactor. The resulting solution was concentrated in vacuo and the residue purified by chromatography using DCM to DCM-10% methanol/7N ammonia as eluant to give the title compound as a beige solid (67 mg, 31%); Mass Spectrum: 483.3 (MH+/retention time 1.56 minutes).
Reaction SMILES: [CH:1](NC(C)C)(C)C.IC.[C:10]([O:14][C:15](=[O:27])[NH:16][C@@H:17]([C:19]1[N:23]([CH2:24][CH3:25])[C:22]([SH:26])=[N:21][N:20]=1)[CH3:18])([CH3:13])([CH3:12])[CH3:11]>O1CCCC1>[C:10]([O:14][C:15](=[O:27])[NH:16][C@@H:17]([C:19]1[N:23]([CH2:24][CH3:25])[C:22]([S:26][CH3:1])=[N:21][N:20]=1)[CH3:18])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)NC(C)C
Reactant: CCn1c(S)nnc1[C@@H](C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CCn1c(SC)nnc1[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropylamine (17.4 ml) and iodomethane (7.7 ml) were added to a tetrahydrofuran (200 ml) solution of the [(R)-1-(4-ethyl-5-mercapto-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester (28.12 g) obtained in Example 8-(3). The mixture was stirred for 1 hour at room temperature, and then precipitated crystals were filtered. The filtrate was concentrated, and the resulting crude crystals were washed with a hexane-ethyl acetate solvent mixture (3:1, 200 ml), followed by drying, to obtain [(R)-1-(4-ethyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester as a white powder (29.5 g).