Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:4]2[C:9]([C:10]=1[C:11]([O:13]C(C)(C)C)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[N:3]([C:18](=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(=O)CC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)c2ccccc2n1C(=O)CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a solution of tert-butyl 2-methyl-1-(3-methylbutanoyl)-1H-indole-3-carboxylate (200 mg, 634.10 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature (25° C.) for 1 hour. The mixture was evaporated and partitioned between dichloromethane and water. The aqueous layer was washed with dichloromethane (10 mL×2), combined the organic layers, dried over sodium sulfate, then filtered and concentrated in vacuum afford the title compound (30 mg, yield: 89%).
Reaction SMILES: [C:1]1([C@H:13]2[C@@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.CC(C)([O-])C.[K+].C(OCC)(=O)C>C(O)(C)(C)C>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@H]1c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccccc12
Yield: 73.2 %

Procedure:
A preparation of (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl) pyrrolidine-2,5-dione (378 mg, 1.02 mmol) was heated to 50° C. in tert-butanol (10 ml) and potassium t-butoxide (11 mg, 98 μmol) for 16 hours. The mixture was poured into ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione as a tan powder (276 mg). 1H NMR (DMSO-d6) 400 MHz δ: 11.54 (s, 1H), 11.03 (s, 1H), 7.32-7.4 (m, 4H), 7.17 (d, 1H, J=7.2 Hz), 7.07 (t, 1H, J=7.6 Hz), 6.96 (t, 1H, J=7.6 Hz), 6.82-6.89 (m, 2H), 4.5 (dd, 2H, J=7.2 and 20 Hz), 4.07 (t, 2H, J=5.2 Hz), 2.87 (t, 2H, J=6 Hz), 2.08 (m, 2H).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:10][Si:11]([C:14]#[C:15][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
As shown in the following Reaction 6, 500 mg (2.15 mmol) of 4-iodobenzaldehyde was melted in 2.7 mL of tetrahydrofuran, and 0.45 mL (3.22 mmol, 1.5 eq) of trimethylsilylacetylene, 0.6 mL (3.44 mmol, 1.6 eq) of diisopropylethylamine (DIEA), 7 mg (0.01 mmol, 0.5 mol %) of dichlorobis-(triphenylphosphine)palladium(II), and 3 mg (0.02 mmol, 1 mol %) of copper iodide was added thereto, and then the reaction solution was stirred under nitrogen atmosphere for 12 hours at room temperature. Next, the reaction solution was filtered with ether, and then was extracted with 1M sodium chloride aqueous solution 1 time. The organic solvent layer was dehydrated with magnesium sulfate, filtered, and then distilled under reduced pressure. The compound distilled under reduced pressure was purified with a column chromatography (mobile phase volume ratio; ethylacetate:n-hexane=1:10) to obtain 420 mg of 4-trimethylsilylethynyl benzaldehyde with the yield of 98%. NMR data of the obtained compound is as follows. [1H NMR (400 MHz, CDCl3): δ 9.81 (s, 1H), 7.63 (d, 2H), 7.42 (d, 2H), 0.13 (s, 9H)].
Reaction SMILES: O1CCCCC1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.[NH2:21][C@@H:22]1[C@@H:26]([OH:27])[CH2:25][N:24]([C:28]2[CH:47]=[CH:46][C:31]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([Cl:45])([F:44])[F:43])=[CH:37][CH:36]=3)=[O:33])=[CH:30][C:29]=2Br)[CH2:23]1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>COCCOC>[NH2:21][C@@H:22]1[C@@H:26]([OH:27])[CH2:25][N:24]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]([Cl:45])([F:43])[F:44])=[CH:39][CH:40]=3)=[O:33])=[CH:46][C:47]=2[C:11]2[NH:7][N:8]=[CH:9][CH:10]=2)[CH2:23]1
Reactant: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2Br)C[C@@H]1O
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C[C@@H]1O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (82 mg, 0.288 mmol) and PdCl2(dppf)-(CH2Cl2) (10.07 mg, 12 μmol) were added to a mixture of 4-((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide (Stage 76.1, 100 mg, 0.206 mmol), Na2CO3 (0.308 mL, 0.617 mmol) in DME (2 mL) under argon atmosphere and the RM was heated at 80° C. for 4 h. The RM was filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 12 g, DCM/EtOH from 98:2 to 8:2). The resulting intermediate was dissolved in DCM (2 mL), treated with TFA (0.198 mL, 2.57 mmol) and the RM was stirred for RT for 3 h. The solvent was evaporated off under reduced pressure and the residue was treated with sat. aq. Na2CO3, and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 12 g, DCM/MeOH from 95:5 to 7:3) and crystallized from n-hexane/DCM to give the title product as a beige solid. HPLC (Condition 7) tR=5.774 min, UPLC-MS (Condition 3) tR=0.77 min, m/z=464.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.73-2.99 (m, 2H) 3.22-3.44 (m, 3H) 3.93-4.04 (m, 1H) 5.33 (br. s, 1H) 6.39 (s, 1H) 6.74-6.94 (m, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.76-8.03 (m, 4H) 10.17 (br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][O:20][NH2:21]>>[CH2:19]([O:20][NH:21][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Product: O=C(NOCc1ccccc1)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
N-Benzyloxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.25 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.36 mmol of O-methyl-hydroxylamine. LC/MS [10.01 min; 480 (M+1)]
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=[O:23]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[O:23])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Solvent: C1CCOC1
Product: O=C(OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (500 mg, 1.77 mmol) was dissolved in 10 ml of THF, to which solution was added 1,1′-carbonyldiimidazole (576 mg, 3.55 mmol), and stirred at room temperature for 1 hour. The THF was distilled off under reduced pressure and extracted three times with water and ethyl acetate. An obtained organic layer was distilled under reduced pressure and recrystallized from hexane/ethyl acetate (1/4) conditions to obtain imidazole-1-carboxylic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a desired solid compound.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:67]([NH:69][CH3:70])=[O:68])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:62][CH:63]([CH3:66])[CH2:64][OH:65])[CH:61]=2)=[CH:55][CH:56]=1>>[OH:65][CH2:64][CH:63]([CH3:66])[CH2:62][N:60]1[CH:61]=[C:57]([C:54]2[N:53]=[C:52]([C:67](=[O:68])[NH:69][CH3:70])[C:51]([NH:50][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:56][CH:55]=2)[CH:58]=[N:59]1
Reactant: CNC(=O)c1nc(-c2cnn(CC(C)CO)c2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(C)CO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Prepared analogously to Compound 1B using replacing compound 1C with 3-amino-6-[1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 18C). 1H NMR (CD3OD, 400 MHz): δ=8.92 (br. s., 1H) 8.51 (s, 1H) 8.37 (br. s., 1H) 8.31 (s, 1H) 7.77 (d, J=8.8 Hz, 1H) 7.54 (d, J=7.8 Hz, 1H) 7.17 (s, 1H) 7.04 (d, J=7.8 Hz, 1H) 4.29 (dd, J=13.8, 6.44 Hz, 1H) 4.00-4.16 (m, 5H) 3.89 (s, 3H) 3.47 (d, J=5.6 Hz, 2H) 3.37 (d, J=21.7 Hz, 2H) 3.00 (s, 3H) 2.26 (dq, J=12.8, 6.4 Hz, 1H) 1.27 (t, J=7.1 Hz, 6H) 0.94 (d, J=6.8 Hz, 3H). MS (ESI): m/z=707.70 [M+H]+. UPLC: tR=1.29 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][Si:9]([C:12]#[C:13][C:14]1[NH:18][C:17]([C@@H:19]2[CH2:24][C@@H:23]3[C@@H:21]([CH2:22]3)[N:20]2C(OC(C)(C)C)=O)=[N:16][CH:15]=1)([CH3:11])[CH3:10]>ClCCCl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][Si:9]([C:12]#[C:13][C:14]1[N:18]=[C:17]([C@@H:19]2[CH2:24][C@@H:23]3[C@@H:21]([CH2:22]3)[NH:20]2)[NH:16][CH:15]=1)([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)C#Cc1c[nH]c([C@@H]2C[C@H]3C[C@H]3N2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (500 μl, 6.49 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (299 mg, 0.865 mmol) in DCE (5 mL) and the reaction was stirred at rt for 30 min. The reaction was concentrated to dryness and then resubmitted to the reaction conditions for 5 h. The reaction was concentrated to yield a TFA salt of (1R,3S,5R)-3-(4-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane as a viscous brown oil which was used without further purification. LC-MS retention time 2.755 min; m/z 246.25 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13]O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][S:17][C:18]2[S:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CO)COC1(C)C
Reactant: Sc1nc2ccccc2s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CSc2nc3ccccc3s2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a stirred, cooled (0° C.) solution of (S)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.36 g), 2-mercaptobenzothiazole (1.48 g) and triphenylphosphine (2.32 g) in THF (80 ml) under an argon atmosphere was added diethyl azodicarboxylate (4.1 ml; 40% solution in toluene). The mixture (soon turning to a yellow suspension, slowly warming up to r.t.) was stirred for 18 h overnight, then diluted with EtOAc and washed with sat. aq. Na2CO3. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: cyclohexane→cyclohexane/EtOAc 85:15) to give (R)-4-(benzothiazol-2-ylsulfanyl-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.1 g) as light yellow viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1NC(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)O)c(NC(=O)C(F)(F)F)c1

Procedure:
An amount of 5.24 g of 4-nitro-N-trifluoroacetyl-anthranilic acid was dissolved in 100 ml of ethyl alcohol, 2 g of a 10% palladium-carbon catalyst were added to the resultant solution, and the resultant mixture was stirred for 2.5 hours at room temperature in a hydrogen gas stream. The resultant reaction mixture was filtered through a Celite filter (trademark, made by Johns Manville Sales), and the catalyst on the Celite filter was washed with ethyl alcohol. The entire amount of the filtrate was collected, concentrated, and dry solidified under a reduced pressure, and the resultant crude product in an amount of 4.7 g was recrystallized from an ethyl alcohol-hexane or ethyl alcohol-water mixed solvent.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.[I-].[K+]>CC(N(C)C)=O>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: C1CCNC1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCN4CCCC4)c23)ccc1OCc1ccccn1
Temperature: 140 °C
Yield: 50.4 %

Procedure:
3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 13/200 mg, 0.43 mmol), pyrrolidine (178 μL, 2.14 mmol) and potassium iodide (0.43 mmol) were mixed in DMA (2 ml). The mixture was heated at 140° C. for 3 minutes in a microwave reactor. The crude mixture was then filtered and purified by preparative HPLC (column beta-basic, Hypercil 51 μm, 21×100 mm) eluting with a mixture of water and acetonitrile containing 2g/l of ammonium carbonate (gradient). After evaporation of the solvents, the remaining solid was triturated in ether, filtered and dried to give the title compound (101 mg, 51%); NMR Spectrum: 1.66 (br s, 4H), 2.54 (br s, 4H), 2.88 (t, 2H), 4.42 (t, 2H), 5.29 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.86-7.90 (m, 2H), 8.29 (s, 1H), 8.60 (br s, 2H); Mass Spectrum: 466 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:23]([CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26])[C:10]2=[O:12]
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2cccc(Cl)c2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cccc(Cl)c4)c3C2=O)C(=O)N1
Yield: 36.4 %

Procedure:
A mixture of 3-(3-chloro-benzyloxy)-phthalic acid (1.6 g, 5.1 mmol), alpha-amino-glutarimide hydrochloride (0.87 g, 5.3 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3-chloro-benzyloxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.74 g, 37% yield); HPLC: Waters Symmetry C18, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 6.44 min (99.8%); mp, 249-251° C.; 1H NMR (DMSO-d6) □ δ 2.02-2.07 (m, 1H, CHH), 2.54-2.62 (m, 2H, CH2), 2.83-2.91 (m, 1H, CHH), 5.12 (dd, J=6, 12 Hz, 1H, CH), 5.39 (s, 2H, CH2), 7.40-7.87 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.92, 48.77, 69.05, 115.72, 116.69, 120.10, 125.65, 126.85, 127.84, 130.42, 133.18, 133.26, 137.07, 138.76, 155.19, 165.32, 166.74, 169.89, 172.75. Anal Calcd For C20H15N2O5Cl+0.1H2O: C, 59.96; H, 3.82; N, 6.99; Cl, 8.85. Found: C, 59.93; H, 3.54; N, 6.91; Cl, 9.00.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[O:18]([CH2:17][N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCOc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(Cl)cn1COc1ccccc1
Temperature: 25 °C

Procedure:
5-Chloropyrimidin-2-one (5 mmol) and triethylamine (5 mmol) were stirred together in dichloromethane (50 ml). When all the solid had dissolved a solution of chloromethoxybenzene (see Preparation 2) (5 mmol) in dichloromethane (25 ml) was added with stirring at room temperature. The resultant mixture was stirred for 24 h at this temperature before the solvent was distilled off. The residue was triturated with water (30 ml), extracted into chloroform (3×20 ml), and the dried (MgSO4) solution evaporated to yield a mixture of the title compound and the O-alkylated isomer in the ratio 3:1; yield 7.00 g (85%). The N-isomer was separated by column chromatography on silica gel; m.p. 146° C. 1H NMR (CDCl3): δ 5.92 (CH2), 6.8-7.4 (Ph), 7.80 and 8.43 (H-4 and H-6, respectively, J 3 Hz). IR (KBr): 1660 cm-1 (CO). MS (70 eV, m/z (% rel. int.)): 236 (7, M), 145 (32), 143 (100), 116 (31), 94 (6), 77 (18).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:20][CH2:21]O>CCOC(C)=O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:20][CH3:21])=[O:11])=[CH:7][CH:8]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
A solution of (trifluoro-p-tolyl)-acetic acid (19.85 g, 97.2 mmol) in EtOH (200 mL) was treated with H2SO4, 36N (16.4 mL, 194 mmol). The reaction was heated at reflux. After 48 hours, the reaction was cooled to 23° C., diluted with EtOAc (750 mL), washed with saturated NaHCO3 solution (2×400 mL) and brine (400 mL), dried over MgSO4, and concentrated in vacuo affording 20.98 g of ethyl 2-(4-(trifluoromethyl)phenyl)acetate.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][CH2:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH3:18])=[O:8]>>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH3:18])=[O:8]
Reactant: Cc1[nH]c2ccccc2c1C(=O)CCCl
Reactant: CNC
Product: Cc1[nH]c2ccccc2c1C(=O)CCN(C)C
Reaction time: 0.5 h

Procedure:
A solution of dimethylamine in IMS (33% w/v; 8 ml) was added to 3-chloro-1-(2-methyl-1H-indol-3-yl)-1-propanone (404 mg) and the mixture was left for 30 min. when a solid was precipitated. The mixture was refrigerated for 15 min. and the solid was filtered off and dried to give the title compound (207 mg). The mother liquors were evaporated to leave a solid which was partly dissolved in ethyl acetate (20 ml). Water (20 ml) was added and the solid remaining out of solution dissolved. The organic phase was extracted with 2M hydrochloric acid (3×20 ml) and the combined acidic extracts were brought to pH 10 with 0.88 ammonia solution. The mixture was extracted with ethyl acetate (3×25 ml), and the combined, dried organic extracts were evaporated to leave a solid which was crystallised from ethanol. The crystals were combined to give the title compound (386 mg), m.p. 172°-175°.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+].[N+](C1C=C(S(O[CH2:42][C@H:43]2[O:45][CH2:44]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:42][C@@H:43]2[CH2:44][O:45]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OC[C@@H]3CO3)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of the foregoing product from Step 1 in DMF (0.04 M) were added cesium fluoride (3 eq) and (S)-glycidyl 3-nitrobenzenesulfonate (1.1 eq). The resulting mixture was stirred at RT overnight, then diluted with EtOAc and washed with water and brine. Drying over Na2SO4, filtration and concentration in vacuo gave the crude product, which was purified by flash chromatography on silica gel (1:5 EtOAc/PE) to afford the title compound as a colourless foam (74%); MS (ES+) m/z 406 (M+H)+; [α]D20=+22 (c=0.5, CHCl3).
Reaction SMILES: [CH:1]([CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.[OH:11][CH2:12][CH2:13][NH:14][NH2:15]>C(O)C>[OH:11][CH2:12][CH2:13][N:14]1[CH:1]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]=[N:15]1
Reactant: NNCCO
Reactant: CCOC(=O)C(C=O)C=O
Solvent: CCO
Product: CCOC(=O)c1cnn(CCO)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Compound 5 was prepared using the classical approach for preparing pyrazoles [7]. Ethyl 2-formyl-3-oxopropionate (2.80 g; 20 mmol) was dissolved in 20 ml of ethanol and cooled to 0° C. 2-Hydroxyethylhydrazine (1.44 g; 20 mmol) was dissolved in 100 ml of ethanol and was added dropwise to the solution of ethyl 2-formyl-3-oxopropionate. The reaction mixture was left overnight at room temperature. The solvent was vacuum removed yielding a yellow oil. Yield: 95%