Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.C([Li])CCC.CN(C)[CH:25]=[O:26].Cl>>[CH:25]([C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[O:26]
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A 1 liter three neck round bottom flask equipped with equalizing addition funnel, magnetic stirer and temperature monitoring device was charged with N-(4-trifluromethylphenyl)-2,2-dimethyl propanamide (10.13 g, 41.4 mmol) and anhydrous tetrahydrafuran (150 mL). The reaction was chilled to -78° C. under nitrogen followed by slow addition of n-butyllithium (50 ml, 2.5 M in hexanes, 124 mmol) over 0.5 hours, such that the temperature of the reaction did not rise above -65° C. The contents were held at -78° C. for one hour, 0° C. for two hours, then chilled back to -78° C. Excess N,N-dimethylformamide (100 mL, 1.37 mol) was added. The contents were warmed to room temperature and stirred for two hours. Aqueous 1 N HCl was added to the reaction until the pH reached 1. The reaction was washed with water (2×200 mL), saturated ammonium chloride solution (2×200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The product was purified by flash chromatography (silica gel, 10% ethyl acetate, 90% hexanes) to yield, upon concentration of the appropriate fractions, N-(2-formyl-4-trifluoromethylphenyl)-2,2-dimethylpropanamide as a solid (7.36 g, 65%): mp 69-73° C. 1H NMR (CDCl3 /300 MHz) 11.5 (br s, 1H), 9.99 (s, 1H), 8.67 (d, 1H, J=8.8 Hz), 7.94 (d, 1H, J=1.6 Hz), 7.83 (m, 1H,), 1.37 (s, 9H). ESHRMS m/z 274.1060 (M+H, Calc'd 274.1055). Anal. Calc'd for C13H14F3NO2 : C, 57.14; H, 5.16; N, 5.13. Found: C, 57.15; H, 5.43; N, 5.01.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1[nH]cnc1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)ncn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To a solution of ethyl 4-bromo-1H-imidazole-5-carboxylate (400 mg, 1.83 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL) was added sodium hydride (100 mg, 4.17 mmol, 1.00 equiv) in portions. The reaction was stirred at room temperature for 20 min then [2-(chloromethoxy)ethyl]trimethylsilane (300 mg, 1.80 mmol, 1.00 equiv) was added. The resulting solution was stirred at room temperature for 5 h and then diluted with 50 mL of ethyl acetate. The mixture was washed with 3×10 mL of brine then the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether to give 330 mg (52%) of ethyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ 7.69 (s, 1H), 5.67 (s, 2H), 4.43-4.36 (m, 2H), 3.58 (t, J=10.8 Hz, 2H), 1.45-1.40 (m, 3H), 0.94 (t, J=10.8 Hz, 2H), 0.05 (s, 9H) ppm.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][S:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[N:16]=1.C(Cl)Cl>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[N:16]=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: COC(=O)CO
Reactant: CCc1cc2c(Cl)nc(SC)nc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 90.4 %

Procedure:
To a suspension of 0.70 g (28.3 mmol) of sodium hydride in 40 mL of benzene was added 1.90 g (24.5 mmol) of methyl glycolate and 6.00 g (18.9 mmol) of 2-(methylthio)-4-chloro-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine. The mixture was heated at 60° C. and monitored by TLC (silica, methylene chloride) for conversion to product. After 3 days, an additional 0.70 g (28.3 mmol) of sodium hydride and 1.90 g (24.5 mmol) of methyl glycolate was added to the reaction. After an additional 3 days, the reaction was cooled to ambient temperature and partitioned by the addition of 100 mL of 2 M sodium hydrogen sulfate and 200 mL of ethyl acetate. The aqueous phase was extracted twice with 50 mL portions of ethyl acetate. The-combined organic phases were dried with magnesium sulfate and concentrated to 7.85 g of yellow solid. The solid was purified by flash chromatography (500 g silica, step gradient from 1:1 heptane-methylene chloride to methylene chloride) to provide 6.35 g (90%) of [[2-(methylthio)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.25 (t, J=7.5 Hz, 3H), 2.54 (s, 3H), 2.58 (q, J=7.5 Hz, 2H), 3.79 (s, 3H), 5.05 (s, 2H), 5.40 (s, 2H), 6.30 (s, 1H), 7.07 (d, J=7.1 Hz, 2H), 7.24 (m, 3H)
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:33]([O-])([OH:35])=[O:34]>>[CH3:1][C:2]1([CH3:12])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[C:9]([N+:33]([O-:35])=[O:34])[CH:10]=[CH:11][C:3]1=2
Reactant: O=[N+]([O-])O
Reactant: CC1(C)OB(O)c2ccccc21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OB(O)c2cc([N+](=O)[O-])ccc21
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
A 22 L round-bottomed-flask equipped with a mechanical stirrer, thermocouple, 2 L dropping funnel and cold bath was charged with 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (508 g, 300 g contained, 1.85 mol) and trifluoroacetic acid (1.54 L). The solution was cooled to 5° C. Trifluoroacetic anhydride (722 mL, 5.56 mol, 3.00 eq) was added via dropping funnel over 15 min. After aging at 0-3° C. for 30 min, nitric acid (90% fuming, 108 mL, 2.31 mol, 1.5 eq) was added dropwise over 2 h 50 min keeping the internal temp below 5° C. After aging for 1 h, icewater (10.4 L) was added over 50 min maintaining the reaction temp below 15° C. to provide a slurry. The slurry was aged at 0° C. overnight to provide an orange suspension. The solids were collected on a frit, rinsed with cold water (5 L) and air dried under a stream of air to constant weight (ca 24 h) to provide 364 g of 3,3-dimethyl-6-nitro-3H-benzo[c][1,2]oxaborol-1-ol as a 92.4 wt % pure solid (88%). LC/MS: m/z 208 (M+H)'; 1H NMR (DMSO-d6) δ: 8.52 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.4, 2.2 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 1.50 (s, 6H)
Reaction SMILES: [C:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:13])=[CH:14][CH:15]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round bottom flask was charged with 4-pivaloylbenzoic acid (7.67 g, 37.2 mmol), ethyl 3-aminopropanoate hydrochloride (6.86 g, 44.6 mmol), HOAT (5.57 g, 40.9 mmol), DCM (93 mL) and TEA (7.80 mL, 55.8 mmol). EDC hydrochloride (7.92 g, 40.9 mmol) was then added in one portion and the reaction allowed to stir at room temperature for 2 hours. DCM added to the reaction mixture and organics washed with an ammonium chloride solution (sat. aq.; 1×), water (2×), brine (1×), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude material. Purification by silica gel flash chromatography (ethyl acetate/heptane) provide ethyl 3-(4-pivaloylbenzamido)propanoate as a yellow oil (4.25 g, 37.4%; over 3 steps). 1H NMR (400 MHz, CDCl3) δ 1.26 (m, J=7.02, 7.02 Hz, 3H) 1.32 (s, 9H) 2.63 (t, J=5.95 Hz, 2H) 3.72 (m, J=6.05, 6.05, 6.05 Hz, 2H) 4.16 (m, J=7.22, 7.22, 7.22 Hz, 2H) 6.92 (br. s., 1H) 7.64-7.68 (m, 2H) 7.75-7.79 (m, 2H); MS (M+1): 306.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10](N)[O:11][C:12]=2[C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(ON=O)CCC>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[CH:10][O:11][C:12]=2[C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(-c2cccnc2Cl)c(-c2cccnc2Cl)o1
Agent: CCCCON=O
Solvent: C1CCOC1
Product: Clc1ncccc1-c1ncoc1-c1cccnc1Cl
Yield: 35 %

Procedure:
To a solution of 4, 5-di-(2-chloropyridin-3-yl)-2-aminooxazole (0.030 g) in tetrahydrofuran (3 mL) was added butylnitrite (0.033 g). The mixture was heated under reflux for 3 hours. The solvent was evaporated, and the residue was fractionated by chromatography to give 4, 5-di-(2-chloropyridin-3-yl)oxazole (0.010 g) as a solid. mp 157-158° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C@@:8]1([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[CH:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[F:25][CH2:26][CH2:27]C1C[C@H]2[C@@H](C=1)[C@](CC(OC(C)(C)C)=O)(C[N+]([O-])=O)C2>>[C:1]([O:5][C:6](=[O:24])[CH2:7][C@@:8]1([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[C:11]([CH2:27][CH2:26][F:25])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CC(CCF)=C[C@H]21
Reactant: CC(C)(C)OC(=O)C[C@@]1(CNC(=O)OC(C)(C)C)C[C@H]2CC=C[C@H]21
Product: CC(C)(C)OC(=O)C[C@@]1(CNC(=O)OC(C)(C)C)C[C@H]2CC(CCF)=C[C@H]21

Procedure:
The compound of interest was obtained as an oil substance (700 mg, 65.8%) in the same way as in paragraph (3-a) using tert-butyl(±)-[(1R,5S,6S)-3-(2-fluoroethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (870 mg, 2.77 mmol).
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:3]2[O:4][C:5]3([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[C:6](=[O:7])[C:2]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: OB(O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)C3(CCCCC3)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)C3(CCCCC3)O2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 49.4 %

Procedure:
To 102 mg of 3-bromo-2-{4-(methylsulfonyl)phenyl}-1-oxa-spiro[4,5]dec-2-en-4-one dissolved in 3 ml toluene and 15 ml ethanol, were added 16 mg of tetrakis(triphenylphosphin)palladium(0), 3 ml of 2 M aqueous sodium carbonate and 35 mg of benzeneboronic acid. The reaction mixture was stirred at 90° C. for 12 hours. The reaction mixture was then purified by a procedure similar to the procedure in Step 6 of Example 53 to afford 50 mg of 2-{4-(methylsulfonyl)phenyl}-3-phenyl-1-oxa-spiro[4,5]dec-2-en-4-one as a solid. mp: 126-127° C. NMR: δ1.77-1.85 (m, 10H), 3.06 (s, 3H), 7.27 (m, 2H), 7.35 (m, 3H), 7.83 (d, J=8.1 Hz, 2H), 7.94 (d. J=8.1 Hz, 2H). IR (cm−1): 2936, 1693, 1621, 1404, 1318, 1147, 1129, 730.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[Cl:19][C:20]1[C:25](Cl)=[N:24][CH:23]=[CH:22][N:21]=1>>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:25]2[C:20]([Cl:19])=[N:21][CH:22]=[CH:23][N:24]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1nccnc1Cl
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1
Temperature: 100 °C

Procedure:
A mixture of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) (1.25 g, 5.04 mmol) and 2,3-dichloropyrazine (0.25 g) was heated to 100° C. for 1 h. The reaction mixture was cooled and partitioned between EtOAc and pH5.2 citrate buffer. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a crude product. Purification by flash column chromatography (5–50% EtOAc hexane) afforded the title compound. M.S (M+1): 361.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[CH2:19]([O:21][C:22](=[O:30])[CH2:23][C:24]1[N:25]=[C:26]([NH2:29])[S:27][CH:28]=1)[CH3:20]>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:29][C:26]3[S:27][CH:28]=[C:24]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:30])[N:25]=3)=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Product: CCOC(=O)Cc1csc(NC(=O)c2sc3ccc(OC)cc3c2OC(C)C)n1
Yield: 72.4 %

Procedure:
Following a procedure analogous to Example 2, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (1.033 g, 3.88 mmol) and ethyl-2-amino-4-thiazoleacetate (709 mg, 4.37 mmol) gives 1.22 g (73%) of product; mp 91°-92° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][C@@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[C:30](=[O:32])[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)N1CCCC1
Yield: 70 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.44 mmol) was reacted with pyrrolidine (0.22 ml, 2.6 mmol) to give the title compound as a beige solid (152 mg, 70%), except that 3 Å molecular sieve was added and that the crude material was purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum 1.60 (d, 3H), 1.81 (m, 2H), 1.94 (m, 2H), 3.47-3.30 (m, 3H), 3.77 (m, 1H), 5.62 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.28 (m, 2H), 7.35 (d, 1H), 7.74-7.68 (m, 3H), 7.82 (dd, 1H), 8.15 (s, 1H), 8.53 (m, 3H), 11.07 (br s, 1H); Mass spectrum MH+ 494.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][NH:25]4)=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5].C1N=[CH:36][N:35]([C:38](N2C=NC=C2)=[O:39])[CH:34]=1.CN>C1COCC1.CCOC(C)=O>[NH2:6][C:4]([C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:11][C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:27]=[C:26]3[C:22]([CH2:23][CH2:24][N:25]3[C:38]([N:35]([CH3:36])[CH3:34])=[O:39])=[CH:21][C:20]=2[O:28][CH3:29])[NH:15][C:14]2=[N:30][CH:31]=[CH:32][C:13]=12)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)NCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)N(C)C)CC2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
A mixture of of 2-fluoro-6-[(2-{[5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (67 mg, 0.15 mmol) and CDI (30 mg, 0.18 mmol) in THF (4 mL) was stirred for 15 min, then treated with a solution of methylamine (2M in THF, 4 mL, 8 mmol) and was heated for 2 days in a sealed vessel at 80° C. More methylamine (2M in THF, 5 mL) was added and the reaction mixture was heated for 22 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL), washed with a saturated Na2CO3 solution (50 mL), water (50 mL) and a saturated NaCl solution (50 mL). The aqueous layers were back extracted with EtOAc (50 mL). The organic layers were combined and concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 6-[(4-{[2-(aminocarbonyl)-3-fluorophenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-N,N-dimethyl-5-(methyloxy)-2,3-dihydro-1H -indole-1-carboxamide as a yellow solid (43 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83 (s, 6H), 2.94 (t, J=8.06 Hz, 2H), 3.73-3.86 (m, 5H), 6.18-6.28 (m, 1H), 6.84-6.95 (m, 2H), 6.97 (s, 1H), 7.31-7.42 (m, 1H), 7.47 (s, 1H), 7.82 (s, 1H), 8.01 (s, 1H), 8.07 (s, 1H), 8.41 (d, J=8.24 Hz, 1H), 10.47 (s, 1H), 11.21 (s, 1H); ESIMS (M+H)+=505.15.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[NH:20][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of methyl (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinate (D33, 2.5 g, 7.6 mmol), and diisopropylethyl amine (2 ml, 11.4 mmol) in dry DCM (25 ml) at 0° C. was added dropwise benzyl chloroformate (1.3 ml, 9.1 mmol) and the mixture was stirred for 1 h from 0° C. to r.t. The mixture was washed with a 20% solution of citric acid and after with brine. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane and ethyl acetate (85:15) to afford the title compound (3.4 g, 97%) as a white solid; Rt (HPLC) 6.56 min; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.42-7.60 (m, 3H); 7.29-7.42 (m, 3H); 7.15-7.25 (m, 3H); 7.06-7.15 (m, 1H); 6.86-7.03 (m, 3H); 5.10 and 5.15 (s, s, 2H); 4.84-5.04 (m, 3H); 4.48 and 4.55 (m, m, 1H); 3.69 and 3.84 (s, s, 3H); 2.27-2.39 (m, 1H); 2.16-2.27 (m, 1H); 2.03-2.16 (m, 1H); 1.91-2.03 (m, 1H).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([C:31]#[CH:32])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[C:27]([C:31]#[C:32][C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH:28]=[CH:29][CH:30]=1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2ccccn2c1I
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
In a flask placed under an argon flow, 2.1 g (5.21 mmol) of 2-((3-iodoimidazo[1,2-a]pyridin-2-yl)methyl)isoindoline-1,3-dione were solubilised in 11 ml of dimethylformamide with magnetic stirring. To this solution, were added: 0.008 g (0.04 mmol) of copper iodide, 0.921 ml (6.25 mmol) of 3-trifluoromethylphenyl acetylene and 10.89 ml (78 mmol) of triethylamine. The reaction medium was degassed with argon for 10 min before adding 0.477 g (0.521 mmol) of Pd2(dba)3. The mixture was stirred at r.t. for 16 h before being filtered on a silica gel cartridge which was then rinsed with 300 ml of ethyl acetate. The organic phase was washed with 3×150 ml of a saturated NaCl aqueous solution, and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate gradient, from 50% to 40% of heptane, v/v). 1.41 g (yield=59%) of 2-((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methyl) isoindoline-1,3-dione were obtained as a brown solid. LC-MS: m/z=446 (MH+); UV purity at 254 nm=97%. 1H NMR (300 MHz, DMSO) δ 8.67 (d, J=6.7 Hz, 1H), 7.91 (dd, J=5.6, 3.0 Hz, 2H), 7.82 (dd, J=5.5, 3.1 Hz, 2H), 7.69 (dd, J=12.5, 8.5 Hz, 2H), 7.63-7.52 (m, 2H), 7.52-7.42 (m, 2H), 7.13 (td, J=6.8, 1.1 Hz, 1H), 5.09 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH3:19])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][Br:27])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CBr)c2F)c1
Temperature: 90 °C
Yield: 27.6 %

Procedure:
A mixture of 3-[(6-bromo-2-fluoro-3-methylphenyl)oxy]-5-chlorobenzonitrile (8.1 g, 23.78 mmol), NBS (5.08 g, 28.5 mmol) and AIBN (0.195 g, 1.189 mmol) in CCl4 (240 ml) was heated at 90° C. for 16 h under an atmosphere of nitrogen. The mixture was cooled to 0° C., filtered thru Celite and concentrated. The crude yellow oil was purified on silica gel (hexanes/ethyl acetate) to give 2.75 g (26%) of 3-{[6-bromo-3-(bromomethyl)-2-fluorophenyl]oxy}-5-chlorobenzonitrile as a clear oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.44 (dd, 1H), 7.34 (t, 1H), 7.18-7.32 (m, 1H), 7.13 (t, 1H), 6.89-7.05 (m, 1H), 4.45 (d, 2H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccc(Cl)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2,3-dichlorobenzene and isolated as colorless gum (6.7 mg, 37%). MS (m/e): 441.3 (MH+).