Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]3[C:16]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)([CH3:20])[NH:17][C:18](=[O:19])[C:12]3=[CH:11][CH:10]=2)[CH:3]=1.[H-].[Na+].[N:28]#[C:29]Br>O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]3[C:16]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)([CH3:20])[N:17]([C:29]#[N:28])[C:18](=[O:19])[C:12]3=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CC1(C2CCCC2)NC(=O)c2ccc(Nc3cc(N)ncn3)c(=O)n21
Reactant: N#CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C2CCCC2)N(C#N)C(=O)c2ccc(Nc3cc(N)ncn3)c(=O)n21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a 2-neck round bottom flask 6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione (2, 0.28 g, 0.82 mmol) was taken in dry tetrahydrofuran (15 mL). The reaction mixture was cooled to 0° C. and sodium hydride (164 mg, 4.11 mmol) was added in portions. After stirring for 10 min at room temperature, cyanogen bromide (436 mg, 4.11 mmol) was added and the resulting reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with aqueous ammonium chloride solution and then concentrated to get the crude mass. This crude was purified by flash chromatography eluting with 2% methanol in dichloromethane. The compound was washed with pentane and dried under vacuum to afford 6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-1,5-dioxo-imidazo[1,5-a]pyridine-2-carbonitrile (Cpd. No. 118) as yellow solid. Yield: 0.018 g, 6%; MS (ESI) m/z 366.16 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.71 (d, J=7.84, 1H), 8.19 (s, 1H), 7.28 (d, J=7.96, 1H), 6.65 (s, 2H), 6.29 (s, 1H), 3.49-3.43 (m, 1H), 2.21 (s, 3H), 1.94 (m, 1H), 1.7-1.58 (m, 4H), 1.48 (m, 1H), 1.23 (m, 1H), 1.06-1.02 (m, 1H).
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([CH3:19])([CH3:18])[CH2:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:20]Cl>C(O)(=O)C>[Cl:20][C:8]1[CH:7]=[C:6]([C:10]([CH3:19])([CH3:18])[CH2:11][C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: ClCl
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc2c1OCC2
Solvent: CC(=O)O
Product: CC(C)(CC(=O)C(F)(F)F)c1cc(Cl)cc2c1OCC2

Procedure:
A solution of 4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one (20.8 g, 76.2 mmol) in 200 mL of acetic acid was treated with a solution of chlorine gas (Cl2) in acetic acid (prepared by bubbling chlorine gas into acetic acid, ˜1.19 M). The reaction was monitored by 1H-NMR. The ratio of the starting material to product was determined based on the integration of CH2 signal of the respective ketones (starting material: δ=3.32 ppm; product: δ=3.32 ppm). The concentration of the Cl2 solution was recalculated based on the NMR ratios and an additional portion of Cl2 solution was added (this process was repeated until NMR showed the complete consumption of the starting material). The mixture was quenched with 500 mL of water and solid sodium bicarbonate (˜500 g) was added carefully during 1 hour. The mixture was poured onto 500 mL of ethyl acetate. The phases were separated and the aqueous layer was extracted with three 500 mL portions of ethyl acetate. The combined organic layers were washed with two 100 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 23.4 g of the title product (quantitative yield), which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[O:16]=[C:15]1[C:14](=[O:20])[NH:1][C:2]2[C:12](=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=2)[NH:13]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Product: CCOC(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of ethyl 3,4-diaminobenzoate (5 g, 27.75 mmol, 1.00 equiv) in diethyl oxalate (100 mL). The resulting solution was stirred overnight at 140° C. in an oil bath. Then the resulting solution was cooled to room temperature. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 3.5 g (54%) of ethyl 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1)[C:7]([N:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])([O-])=O.O.O.[Sn](Cl)Cl>CN(C=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1)[C:7]([N:9]([CH2:15][C:16]([F:17])([F:18])[F:19])[CH2:10][C:11]([F:13])([F:14])[F:12])=[O:8]
Reactant: O=C(c1ccc(NCc2ccsc2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)N(CC(F)(F)F)CC(F)(F)F)ccc1NCc1ccsc1

Procedure:
Same procedure used as above using 3-nitro-4-[(3-thienylmethyl)amino]-N,N-bis(2,2,2-trifluoroethyl)benzamide (138 mg, 0.312 mmol) and tin(II) chloride dihydrate (210 mg, 0.936 mmol) in 5 mL of DMF. Yield: 125 mg (97%); MS (ESI) 412.08 (MH+).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:34][CH3:35])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:21].C1CCCCC1.N>C(OCC)(=O)C.CO>[CH2:34]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:30][CH2:29]1)[CH3:35]
Reactant: CCN(CC)CCOCCC1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: N
Solvent: C1CCCCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CC)CCOCCC1CCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 71 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[2-[2-(diethylamino)ethoxy]ethyl]piperidine in a yield of 71% of theory. Colourless crystals, m.p. 119°-120° C. (cyclohexane), Rf 0.43 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: ethyl acetate/methanol/conc. ammonia 100/30/3, v/v/v)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:16])(=O)=O.O.C(OCC)(=O)C>O1CCCC1>[Cl:16][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCl)c1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
3′-Nitroacetophenone (2.00 g) was dissolved in tetrahydrofuran (24.2 ml), and sulfuryl chloride (4.90 g) was dropwise added thereto at 22° C. over 15 minutes. After stirring for 2 hours, water (150 ml) was added to the reaction mixture and stirred for 1 hour. Ethyl acetate was added, and the separated organic layer was washed with aqueous saturated sodium bicarbonate/aqueous saturated sodium chloride mixed solvent. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and stirred, and the precipitated crystal was then filtered and dried under reduced pressure to yield the desired 2-chloro-3′-nitroacetophenone (1.41 g; 58.3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([OH:22])=O)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([Cl:25])=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1-(4-Bromo-phenyl)-5-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (5.4 g, 14.3 mmol) prepared in Step 4 was added to thionyl chloride (50.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 1-(4-bromo-phenyl)-5-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NCC(C2CCCCC2)c2ccccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]cc(C2CCCCC2)c2ccccc12
Reaction time: 1.25 h

Procedure:
50 g of 4-cyclohexyl-3,4-dihydro-2H-isoquinoline-1-one and 20 l g of methanol-wet 30% Pd/C were heated while to 220° C in a stream of argon. Thin-layer chromatographic analysis revealed that the reaction was practically completed after 75 minutes. The product was dissolved in chloroform, the catalyst was separated and the organic phase was evaporated. After recrystallization from acetone, colorless crystals were obtained. M.p. 111° to 112° C
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.CC(OC([NH:38][CH2:39][C:40](O)=[O:41])=O)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:38][CH2:39][C:40]([NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:3]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cncc(N)c4)sc3n2)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NCC(=O)Nc1cncc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.1 %

Procedure:
To a solution of tert-butyl 4-(2-(5-aminopyridin-3-yl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (20 mg, 0.047 mmol) in DMF (1 ml) is added Boc-gly-OH (16 mg, 0.093 mmol), HATU (35 mg, 0.093 mmol) and Hunig's base (0.024 mmol, 0.14 mmol) and the mixture is stirred at room temperature for 3 h. EtOAc (10 ml) is added and the solution is washed with H2O and brine. The organic layer is dried over Na2SO4. After removing EtOAc in vacuo, the residue is purified by Biotage column chromatography (MeOH/DCM: 1/100 to 1/10 gradient) to give the desired product (20 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1.ClC[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Br>CN(C)C=O.C(O)CCC.O>[BrH:1].[Br:1][C:2]1[C:7]([O:8][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1
Reactant: OCc1ccc(O)c(Br)n1
Reactant: COc1ccc(CCCCCCCCCCl)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCCCCCCCOc2ccc(CO)nc2Br)cc1
Temperature: 25 °C

Procedure:
The crude 2-bromo-3-hydroxy-6-hydroxymethylpyridine (vide supra, 1.12 mol) was dissolved in dimethyl formamide (1150 ml) at 60° C. 1-Chloro-8-(4-anisyl)-octane (342 g, 1.34 mmol) and potassium carbonate (388 g, 2.81 mol) were added. It was found to be important that the potassium carbonate was ground to as fine a powder as possible. The mixture was stirred vigorously and heated to 90°-95° C. until the assay of 2-bromo-3-hydroxy-6-hydroxymethylpyridine (by HPLC) fell below 3% (approx 5 h). The mixture was then cooled to room temperature, poured into water (10 L) and extracted with ethyl acetate (3×670 ml). The combined ethyl acetate extracts were washed with water (2×500 ml) and dried before being evaporated to dryness. The crude reaction product was dissolved in butan-1-ol (2700 ml) and hydrogen bromide gas (120 g) passed through the solution keeping the temperature below 70° C. After allowing the mixture to cool to 10° C. with vigorous stirring the solid product was filtered and washed with ethyl acetate (2×500 ml). The solid product was dried under vacuum at 60° C. for 4 days. Yield 421 g, 75%.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:14][CH2:18][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][N:24]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the compound of Example 44A for the compound of Example 1E, and substituting 2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.78 (s, 2H) 8.07 (d, J=8.54 Hz, 1H) 7.98 (d, J=1.53 Hz, 1H) 7.60 (dd, J=8.39, 1.68 Hz, 1H) 4.09 (s, 3H) 3.80-3.92 (m, 1H) 3.07-3.24 (m, 1H) 2.55-2.73 (m, 4H) 2.26-2.47 (m, 4H) 1.57-1.80 (m, 4H) 1.43-1.53 (m, 2H). MS: (M+H)+=381.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C([Li])CCC.[C:14]12([C:24](Cl)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>C1COCC1.CCCCCC>[C:14]12([C:24]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:25])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: OCc1cccnc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(OCc1cccnc1)C12CC3CC(CC(C3)C1)C2
Yield: 77.8 %

Procedure:
The method followed that described in Example 1, but using 3-pyridylcarbinol (240 mg, 2.2 mmol) in THF (10 ml), n-butyllithium (2.5 M; 0.84 ml, 2.1 mmol) in hexane, and 1-adamantanecarbonyl chloride (397 mg, 2.0 mmol) in THF (2 ml). Chromatography, on elution with petrol-ether-triethylamine 200:50:1, gave the title compound (422 mg, 78%) as an oil. IR νmax 1728 cm-1 ; 1H-NMR (CDCl3) δ1.71 and 1.91 (12H, 2s, adamantyl CH2), 2.02 (3H, s, adamantyl CH), 5.11 (2H, s, OCH2), 7.30 (1H, m, Py 5-H), 7.66 (1H, m, Py 4-H), 8.56 (1H, m. Py 6-H), 8.61 (1H, m, Py 2-H). Anal. Calcd: C, 75.24; H, 7.80; N, 5.16. Found: C, 75.09; H, 7.84; N, 5.03%.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:27])[CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[O:4].[Li+].[OH-]>O1CCCC1>[C:17]1([O:16][CH2:15][C:14]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C@H:5]2[C:3]([OH:4])=[O:2])=[O:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@@H]1Cc2ccccc2N1C(=O)COc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1Cc2ccccc2N1C(=O)COc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of (2S)-N-[(1-naphthoxy)acetyl]indoline-2-carboxylic acid methyl ester (1.0 g, 2.77 mmol) in tetrahydrofuran (3.3 mL) at 0° C. was added 1.0 N LiOH solution (3.3 mL, 3.3 mmol). After stirring at 0° C. for 2 hours the mixture was concentrated, diluted with water, acidified to pH 3, and extracted with EtOAc. The EtOAc extract was washed with saturated NaCl, dried (Na2SO4), and evaporated to give the title compound (0.918 g, 96%) as an off-white solid. 1H NMR (CD3OD): δ8.36-8.33 (m, 1H), 8.15 (d, 1H, J=7.8 Hz), 7.81-7.78 (m, 1H), 7.49-7.18 (m, 7H), 7.10-7.04 (m, 1H), 6.92 (d, 1H, J=7.5 Hz), 5.32-4.94 (m, 5H), 3.69-3.34 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:25]2[CH2:28][C:27](=O)[CH2:26]2)=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O>C1COCC1.CN(C)C1C=CN=CC=1.CCOCC>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH:24]([C:21]2[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=2)[N:25]2[CH2:28][C:27](=[C:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[C:10]#[N:11])[CH2:26]2)=[CH:31][CH:32]=1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: N#CCc1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: N#CC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 540 mg (3.53 mmol) of 3,5-difluorophenylacetonitrile in 8 mL of THF a solution of 1.41 mL (3.53 mmol) of butyllithium (2.5M solution in hexanes) was added and it was stirred for 30 minutes at −78° C. Then a solution of 985 mg (3.21 mmol) of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one (1) in THF was added and it was stirred for 3 h at −78° C. Then 510 mg (4.17 mmol) of 4-dimethylaminopyridine, 840 uL (4.82 mmol) of N,N-diisopropylethylamine and 558 uL (7.06 mmol) of methanesulfonyl chloride was added and it was stirred at −78° C. to rt overnight. The solution was poured into 80 mL of ether and washed with 10 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate=9:1 to afford the title compound; 1NMR (CDCl3) δ 3.84 (m, 2H), 4.25 (m, 2H), 4.54 (s, 1H), 6.76 (m, 1H), 6.78 (m, 2H), 7.33 (m, 3H), 7.38 (m, 2H); Mass Spectrum: m/e=430 (M+1 35Cl, 35Cl) and 432 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2].C(OC(=O)C(C)(OC1C=CC=CC=1)CC1C=CC(O)=CC=1)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1cccc(Br)c1
Agent: [Pd]
Agent: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(Br)c1
Reaction time: 2 h

Procedure:
3-(4-Benzyloxy-phenyl)-2-(3-bromo-phenoxy)-2-methyl-propionic acid ethyl ester (3.7 g, 7.8 mmol) was dissolved in ethanol (140 mL), treated with 5% palladium on carbon (0.37 g), and stirred under an atmosphere of hydrogen for 2 h. The suspension was filtered through celite and concentrated in vacuo. The residue was purified by flash column chromatography (25% ethyl acetate in hexanes) to provide a mixture of the title compound and 3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester as a light yellow oil (2.8 g, 94%). 1H NMR (400 MHz, CDCl3): δ 7.24-6.94 (m, 4H), 6.836.80 (m, 1H), 6.75-6.71 (m, 3H), 5.12 (s, 1H), 4.19 (q, 2H, J=7.04 Hz), 3.24 (d, 1H, J=13.69 Hz), 3.06 (d, 1H, J=13.69 Hz), 1.40 (s, 3H), 1.26-1.17 (m, 3H). MS [EI−] 377 (M−H)+. Rf=0.24 in 25% ethyl acetate in hexanes.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(C)OC)=[O:6].[CH2:15]([Mg]Cl)[CH2:16][CH2:17][CH3:18]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:5](=[O:6])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:12][CH:13]=1
Reactant: CCCC[Mg]Cl
Reactant: CON(C)C(=O)c1cccc(Br)c1C
Solvent: C1CCOC1
Product: CCCCC(=O)c1cccc(Br)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 3-bromo-N,2-dimethyl-N-(methyloxy)benzamide (2.55 g, 9.88 mmol) in anhydrous THF (28 mL) under nitrogen at −78° C. was added a butylmagnesium chloride (20% wt in THF/toluene, 6.94 mL, 11.90 mmol) drop-wise over 15 min. The resulting solution was stirred at −78° C. for 1 h, was allowed to warm to 0° C. and then stirred with slow warming to ambient temperature over 20 h. The reaction was then quenched with water (50 mL) and extracted with EtOAc (2×60 mL). Some saturated aqueous NH4Cl was added to disperse the emulsion formed. The resulting organic layer was then washed with brine (100 mL), dried (Na2SO4), filtered and reduced under vacuum. Purification by SPE (silica, 50 g cartridge), eluting with cyclohexane:EtOAc (gradient 49:1 to 9:1) afforded the title compound as a colourless oil (706 mg).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[C:15](OS(C(F)(F)F)(=O)=O)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[Cl-].[Li+].[CH2:32]([O:34][CH:35]=[CH:36][Sn](CCCC)(CCCC)CCCC)[CH3:33]>CN(C=O)C.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>[CH2:35]([O:34][CH:32]=[CH:33][C:15]1[C:14]([C:24]([O:26][CH3:27])=[O:25])=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][C:5]3[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=12)[CH3:36]
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC=Cc1c(C(=O)OC)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 79 °C
Reaction time: 9 h
Yield: 89.2 %

Procedure:
To a solution of methyl 1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (2 g, 4.62 mmol) in DMF (27 mL) was added lithium chloride (0.59 mg, 13.88 mmol). Dry nitrogen was bubbled through the mixture for for 10 min, and then dichlorobis(triphenylphosphine)palladium(II) (0.16 g, 0.23 mmol) was added. The mixture was heated to 79° C., and a solution of ethoxyvinyl tributyltin (mixture of isomers: 1,2-E:1,2-Z:1,1=1:0: 0.97:0.18) [prepared according to A. Leusik, H. A. Budding, J. W. Marsman, J. Organomet. Chem., 1967, 9, 285-294] (1.82 g, 5.08 mmol) in DMF (23 mL). The resulting mixture was stirred for 9 h at 70° C. under nitrogen atmosphere. It was quenched with saturated sodium chloride and filtered to remove solid precipitate then concentrated. Purification by flash chromatography (Biotage) over silica gel (1:1 to 1:3, hexane/ethyl acetate) afforded the title product as brown glue (1.46 g, 89.2% yield). LCMS (APCl, M+H+): 355.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:11])[CH3:10].[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[CH2:19][Cl:18])=[C:3]([C:9]([OH:11])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:10])[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: CC(O)(c1ccccc1)c1cc(Br)ccc1N
Product: CC(O)(c1ccccc1)c1cc(Br)ccc1NC(=O)CCl

Procedure:
Prepared from 1-(2-amino-5-bromophenyl)-1-phenylethanol and chloroacetyl chloride according to the acylation procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.42 (s, 1H), 7.93 (d, J=8.71 Hz, 1H), 7.64 (d, J=1.86 Hz, 1H), 7.52 (dd, J=1.77, 8.71 Hz, 1H), 7.33-7.18 (m, 5H), 6.99 (s, 1H), 4.17 (d, J=14.92 Hz, 1H), 3.99 (d, J=14.98 Hz, 1H), 1.84 (s, 3H); MS (ES) m/z 366/368/370 ([M−H]−, 100%); Anal. Calc. For C16H15BrClNO2: C, 52.13; H, 4.10; N, 3.80. Found: C, 52.18; H, 4.05; N, 3.77.