Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(CCN(C)C)C.C([Li])(CC)C.C1COCC1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29](Cl)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O.C(OCC)(=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]2[CH:27]1[CH2:28]2)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(Cl)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2CC21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
TMEDA (0.11 mL) was slowly added dropwise at −78° C. to a mixture of sec-butyllithium (1.4 M; 0.52 mL) and THF (1.8 mL). Then it was stirred for a further 30 min at −78° C. and then a solution of 4-chloro-piperidine-1-carboxylic acid tert-butyl ester (160 mg) in a little THF was slowly added dropwise. The reaction mixture was stirred for 2 h at −78° C., then it was allowed to return slowly to room temperature. Ethyl acetate and water were added to the reaction mixture and the aqueous phase was extracted several times with ethyl acetate. The organic phases were combined, dried over sodium sulfate and the solvent was removed in vacuum.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2N)[N:9]=1.[N+:38](C1C=CC(CBr)=CC=1)([O-])=O>>[F:33][C:32]([F:35])([F:34])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH2:38])=[CH:26][CH:27]=2)[N:9]=1
Reactant: Nc1ccccc1Cn1nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(Cc2ccccc2)c1=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: Nc1ccc(Cn2nc(CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(Cc3ccccc3)c2=O)cc1

Procedure:
Prepared as for the compound of Example 3 using p-nitrobenzyl bromide.
Reaction SMILES: COCC(O[CH:7]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[CH:31]=[C:30]2[CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:8]([CH:24]([CH3:26])[CH3:25])[CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O.C(CN)O>C(O)C.[Pd]>[CH3:41][O:40][CH2:39][CH2:38][CH2:37][C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[C:27]([CH2:7][CH:8]([CH:24]([CH3:25])[CH3:26])[CH2:9][CH:10]3[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[N:11]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:28]=2)[N:32]([CH3:36])[CH:31]=1
Reactant: COCCCc1cn(C)c2ccc(C(OC(=O)COC)C(CC3COC(C)(C)N3C(=O)OC(C)(C)C)C(C)C)cc12
Agent: [Pd]
Solvent: NCCO
Solvent: CCO
Product: COCCCc1cn(C)c2ccc(CC(CC3COC(C)(C)N3C(=O)OC(C)(C)C)C(C)C)cc12

Procedure:
A solution of 2.80 g of tert-butyl 4-(2-{(2-methoxyacetoxy)-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-yl]-methyl}-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (diastereomer mixture) in 140 ml of ethanol is hydrogenated at 0° C. in the presence of 0.294 ml of ethanolamine and 3.34 g of 10% Pd/C over 3.5 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.48 (1:1 EtOAc-heptane). Rt=29.41 (gradient II).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)=[O:4].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:15]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=2)=[O:4])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: CCCOc1ccc(C(=O)CBr)cc1
Reactant: c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(C(=O)Cn2cncn2)cc1
Yield: 30.4 %

Procedure:
By substantially following the procedure of Example 608a using 29 g of 2-bromo-4'-propoxyacetophenone (Example 585b), 10 g of 1,2,4-triazole, 15 g (116 mmole) of diisopropylethylamine, and 100 ml of tetrahydrofuran, 8.4 g of the desired compound, mp 97°-99° C., was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][CH2:13][N:14]3[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:27](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:28].[C:43]([NH2:49])(=[NH:48])[C:44]([CH3:47])([CH3:46])[CH3:45].CCN(C(C)C)C(C)C.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[C:44]([C:43]1[N:49]=[C:27]([NH:1][C:2]2[C:3]([O:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH2:11][CH2:12][CH2:13][N:14]4[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[N:4][CH:5]=[CH:6][CH:7]=2)[S:28][N:48]=1)([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)C(=N)N
Reactant: Nc1cccnc1Oc1cccc2c1CCCN2C(=O)c1ccccc1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nsc(Nc2cccnc2Oc2cccc3c2CCCN3C(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.2 %

Procedure:
A mixture of (5-(3-aminopyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)(phenyl)methanone (Example A171d) (224 mg, 0.58 mmol), 1,1′-thiocarbonyldi-2(1H)-pyridone (269 mg, 1.16 mmol) in DCM (10 mL) was agitated at rt for 4 h. The mixture was evaporated and diluted in THF (5 mL), pivalamidine (79 mg, 0.58 mmol) and DIPEA (205 μL, 1.16 mmol) were added and mixture was heated at 80° C. in a sealed tube for 24 h. The solution was cooled down and DEAD (183 μL, 1.16 mmol) was added, mixture was stirred for 2 h. The reaction mixture was evaporated in vacuo and purified using preparative HPLC to afford the final product (40 mg). (M+H)+=486.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[S:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:16]2[S:17][CH:18]=[C:14]([CH3:13])[CH:15]=2)=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: Cc1csc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1csc(-c2nnc(Cl)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,4-Dichlorophthalazine (1.40 g, 7.03 mmol), 4-methylthiophen-2-ylboronic acid (999 mg, 7.03 mmol), and PdCI2(DPPF)(721 mg, 985 μmol) were added into a sealed tube. The tube was purged with Argon. Then sodium carbonate (2.0 M in water)(7.74 ml, 15.5 mmol) and 1,4-dioxane (35.2 ml, 7.03 mmol) were added. The tube was sealed, stirred at rt for 5 min, and placed in a preheated oil bath at 110° C. After 1 h, LC-MS showed product and byproduct (double coupling), and SM dichlorophthalazine. The reaction was cooled to rt, filtered through a pad of celite with an aid of EtOAc, concentrated, and loaded onto column. The product was purified by column chromatography using Hex to remove the top spot, then 80:20 Hex:EtOAc to collect the product. The product, 1-chloro-4-(4-methylthiophen-2-yl)phthalazine was obtained as yellow solid. LC-MS showed that the product was contaminated with a small amount of SM dichlorophthalazine and biscoupling byproduct. MS m/z=261 [M+1]+. Calcd for C13H9ClN2S: 260.12.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7](#[N:9])[CH3:8].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>C1COCC1>[OH:15][CH:14]([C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([OH:10])[CH:12]=1)[CH2:8][C:7]#[N:9]
Reactant: CC#N
Reactant: O=Cc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCC(O)c1cccc(O)c1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of KOtBu (68.5 g, 614 mmol) in THF (350 mL), cooled to −50° C., was added acetonitrile (30.3 mL, 540 mmol), dropwise over a period of 5 min. The resulting mixture was stirred at −50° C. for 30 min following which a solution of 3-hydroxybenzaldehyde (30.0 g, 244 mmol) in THF (150 mL) was added slowly, over a period of 10 min. This was then allowed to warm to 0° C. and stirred for another 3 h during which the reaction was found to be complete. The reaction was quenched by slow addition of ice-water followed by extraction with EtOAc. The combined organics were washed with water, brine and dried over Na2SO4. The solution was concentrated under reduced pressure to give 3-hydroxy-3-(3-hydroxyphenyl)propanenitrile (127) as yellow oil which was purified by flash column chromatography (0 to 20% EtOAc-hexanes gradient). Yield (25.0 g, 62%): 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.90-6.93 (m, 1H), 6.82 (dd, J=8.0, 2.4 Hz, 1H), 4.91-5.03 (m, 1H), 2.76 (d, J=6.4 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([OH:15])(=[O:14])[CH2:12][CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:11]([O:15][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:14])[CH2:12][CH3:13]
Reactant: CCC(=O)O
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)COC(=O)CC

Procedure:
A solution of 71 ml of ethyl 4-chloro-3-oxobutyrate in 165 ml of toluene is added to a boiling solution of 73 ml of propionic acid and 132 ml of triethylamine in 833 ml of toluene in the course of 30 minutes. The mixture is boiled under reflux for 90 minutes and then cooled, the triethylamine hydrochloride which has precipitated out is filtered off with suction and extracted twice with 300 ml of water each time and the solvent is distilled off in vacuo. The residue is subjected to fractional distillation under a high vacuum.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=O.C(O)(=O)C.[O-:19][C:20]#[N:21].[K+]>O>[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7](=[O:9])[NH:21][C:20]1=[O:19]
Reactant: N#C[O-]
Reactant: COC(=O)c1ccccc1NCCO
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)n(CCO)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a stirred mixture of 10 parts of methyl 2-[(2-hydroxyethyl)amino]benzoate and 100 parts of acetic acid is added dropwise a solution of 4.5 parts of potassium cyanate in 25 parts of water. Upon completion, stirring at room temperature is continued overnight. The reaction mixture is evaporated. The solid residue is stirred with water. The product is filtered off, washed with water and ethanol, and dried, yielding 5 parts (48%) of 1-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione; mp. 273.6° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17].C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CC(C)=O>[NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:25][CH3:26])=[O:8])=[CH:4][C:3]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17]
Reactant: CCI
Reactant: Nc1sc(C(=O)O)cc1C(=O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C(=O)c2ccccc2Cl)c(N)s1

Procedure:
5-Amino-4-(2-chlorobenzoyl)thiophene-2-carboxylic acid (240 g), potassium carbonate (176 g) and ethyl iodide (150 ml) were added to acetone (5 l), and the mixture was refluxed overnight. The solvent was evaporated, and ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added. The precipitated layer was taken out, washed with brine, dried over sodium sulfate and concentrated. The resulting crystals were collected by filtration and washed with ethyl acetate to give 126 g of ethyl 5-amino-4-(2-chlorobenzoyl)thiophene-2-carboxylate.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@@H:59]1[CH:64]2[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]2)[CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][C@@H:59]5[CH:64]6[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]6)[CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-(+)-3-aminoquinuclidine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.43 (m, 3 H) 1.57-1.92 (m, 12 H) 2.69 (d, J=6.57 Hz, 2 H) 2.71 (m, 3 H) 2.89 (m, 1 H) 3.13 (m, 1 H) 3.31 (s, 3 H) 3.95 (s, 3 H) 3.97-4.16 (m, 2 H) 4.45 (m, 1 H) 7.47 (d, J=8.0 Hz, 1 H) 7.49 (s, 1 H) 7.93 (s, 1 H) 8.14 (d, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.0 Hz, 1 H). [M+H] calculated for C29H37F2N7O3, 570; found 570.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20](Cl)[N:19]=[C:18]([Cl:23])[N:17]=2)=[CH:11][C:10]=1[Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[OH-].[Na+].O>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([NH:32][CH:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:19]=[C:18]([Cl:23])[N:17]=2)=[CH:11][C:10]=1[Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(Cl)nc(Nc2ccc(OCc3ccccc3)c(Cl)c2)n1
Reactant: NC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Clc1nc(Nc2ccc(OCc3ccccc3)c(Cl)c2)nc(NC2CCCCCC2)n1

Procedure:
To 160b (1.0010 g, 2.6 mmol) dissolved in acetone (25 mL) was added a solution of N-cycloheptylamine (0.35 mL, 2.6 mmol) in acetone (5 mL) followed by addition of 2.5 N NaOH (1.0 mL, 2.6 mmol) and water (2.5 mL). The reaction mixture was allowed to stir at reflux for 3 hours under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. After filtering, the sample was concentrated by rotary evaporation and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded a white solid (160c, 855 mg, 72%), mp 110° C.; HPLC: Inertsil ODS-3V C18, 30:70 [KH2PO4 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 47.3 min, 94.7% purity; MS (TOF MS ES+): m/z 535 (44.7), 460 (73.3), 458 (M+H, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[CH:18]([C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[C:31]([CH:38]([CH3:40])[CH3:39])[C:30]=3[O:41][CH2:42][CH2:43][CH3:44])[C:22]=2[CH:21]=1)=O.O>CN(C=O)C>[CH2:4]([O:5][C:6](=[O:7])[C:8]([F:9])=[CH:18][C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[C:31]([CH:38]([CH3:39])[CH3:40])[C:30]=3[O:41][CH2:42][CH2:43][CH3:44])[C:22]=2[CH:21]=1)[CH3:3]
Reactant: CCCOc1c(-c2cccc3sc(C=O)cc23)cc(C(C)C)cc1C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(-c2cccc3sc(C=C(F)C(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Temperature: 40 °C

Procedure:
To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil) in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents) of triethyl phosphonofluoroacetate (diluted in 1 mL of dry DMF) at 0° C. After the gas evolution has ceased, 0.51 mmol of 2-formyl-4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene diluted in 3 mL of dry DMF was added dropwise. The red mixture was slowly heated to 40° C. until complexion. After cooling, water was added and the solution was extracted 2 times with ethyl acetate. The organic layers were combined, washed with water and brine and dried over MgSO4. After evaporation of the solvents, the crude oil is purified over a short plug of silica gel (eluent: 95/5 hexane/ethyl acetate) to afford 2-fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[NH:22][C:21]([C:23]([C:55]4[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=4)=[C:24]4[N:54]=[C:27]([C:28]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)=[C:29]5[NH:46][C:32](=[C:33]([C:39]6[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=6)[C:34]6[CH:35]=[CH:36][C:37]=2[N:38]=6)[CH:31]=[CH:30]5)[CH:26]=[CH:25]4)=[CH:20][CH:19]=3)=[CH:13][CH:12]=1)([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[Zn:62](OC(C)=O)OC(C)=O.O.O>C(Cl)(Cl)Cl.CO>[Zn+2:62].[CH2:1]([C:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18]3[NH:22][C:21]([C:23]([C:55]4[CH:56]=[CH:57][C:58]([CH3:61])=[CH:59][CH:60]=4)=[C:24]4[N:54]=[C:27]([C:28]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)=[C:29]5[NH:46][C:32](=[C:33]([C:39]6[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=6)[C:34]6[CH:35]=[CH:36][C:37]=2[N:38]=6)[CH:31]=[CH:30]5)[CH:26]=[CH:25]4)=[CH:20][CH:19]=3)=[CH:15][CH:16]=1)([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: CC(=O)O[Zn]OC(C)=O
Agent: C=CCC(CC=C)(CC=C)c1ccc(-c2c3nc(c(-c4ccc(C)cc4)c4ccc([nH]4)c(-c4ccc(C)cc4)c4nc(c(-c5ccc(C)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: [Zn+2]
Reaction time: 2 h

Procedure:
A solution of 1 (132 mg, 167 μmol) in CHCl3 (13 mL) was treated with a solution of Zn(OAc)2.2H2O (183 mg, 0.832 mmol) in MeOH (2.6 mL) at room temperature. The reaction was followed by TLC. The reaction was complete in 2 h. The reaction mixture was washed with saturated aqueous NH4Cl and extracted with CH2Cl2. The combined organic layer was dried (Na2SO4), concentrated and chromatographed [silica, hexanes/ethyl acetate (9:1)] to afford a pink solid (132 mg, 93%): 1H NMR δ 2.66-2.78 (m, 15H), 5.12-5.28 (m, 6H), 5.80-5.96 (m, 3H), 7.50-7.60 (m, 6H), 7.67 (d, J=8.4 Hz, 2H), 8.04-8.14 (m, 6H), 8.16 (d, J=8.4 Hz, 2H), 8.88-8.94 (m, 2H), 8.94-9.02 (m, 6H); MALDI-MS obsd 852.4; FABMS obsd 852.3193, calcd 852.3170 (C57H48N4Zn); λabs 424, 551 nm.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=2[F:22])[N:4]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:3]=1.[CH3:33][Zn]C.C(O)(=O)C.Cl>O1CCOCC1.C1(C)C=CC=CC=1>[F:22][C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[N:4]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:3]=[C:2]([CH3:33])[C:10]=12
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Reactant: C[Zn]C
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Oc2ccnc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: 100 °C

Procedure:
100 mg (0.19 mmol) of N-[4-({3-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)-3-fluorophenyl]acetamide are dissolved in dioxane (2.5 ml). The solution is degassed and vented with argon. 0.29 ml (0.58 mmol) of a 2M solution of dimethylzinc in toluene and 7.9 mg (0.01 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride/methylene dichloride complex are added, and the mixture is heated at 100° C. for 2.5 hours. The mixture is allowed to cool to RT, acetic acid and 1M hydrochloric acid are added and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([N:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:12]=O)([CH3:10])([CH3:9])[CH3:8].[C:20]([N:24]([Si](C)(C)C)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[Cl-:4].[C:7]([N:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:12]=[N+:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N(c1ccccc1)[Si](C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)N(C=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)N(C=[N+](c1ccccc1)C(C)(C)C)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Oxalyl chloride (0.42 mL, 5.0 mmol) was added dropwise to a solution of 2a (0.582 g, 3.28 mmol) in toluene (10 mL) at −78° C. The reaction mixture was stirred for 2 h at room temperature. After evaporation of all the volatiles by vacuum, CH2Cl2 (10 mL) was added. 3a (0.778 g, 3.50 mmol) was added to the reaction solution at −78° C., and the reaction mixture was slowly warmed to room temperature for 30 min. After stirring for 3 h at room temperature, the reaction solution was concentrated to 2 mL. The solution was dropped to a rapidly stirred hexanes (10 mL). The precipitated solid was collected and was washed with hexane (10 mL×2) to give 4a (1.028 g, 90.8%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.11-6.78 (m, 10H), 1.56 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 153.8, 136.1, 130.3, 128.9, 66.2, 29.7. HRMS-ESI (m/z): [M]+ calcd for C21H29ClN2, 309.2325. found, 309.2322.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:24]1[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:45][S:46]SC>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][C:30]=2[S:46][CH3:45])[C:25]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:24]1[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Reactant: CSSC
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccnc2c(-c3ccc(F)cc3)c(-c3ccncc3)n(C(=O)OC(C)(C)C)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2,2,6,6-Tetramethylpiperidine (1.76 ml, 10.40 mmol) was dissolved in tetrahydrofuran (39 ml) and placed under an atmosphere of nitrogen. The solution was cooled to −78° C. and n-butyllithium (3.96 ml, 9.91 mmol, 2.5 M solution of in hexanes) was added at such a rate that the internal temperature did not exceed −70° C. The reaction mixture was warmed to −10° C. for 30 min., then re-cooled to −78° C. A solution of 1-tert-butoxycarbonyl-3-(4-fluorophenyl)-2-(pyridin-4-yl)-pyrrolo[3,2-b]pyridine (0.965g, 2.47 mmol) in tetrahydrofuran (32 ml) was cooled to −78° C. and then added via cannula at such a rate that the internal temperature did not exceed −70+ C. After 1 h, dimethyldisulfide (0.29 ml, 3.22 mmol) was added and the resulting solution was stirred for an additional 1 h at −78° C. The reaction mixture was quenched with saturated ammonium chloride solution and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude residue was purified by flash chromatography using 20% acetone/hexanes as the eluant to give 1-tert-butoxycarbonyl-3-(4-fluorophenyl)-7-methylthio-2-(pyridin-4-yl)-pyrrolo[3,2-b]pyridine. MS: 435 (M).