Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:35])=[C:6]([C:8]2([S:22]([C:25]3[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)(=[O:24])=[O:23])[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])[CH2:10][CH2:9]2)[CH:7]=1.[F-].[Cs+].[C:38](P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Sn](C)(C)C>O1CCOCC1.CCOCC.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:35][C:5]1[CH:4]=[CH:3][C:2]([CH3:38])=[CH:7][C:6]=1[C:8]1([S:22]([C:25]2[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])[CH2:10][CH2:9]1
Reactant: O=S(=O)(NC1CCC(c2cc(Br)ccc2F)(S(=O)(=O)c2ccc(C(F)(F)F)nc2)CC1)C(F)(F)F
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: C[Sn](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(F)c(C2(S(=O)(=O)c3ccc(C(F)(F)F)nc3)CCC(NS(=O)(=O)C(F)(F)F)CC2)c1
Temperature: 100 °C

Procedure:
The compound prepared in Example 75 (50 mg) in dioxane was treated with cesium fluoride (2.2 equivalents), tri-tert-butylphosphine (12 mol %), tetramethyltin (2 equivalents), and Pd2(dba)3 (3 mol %) and heated at 100° C. for 3 h. The reaction mixture was cooled, diluted with ether, filtered and the filtrate evaporated in vacuo. Purification by column chromatography gave the toluene derivative (13 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:22][N:23]([CH3:28])[S:24]([NH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=1)(=[O:26])=[O:25]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(CNS(=O)(=O)N(C)C)cc1
Temperature: 0 °C

Procedure:
4-(aminomethyl)benzoic acid methyl ester (0.2676 g, 1.620 mmol) was dissolved in dichloromethane (15 ml). DMAP (0.0248 g, 0.203 mmol) and DIEA (0.35 ml, 2.004 mmol) were added. The solution was cooled to 0° C. Dimethylsulfamoyl chloride (0.18 ml, 1.676 mmol) was added. The reaction was allowed to stir until completion. The reaction was diluted with DCM and washed with aqueous sodium hydrogen carbonate. The aqueous layer was extracted with DCM two times. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane (6-50%). MS: cal'd 273 (MH+), exp 273 (MH+).
Reaction SMILES: [C:1]([O:5][C@@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([OH:14])=O)[C@@H:8]([C:15]([O:17][CH3:18])=[O:16])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C@@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[O:14])[C@@H:8]([C:15]([O:17][CH3:18])=[O:16])[CH2:7]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (2S,3S,5S)-5-tert-butoxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid (43.0 mg, 0.000166 mol), 1-phenyl-piperazine (0.03166 mL, 0.0002073 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.09168 g, 0.0002073 mol) in N,N-dimethylformamide (0.40 mL, 0.0052 mol) was added N,N-diisopropylethylamine (0.03611 mL, 0.0002073 mol). The reaction was stirred at rt for 2 h, then quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to dry. The residue was used directly in next step. MS (ESI): (M+H)+=404.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([N:19]3[CH2:24][CH2:23][C:22]([C:26]4[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=4)([OH:25])[CH2:21][CH2:20]3)=[N:13][C:14](SC)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1CCN2C(=NCCC2)CC1.[C:55]([O:59][CH3:60])(=[O:58])[CH2:56][OH:57]>CC(C)=O.C1COCC1.O>[CH3:60][O:59][C:55](=[O:58])[CH2:56][O:57][C:14]1[N:13]=[C:12]([N:19]2[CH2:24][CH2:23][C:22]([C:26]3[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=3)([OH:25])[CH2:21][CH2:20]2)[C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(N2CCC(O)(c3ccc(Br)cc3)CC2)n1
Reactant: COC(=O)CO
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)c(N2CCC(O)(c3ccc(Br)cc3)CC2)n1
Reaction time: 12 h

Procedure:
To a solution of 4-[4-(4-bromophenyl)-4-hydroxy-piperidin-1-yl]-2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (700 mg, 1.35 mmol) in acetone (50 mL) was added m-CPBA (330 mg, 1.49 mmol) and the mixture was stirred for 12 h. The mixture was concentrated under reduced pressure and the intermediate product was isolated by trituration from a mixture of hexanes and dichloromethane (1:1, 25mL). This afforded 534 mg of the intermediate product as a mixture of sulfoxide and sulfone. Said intermediate product was used hereinafter without further purification. To a solution of the sulfone/sulfoxide mixture (150 mg, 0.28 mmol) in THF (10 mL) was added DBU (200 mL) followed by methyl glycolate (50 mg, 0.56 mmol). The mixture was heated at reflux for 12 h. The mixture was poured into water and extracted with ethyl acetate (3×25 mL). The combined extracts were washed with water and brine and were dried over magnesium sulfate. Filtration and concentration afforded a white solid which was purified via recrystallization from hexane and dichloromethane (10:1). The afforded 125 mg of the titled product.
Reaction SMILES: [CH2:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.O>CC(C1C=C(C(C)(C)C)C(=O)/C(=C/N[C@H]2[C@H](N/C=C3/C=C(C(C)(C)C)C=C(C(C)(C)C)C/3=O)CCCC2)/C=1)(C)C.[Co].C(O)(=O)C.O1CCCC1>[CH2:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[C@H:2]1[O:4][CH2:3]1
Reactant: CC(C)(C)OCC1CO1
Agent: [Co]
Agent: CC(C)(C)C1=C/C(=C/N[C@@H]2CCCC[C@H]2N/C=C2\C=C(C(C)(C)C)C=C(C(C)(C)C)C2=O)C(=O)C(C(C)(C)C)=C1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC[C@@H]1CO1
Temperature: 0 °C
Yield: 43.5 %

Procedure:
In a 500 ml round bottomed flask equipped with thermometer and a magnetic stirrer and an ice bath 6.04 g (1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis-(3,5-di-t-butylsalicylidene) cobalt (II) (10 mmol; Strem Chemicals) and 260.38 g rac tert-butyl glycidyl ether (2000 mmol) and 2.40 g acetic acid (40 mmol) and 20 ml THF (tetrahydrofurane) were cooled under stirring to 0° C. and 19.82 g deionized water (1100 mmol) were added all at once. The dark red reaction mixture was stirred under an air atmosphere for 0.5 h at 0° C. and for 23 h at RT. Vacuum distillation over a column filled with “Fenske” glass rings (20×2 cm column; “Fenske” glass rings Ø≅4 mm) afforded 113.2 g (43.5%) (S)-tert-butyl glycidyl ether (S)-1 as colorless liquid, b.p. 84-86° C./100 mbar.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C2(C(=O)O)CCCC2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C(O)C1(c2ccc(CBr)cc2)CCCC1
Yield: 133.4 %

Procedure:
To a solution of 1-(4-methylphenyl)cyclopentane carboxylic acid tbutyl ester (2.00 g, 7.68 mmol) in CCL4 (80 mL) was added N-bromosuccinimide (1.37 g, 7.68 mmol) and benzoyl peroxide (0.050 g). This mixture was brought to reflux by heating, and maintained at reflux for 2 hours using a sun lamp (250 W). Additional N-bromosuccinimide (0.34 g, 1.9 mmol) was added, and after 20 minutes the solution was concentrated to 40 mL. The white precipitate was removed by filtration. The filtrate was concentrated to give 1-(4-bromomethylphenyl)cyclopentane carboxylic acid tbutyl ester (2.9 g, 100%) as a yellow oil which was used without additional purification.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.C[O:15][C:16](=[O:19])[CH2:17][NH2:18].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([NH:18][CH2:17][C:16]([OH:19])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCNCC(=O)O
Reaction time: 1 h

Procedure:
To a solution of decanoyl chloride (5) (2.7 mL, 13 mmol, 1.0 eq) in methylene chloride (20 mL) in an ice/acetone bath was added a mixture of glycine methyl ester hydrochloride (91) (2.0 g, 16 mmol, 1.2 eq) and DIPEA (5.1 mL, 29 mmol, 2.2 eq) in methylene chloride (20 mL) dropwise. The reaction was stirred a further 60 min after complete addition, then washed with 3N hydrochloric acid (50 mL) twice, followed by saturated sodium bicarbonate (50 mL). The organics were dried over magnesium sulfate and the solvents removed under reduced pressure. n-Decylglycine, a compound of formula (96) (3.0 g, 12 mmol, 95%) was obtained, and used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:25]=[CH:24][C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.ClCCl.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3=NCCO3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(C2=NCCO2)ccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg tert-butyl 4-[4-(4,5-dihydrooxazol-2-yl)-phenoxy]-piperidine-1-carboxylate are taken and mixed with 6 ml of a (5/1) dichloromethane/trifluoroacetic acid mixture. The reaction mixture is stirred at ambient temperature and after 15 min it is cautiously mixed with a saturated NaHCO3 solution. The organic phase is dried and evaporated to dryness. 20 mg (V-2) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[F:37])#[N:30]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:33]2[CH:34]=[CH:35][C:36]([F:37])=[C:31]([CH:32]=2)[C:29]#[N:30])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)[C:11]([F:12])([F:13])[F:14]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(c1cc(Oc2ccc(F)c(C#N)c2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 3-cyano-4-fluorophenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as an off-white solid. MS (m/e)=535.2 [M+H+].
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]2[O:14][C:13](=[O:15])[C@H:12]([O:16][CH3:17])[C@@H:11]2[OH:18])[OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:20][C@@H:21]1[C:27](=[O:28])[NH:26][C:25]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:24]=2[O:23][CH2:22]1.C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH:1]1(/[CH:6]=[CH:7]/[C@@H:8]([OH:9])[C@H:10]([OH:14])[C@@H:11]([OH:18])[C@@H:12]([O:16][CH3:17])[C:13]([NH:20][C@@H:21]2[C:27](=[O:28])[NH:26][C:25]3[CH:29]=[CH:30][CH:31]=[C:32]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:24]=3[O:23][CH2:22]2)=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1COc2c(cccc2-c2ccccc2)NC1=O
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H]1COc2c(cccc2-c2ccccc2)NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C1CCCC1
Temperature: 25 °C

Procedure:
100 mg of 32 (390 μmol), 113 mg of 38 (390 μmol) and 162 mg of sodium 2-ethylhexanoate (0.98 mmol) in 2 mL of THF are successively introduced into a Wheaton tube, with stirring and under an argon atmosphere. The stirring is maintained at RT for 24 h. The reaction medium is concentrated to dryness. The residues are chromatographed on a silica cartridge (8 g, eluent AcOEt). 79 mg of expected product Ex16 are recovered.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:5][CH2:6]1)=[O:36]
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: C[C@H](O)C(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[N:7][CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[N:7][C:6]2[C:13](=[O:14])[NH:15][CH:3]=[CH:4][C:5]=2[CH:10]=1
Reactant: COc1cnc(C(N)=O)c(CC(OC)OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cnc2c(=O)[nH]ccc2c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a mixture of 3-(2,2-dimethoxyethyl)-5-methoxypicolinamide (6.74 g, 28.1 mmol) in toluene (112 ml) was added 4-methylbenzene sulfonic acid (monohydrate; 0.534 g, 2.81 mmol). The reaction mixture was heated to reflux for 20 h. The reaction mixture was cooled to rt and concentrated in vacuo to a volume of ca. 15 mL. The residue was triturated with heptanes and filtered to afford 3-methoxy-1,7-naphthyridin-8(7H)-one (4.53 g, 25.7 mmol, 92% yield) as a crude, tan solid that was advanced without further purification. Crude LCMS showed complete conversion to product MS m/z=177.1 [M+H]
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Sn](C)(C)[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=1>CN1C(=O)CCC1.CCOC(C)=O.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]>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([C:2]2[C:3](=[O:17])[CH2:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[N:40][CH:41]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Reactant: C[Sn](C)(C)c1ccc(Cl)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(Cl)cn3)C(=O)CC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
To a degassed r.t. solution of 2-bromo-3-(4-(methylsulfonyl)-phenyl)-2-cyclopenten-1-one (0.630 g, 2.0 mmol), Pd2 (dba)3 (0.036 g, 0.04 mmol), and AsPh3 (0.098 g, 0.32 mmol) in NMP (5 mL) was added a degassed NMP solution (8 mL) of 2-trimethylstannanyl-5-chloropyridine (~4.0 mmol). The resulting mixture was heated to 60° C. for 16 h, then to 100° C. for a further 2 h. The mixture was then cooled to r.t., diluted with EtOAc, washed 2 times with 10% NH4OH and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (70% EtOAc/hexanes) followed by a CH2Cl2 /Et2O swish to provide 130 mg of the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH2:28])=[N:25][C:26]=3[F:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:38]=O)[C:33]([O:36][CH3:37])=[N:34][CH:35]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:28][CH2:38][C:32]4[C:33]([O:36][CH3:37])=[N:34][CH:35]=[C:30]([F:29])[CH:31]=4)=[N:25][C:26]=3[F:27])=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Br)cc23)c(F)n1
Reactant: COc1ncc(F)cc1C=O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(F)cc1CNc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Br)cc23)c(F)n1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
To 5-(1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-ylamine (167, 0.342 g, 0.741 mmol) in 10 mL of acetonitrile, 5-fluoro-2-methoxy-pyridine-3-carbaldehyde (37, 0.118 g, 0.763 mmol), triethylsilane (0.529 mL, 3.71 mmol) and trifluoroacetic acid (0.286 mL, 3.71 mmol) were added. The reaction was heated at 80° C. for 4 hours, then concentrated under vacuum and combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as an off-white solid (168, 367 mg). MS (ESI) [M−H+]−=599.6 and 601.6.
Reaction SMILES: C(O[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([C:33]2[NH:34][C:35]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:27][CH2:26]1.CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([C:33]2[NH:34][C:35]3[C:40]([C:41]=2[CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:27][CH2:26]1
Reactant: O=C(c1cc2ccccc2[nH]1)N1CCN(c2ccccc2Cl)CC1
Reactant: CC(=O)OC(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1)N1CCN(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
Benzhydryl acetate (2.2 g, 9.71 mmol) and 2-[4-(2-chlorophenyl)piperazinylcarbonyl]indole (3.0 g, 8.83 mmol) were dissolved in a mixed solvent of methylene chloride (50 ml) and chloroform (50 ml), and methanesulfonic acid (1.72 ml, 26.5 mmol) was added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution for neutralization followed by extraction with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 6.5 g of a crude product. The obtained crude product was washed with ethanol (60 ml) under heating to give 4.0 g (yield: 89%) of the title compound.
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[NH:41][C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]5[O:28][CH2:27][CH2:26][N:25]([C:29]6[C:38]7[C:33](=[CH:34][CH:35]=[C:36]([CH3:39])[CH:37]=7)[N:32]=[CH:31][N:30]=6)[CH2:24][C:23]=5[CH:40]=4)[CH:18]=[C:13]3[N:12]=2)C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:39][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][N:30]=[C:29]2[N:25]1[CH2:24][C:23]2[CH:40]=[C:19]([C:17]3[CH:18]=[C:13]4[N:12]=[C:11]([NH2:10])[NH:41][C:14]4=[N:15][CH:16]=3)[CH:20]=[CH:21][C:22]=2[O:28][CH2:27][CH2:26]1
Reactant: Cc1ccc2ncnc(N3CCOc4ccc(-c5cnc6[nH]c(NC(=O)OCc7ccccc7)nc6c5)cc4C3)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc2ncnc(N3CCOc4ccc(-c5cnc6[nH]c(N)nc6c5)cc4C3)c2c1
Yield: 4.3 %

Procedure:
Phenylmethyl{6-[4-(6-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-3H-imidazo[4,5-b]pyridin-2-yl}carbamate (0.1 g, 0.18 mmol) in acetic acid (8 ml) was placed under nitrogen. Palladium on carbon (0.25 g, 10 W %) was added and the reaction mixture saturated with hydrogen then stirred at room temperature for 12 h. The reaction mixture was filtered through a pad of celite then concentrated. The residue was taken into a minimum of methanol and purified by preparative reverse phase HPLC to give 6-[4-(6-methylquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-3H-imidazo[4,5-b]pyridin-2-amine (0.0033 g). 1H NMR (400 MHz, d6-DMSO); δ 8.52 (s, 1H), 8.32-8.12 (s, 1H), 7.84-7.47 (m, 6H), 7.07-7.00 (d, 1H), 6.80-6.50 (s, 1H), 5.04 (s, 2H), 4.56-4.44 (m, 2H), 4.20-4.09 (m, 2H), 2.83 (s, 3H); MS (EI) for C24H21N7O: 424.1 (MH+).
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1)=[O:7])[CH3:4].C([O-])([O-])=O.[K+].[K+].[N+:21]([C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)([O-:23])=[O:22].[Br-]>CC(C)=O.CC(=O)OCC.O>[CH2:3]([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:26]2[CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:28]=[N:27]2)[N:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1nc(CCl)cs1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1nc(Cn2cc([N+](=O)[O-])cn2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-chloromethyl-thiazole-2-carboxylic acid ethyl ester (1.84 g, 8.93 mmol) in acetone (20.0 mL) was treated, under inert atmosphere (N2) with K2CO3 (6.23 g, 44.66 mmol) followed by 4-nitro-1H-pyrazole (1.00 g, 8.93 mmol) and TBA bromide (576 mg, 1.79 mmol). The resulting mixture was stirred at rt overnight. Water (40 mL), followed by EA (50 mL) were added. The aq. layer was extracted with EA (50 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC: rf (50:50 hept-EA)=0.30. LC-MS-conditions 02: tR=0.90 min; [M+H]+=283.25.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12](OC)=[O:13].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[CH2:12][OH:13]
Reactant: COC(=O)/C=C/C=C/c1ccccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC/C=C/C=C/c1ccccc1Cl
Reaction time: 0.08 h
Yield: 93.8 %

Procedure:
To a solution of 20 g of methyl (2E, 4E)-5-(2-chlorophenyl)-2,4-pentadienoate dissolved in 150 ml of toluene, 215 ml of diisobutylaluminum hydride (1.5M toluene solution) was added dropwise under ice-cooling over 1 hour. After stirring at the same temperature for 5 minutes, saturated aqueous ammonium chloride was slowly added, and the insolubles were filtered off. The filtrate was washed twice with saturated aqueous ammonium chloride, dried and then the solvent was distilled off to give 16.4 g of (2E, 4E)-5-(2-chlorophenyl)-2,4-pentadien-1-ol as an oily substance.