Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:10]=[C:11]([C:30]#[CH:31])[C:12]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13][CH:14]=1.[OH:32][N:33]=[C:34](Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[Br:8][C:9]1[N:10]=[C:11]([C:30]2[O:32][N:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:31]=2)[C:12]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[N:13][CH:14]=1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: ON=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Triethylamine (50.82 mg, 70.00 μL, 0.5022 mmol) was added to a solution of tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (200 mg, 0.5022 mmol) and N-hydroxybenzimidoyl chloride (78.13 mg, 0.5022 mmol) in THF (16.00 mL) and the reaction mixture stirred at RT for 1 hour. After this time the reaction mixture was heated under reflux for 3 hours, cooled to RT and concentrated in vacuo. The residue was purified by column chromatography eluting with 10% EtOAc/ Petroleum ether to give the product as a colourless oil that crystallised on standing (182 mg, 70% Yield). 1H NMR (400.0 MHz, DMSO) d 1.41 (18H, s), 7.37 (1H, s), 7.52 (3H, m), 7.90 (2H, m), 8.68 (1H, s); MS (ES+) 519.05
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:23][CH3:24])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:36][C:37]#[N:38]>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:23][CH3:24])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:36][C:37]#[N:38])[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: N#CCCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(CC#N)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 37.3 %

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (Example 2, 70 mg, 0.17 mmol) was dissolved in DMA (5 ml). Potassium carbonate (96 mg, 0.70 mmol) and chloroacetonitrile (17 μl, 0.25 mmol) were added. The mixture was stirred at 60° C. for 4 hours. The solvent was evaporated and the residue was partitioned between DCM (20 ml) and water (20 ml). The aqueous layer was extracted with DCM (2×10 ml) and the extractions combined with the DCM layer. The combined DCM fractions were filtered through a silicone-treated filter paper and evaporated. The residue was purified by chromatography, eluting with 0 to 2% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated, and the residue triturated with diethyl ether, giving the product as a white solid (28 mg, 36%); 1H NMR: 1.67-1.80 (m, 2H), 2.03-2.13 (m, 2H), 2.46 (m, 2H), 2.77-2.85 (m, 2H), 3.76 (s, 2H), 3.92 (s, 3H), 4.55 (m, 1H), 7.20 (s, 1H), 7.27 (dd, 1H), 7.47 (dd, 1H), 7.52 (dd, 1H), 7.80 (s, 1H), 8.35 (s, 1H), 9.54 (s, 1H); Mass Spectrum: 412.4, 444.4.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6](Br)[N:7]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.C1CC=CCC=1>[Pd].O1CCCC1>[CH3:19][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[N:4]1[CH:5]=[CH:6][N:7]=[C:2]([O:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]1=[O:20]
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: Oc1ccccc1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: C1=CCC=CC1
Product: COC(=O)c1ccc(C)c(-n2ccnc(Oc3ccccc3)c2=O)c1
Temperature: 120 °C

Procedure:
A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 400 mg), phenol (400 mg), N,N-diisopropylethylamine (0.4 mL) and tetrahydrofuran (2 mL) was heated within a microwave for 3 h at 120° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 38 mg) and tetrahydrofuran (1 mL). 1,4-Cyclohexadiene (2 mL) was added and the mixture was heated under atmosphere of nitrogen within a microwave for 15 minutes at 90° C. before being cooled to room temperature. The mixture was filtered and concentrated to give a crude product that was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:15]([O:14][C:10](=[O:13])[CH:11]=[CH:12][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH3:16]
Reactant: C=CC(=O)OCC
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C#N)cc1
Temperature: 97.5 °C
Yield: 99.4 %

Procedure:
To a solution of 4-bromobenzonitrile (50 g, 0.275 mol) and ethyl acrylate (35.4 g, 0.412 mol) in dry DMF (250 mL), palladium acetate (0.61 g, 0.0027 mol), tris-o-tolylphosphine (3.34 g, 0.011 mol) and triethylamine (57.3 mL, 0.412 mol) were added and refluxed at 95-100° C. for 2 h under an argon atmosphere. The reaction was quenched by adding water (250 mL) and extracted with ether (3×250 mL). The combined extract was washed with 1.5 N HCl (250 mL), water and brine and dried over sodium sulfate (anhydrous). Solvent evaporation under reduced pressure and purification by column chromatography over neutral alumina, using ethyl acetate in petroleum ether as eluent, yielded 55 g (90%) of the sub-title compound as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.Cl[C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C>ClCCl>[CH3:35][O:34][C:32](=[O:33])[NH:1][CH2:2][C@H:3]1[CH2:4][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:6]1
Reactant: COC(=O)Cl
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 50 mg (0.125 mmol) of trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine in 2 ml of dry dichloromethane are added at RT 12 μl (0.150 mmol) of methyl chloroformate (Fluka, Buchs, Switzerland) and 21 μl (0.150 mmol) of triethylamine. After stirring for 2 h at RT, working-up is effected by partitioning between water and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated in vacuo to provide trans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamic acid methyl ester. Analytical HPLC: tR=7.08 min (Grad 2); ES-MS: m/eo=458.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:18])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[S:11][CH2:10][CH2:9][C:8]2=[O:17].Cl[CH2:20][CH2:21]Cl.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:18])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[S:11][CH2:10][C:9]1([CH2:21][CH2:20]1)[C:8]2=[O:17]
Reactant: ClCCCl
Reactant: COCOc1c(C)c(C)c2c(c1C)C(=O)CCS2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1c(C)c(C)c2c(c1C)C(=O)C1(CC1)CS2
Temperature: 25 °C
Reaction time: 19 h

Procedure:
6-Methoxymethoxy-5,7,8-trimethyl-2,3-dihydro-4H-thiochromen-4-one (23 mg) was dissolved in anhydrous DMF (5 mL) and treated with 1,2-dichloroethane (6.8 μL) and NaH (60% in mineral oil, 8.2 mg), and stirred for 19 h at ambient temperature. The reaction mixture was poured into H2O and extracted with EtOAc. The organic layer was collected and dried over Na2SO4 followed by solvent evaporation. Column chromatography (SiO2: hexane:EtOAc, from 9:1 to 1:1 v/v) yielded a fraction containing impure desired product 6-methoxymethoxy-5,7,8-trimethyl-2,3-dihydro-4H-thiochromen-4-one (<1 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Na+].[I-].[SH:9][C:10]1[N:14]=[CH:13][NH:12][N:11]=1>CO>[CH2:2]([S:9][C:10]1[N:14]=[CH:13][NH:12][N:11]=1)[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCBr
Reactant: Sc1nc[nH]n1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: C=CCCCSc1nc[nH]n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
5-bromopent-1-ene (10 mmol) and NaI were dissolved in 30 ml MeOH and stirred at room temperature for 12 h. 10 mmol 3-mercapto-1H-1,2,4-triazole (potassium salt) in 10 ml MeOH was added to above solution and further stirred for 24 hours. After the solvent MeOH was evaporated in vacuum, a mixture of hexane and ethyl acetate (1/1 in volume) 100 ml was added and stirred for 5 minutes. The precipitate was removed by filtration. The solvent in the filtrate was removed in vacuum. The residual was separated with a Si gel column (solvents: 1 ethyl acetate/1 hexane in volume). 1.2 g product was obtained as colorless oil. Yield: 71%. 1H NMR (CDCl3): 10.83 (1H, brs.), 8.17 (1H, s), 5.75 (1H, m), 4.99 (2H, m), 3.16 (2H, t), 2.19 (2H, m), 1.82 (2H, m).
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:17][O:18][C:19](=[O:21])[CH3:20])=O)C1C=CC=CC=1.[ClH:22].[H][H]>C(O)C.[C].[Pd]>[ClH:22].[C:19]([O:18][CH2:17][C@@H:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][NH:11]1)(=[O:21])[CH3:20]
Reactant: [H][H]
Reactant: CC(=O)OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)OC[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-acetoxymethyl-4-hydroxypyrrolidine (32.59 g) in ethanol (489 ml), 5% palladium-carbon (4.89 g) and 6N hydrochloric acid (18 ml) were added. The mixture was stirred at room temperature for 1 hour under an atmospheric pressure of hydrogen, followed by removal of the catalyst. Removal of the solvent gave (2S,4R)-2-acetoxymethyl-4-hydroxypyrrolidine hydrochloride.
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[S:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].S(Cl)([Cl:21])(=O)=O>>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[S:8][CH:7]([Cl:21])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: C=CC(=O)N1CCSc2ccc(OC)cc2C1
Product: C=CC(=O)N1Cc2cc(OC)ccc2SC(Cl)C1
Yield: 52.7 %

Procedure:
4-Acryloyl-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (4.0 g) and sulfuryl chloride (2.3 g) were reacted in the same manner as in Experimental Example 7 to give 4-acryloyl-2-chloro-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:21]([N-]C(C)C)(C)C.[Li+].IC.O>C1COCC1.CCCCCCC.C1COCC1>[CH2:1]([O:3][C:4]([CH:6]1[C:12](=[O:13])[CH:11]([CH3:21])[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Li+]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 2 g (7.01 mmol) 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (route 1 step a) in 25 mL anhydrous THF at −78° C. was added 9.7 mL (17.46 mmol) of a 1.8 M solution of lithium diisopropylamide in heptane/THF dropwise under an atmosphere of nitrogen. The reaction mixture was stirred at −78° C. for 30 minutes and then warmed up to 0° C. 0.48 mL (7.70 mmol) iodomethane was added at 0° C. and the reaction was left to warm up to room temperature over a period of 2 hours. 100 mL of H2O was added and the mixture was extracted with EtOAc (3×100 mL), the organic layers were combined, washed with H2O (2×100 mL) and saturated brine (100 mL) and dried over MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 9:1).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31](B4OC(C)(C)C(C)(C)O4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1>>[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:21]4[C:16]5[C:17](=[N:18][C:13]([C:3]6[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=6[F:12])=[N:14][CH:15]=5)[NH:19][N:20]=4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=464.1. 1H NMR (300 MHz, DMSO-d6) δ: 9.86 (s, 1H), 8.34 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.18 (t, J=8.3 Hz, 1H), 4.52 (s, 2H), 3.94 (s, 6H), 3.07-2.90 (m, 1H), 0.97-0.76 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[S:38](Cl)(=[O:40])=[O:39])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33](/[CH:36]=[CH:37]/[S:38]([N:13]2[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]3[CH2:12]2)(=[O:40])=[O:39])=[CH:34][CH:35]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(F)cc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CN(S(=O)(=O)/C=C/c3ccc(F)cc3)CCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (50 mg, 0.17 mmol) in chloroform (2 mL) were sequentially added pyridine (0.5 mL) and (E)-2-(4-fluorophenyl)vinylsulfonyl chloride (43 mg, 0.24 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from diisopropyl ether to obtain the title compound (27 mg, yield 64%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][N:12]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[S:13]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:36]=[CH:35][C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)[CH:28]=[C:23]3[C:22](=[O:37])[C:21]=2[CH:38]=1)(=[O:15])=[O:14].[CH3:45]I.[Cl-].[NH4+]>C1COCC1.O>[CH3:11][N:12]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[S:13]([CH:16]([C:17]1[CH:18]=[CH:19][C:20]2[CH:36]=[CH:35][C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)[CH:28]=[C:23]3[C:22](=[O:37])[C:21]=2[CH:38]=1)[CH3:45])(=[O:15])=[O:14]
Reactant: CI
Reactant: CN(c1ccccc1)S(=O)(=O)Cc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1)S(=O)(=O)N(C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Lithium bis(trimethylsilyl)amide (1063 μl, 1.063 mmol, 1 M in THF) was added to a solution of N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]N-phenylmethanesulfonamide (250 mg, 0.531 mmol) in THF (5.3 mL) at −78° C. After stirring for 30 minutes at −78° C., the solution was warmed to room temperature and then cooled to −78° C. before adding a solution of methyl iodide (100 μl, 1.594 mmol) in THF (3.75 mL) dropwise. After 2 hours, the reaction was warmed to room temperature, acidified with aqueous ammonium chloride (saturated) and water (75 mL), then extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid. LRMS (APCI) calculated for C27H24N4O3S [M+H]+, 485.2. found 485.1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@H:13]1[C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>[Cl-].C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC.CN1CCCC1=O>[N:1]([C@H:18]1[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C@H:13]1[NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:11])=[N+:2]=[N-:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 74 h

Procedure:
Sodium azide (357.6 mg) and tetrahexylammonium chloride (323.8 mg) were added at room temperature to a solution (2 mL) of ethyl (1S,3R,4R)-3-[(t-butoxycarbonyl)amino]-4-methanesulfonyloxycyclohexanecarboxylate (1.01 g) in N-methyl-2-pyrrolidone, followed by stirring at 60° C. for 74 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with aqueous saturated sodium bicarbonate solution and water, followed by drying over magnesium sulfate anhydrate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane ethyl acetate=4:1), to thereby yield 712.2 mg of the title compound. Spectral data of this compound were found to be identical with those of the compound of Example 5.
Reaction SMILES: C[Sn](C)C.C[Sn](C)C.Br[C:10]1[O:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:12][CH:11]=1.Br[C:22]1[CH:23]=[C:24]([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH:25]=[C:26]([F:28])[CH:27]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[O:14][C:10]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:23]=2)=[CH:11][CH:12]=1
Reactant: Brc1ccc(-c2ccccn2)o1
Reactant: Fc1cc(Br)cc(-n2ccnc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Product: Fc1cc(-c2ccc(-c3ccccn3)o2)cc(-n2ccnc2)c1
Temperature: 80 °C
Reaction time: 19 h
Yield: 65.8 %

Procedure:
Title compound synthesis: Pd(PPh3)4 (10 mg, 0.009 mmol) was added to absolution of hexamethylditin (169 mg, 0.52 mmol) and 5-bromo-2-(2-pyridyl)-furan (90 mg, 88% purity, 0.36 mmol) in toulene (2 mL) under argon. The resulting solution was stirred at 80° C. for 19 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (10 mg, 0.009 mmol) and 1-(3-bromo-5-fluoro-phenyl)-1H-imidazole (86 mg, 0.36 mmol) were added and the resulting solution was stirred at 110° C. for 36 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5 g silica gel SPE tube, 0–3% methanol in 1:1 chloroform:ethyl acetate) afforded 72.3 mg (66%) of 2-(2-pyridyl)-5-(5-fluoro-3-(1-imidazolyl)phenyl)-furan. 1H-NMR (CDCl3), δ (ppm): 8.63 (d, 1H), 7.93 (s, 1H), 7.78 (m, 2H), 7.57 (s, 1H), 7.45 (m, 1H), 7.35 (s, 1H), 7.23 (m, 3H), 7.03 (m, 1H), 6.91 (d, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[OH-].[Na+]>O.C(O)C>[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:2][OH:3])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=NO)cc1
Yield: 68.7 %

Procedure:
Hydroxylamine hydrochloride (41.7 g) in 70 ml of water was added to a solution of 36.1 g of 4-methylbenzaldehyde in 180 ml of absolute ethanol. A solution of 18 g of sodium hydroxide in 36 ml of water was added in portions during 5 to 10 minutes. The reaction mixture was then heated to boiling and filtered hot, and the filtrate was cooled in a dry ice-acetone bath. Water was added to the cooled filtrate until solid product precipitated. The solid was separated by filtration, air-dried overnight, and recrystallized from hexane to give 27.9 g of 4-methylbenzaldoxime, m.p. 73°-77°.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]N)=[CH:5][CH:4]=1.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(O)(=O)C.S(=O)(=O)(O)O.O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[O:9][C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:13]=3[C:5]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NOc1ccc(Br)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
The product of step A (13.7 g, 61.02 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (13.37 g, 67.12 mmol) in acetic acid (36 mL) and concentrated sulfuric acid (4 mL) were heated to 110° C. for 2 h. After concentrating in vacuo the reaction mixture was diluted with dichloromethane (100 mL) and water (200 mL), basified with saturated aqueous potassium carbonate solution at 0° C. and extracted with dichloromethane. The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 2-propanol (102 mL) and water (120 mL) before addition of potassium carbonate (9.5 g, 68.95 mmol) and di-tert-butyl dicarbonate (15 g, 68.9 mmol). The reaction mixture was stirred at 0° C. for 2 h then diluted with water (200 mL) and extracted three times with dichloromethane. The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 90:10 hexane/ethyl acetate) to give tert-butyl 8-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (8.7 g, 40%) as a light-pink solid: 1H NMR (CDCl3, 300 MHz) δ 7.53 (d, J=1.2 Hz, 1H), 7.36-7.25 (m, 2H), 4.51 (s, 2H), 3.82 (t, J=5.4 Hz, 2H), 2.84 (t, J=5.4 Hz, 2H), 1.50 (s, 9H).