Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](N)=[C:8]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Br:22])[CH:15]=2)[C:7]=1[F:23])[CH3:2].C(ON=O)(C)(C)C.[ClH:32]>CC#N>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:32])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Br:22])[CH:15]=2)[C:7]=1[F:23])[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)Cc1ccc(N)c(Oc2cc(Br)cc(C#N)c2)c1F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2cc(Br)cc(C#N)c2)c1F
Temperature: 60 °C
Yield: 64 %

Procedure:
The aniline 117b (3.98 g, 10.10 mmol) was dissolved in anhydrous CH3CN (35 mL) under nitrogen. This solution was then added dropwise to a mixture of tert-butylnitrite (2.40 mL, 20.20 mmol) and CuCl2 (2.72 g, 20.20 mmol) that had been prepared under nitrogen and warmed to 60° C. The reaction temperature was maintained at 60° C. for 2 h, then cooled to 0° C. A 5% aqueous HCl solution (80 mL) was added, and the mixture was extracted with 1:1 EtOAc/hexanes (3×75 mL). The combined organics were washed with brine (75 mL), dried over anhydrous MgSO4, and evaporated. The remaining oil was purified by flash chromatography on silica gel (0% to 30% EtOAc/Hexanes) to provide 2.67 g (64%) of the [4-chloro-3-(3-bromo-5-cyano-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (117c).
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[F:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>CC(O)(C)C>[F:17][C:18]1[CH:19]=[C:20]2[C:21]([C:3]([S:4][C:5]3[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)=[C:2]([CH3:15])[NH:24]2)=[CH:22][CH:23]=1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Reactant: NNc1cccc(F)c1
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1[nH]c2cc(F)ccc2c1Sc1cccc(CC(=O)O)c1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
[3-(2-Oxo-propylsulfanyl)-phenyl]-acetic acid (0.500 g, 2.2 mmol) and 3-fluorophenylhydrazine hydrochloride (0.400 g, 2.45 mmol) were dissolved in t-BuOH (10 mL). The reaction was stirred at 70° C. for 1.5 hours then submitted to aqueous workup. Purification by preparatory HPLC (10-100% ACN in H2O) afforded a 5:3 mixture of separable regioisomers of which the title compound was the major component.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10]2.[CH3:26][O:27][C:28]([N:30]1[CH2:34][CH2:33][C:32]([CH:41]=[O:42])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31]1)=[O:29]>C1COCC1>[CH3:26][O:27][C:28]([N:30]1[CH2:34][CH2:33][C:32]([CH:41]([OH:42])[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([Si:16]([CH:20]([CH3:21])[CH3:22])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10]3)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31]1)=[O:29]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reactant: COC(=O)N1CCC(C=O)(c2ccccc2)C1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)N1CCC(c2ccccc2)(C(O)c2ccc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
tert-Butyllithium (1.7 M in pentane, 8.9 mL, 15.10 mmol) was added at −78° C., under nitrogen atmosphere to a solution of 5-bromo-1-triisopropylsilanyl-1H-indole (2.42 g, 6.86 mmol) in THF (25 mL). The resulting pale yellow solution was stirred at −78° C. for 15 minutes, then a solution of 3-formyl-3-phenyl-pyrrolidine-1-carboxylic acid methyl ester (1.60 g, 6.86 mmol) in THF (5 mL) was then slowly added. The reaction mixture was stirred at −78° C. for 30 minutes and then warmed to room temperature over a period of 1 hour. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl and diluted with water. The resulting mixture was extracted with EtOAc, and the combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (10% to 50% of EtOAc in hexane) to give 1.76 g (51% yield) of 3-[hydroxy-(1-triisopropylsilanyl-1H-indol-5-yl)-methyl]-3-phenyl-pyrrolidine-1-carboxylic acid methyl ester as a white foamy solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18](Cl)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35]>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([F:31])[CH:33]=3)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)ccn23)c1
Reactant: Nc1cccc(F)c1
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Nc3cccc(F)c3)c3c(-c4ccccc4)ccn23)c1
Yield: 38.7 %

Procedure:
A mixture of N-(tert-butyl)-5-(1-chloro-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.050 g, 0.11 mmol) and 3-fluoroaniline (0.151 g, 1.36 mmol) was heated in a s sealed tube at 100° C. for 12 h. The volatile components were removed under reduced pressure and the resulting residue was purified by preparative HPLC (Condition B-6 described in general methods) to obtain N-(tert-butyl)-5-(1-((3-fluorophenyl)amino)-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.022 g, 38%) as a pale yellow solid. LCMS Method B-7: retention time 2.14 min, [M+1]=517.0, Purity 94.7%. LCMS Method B-8: retention time 1.74 min, [M+1]=517.0, Purity 95.4%. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.19 (s, 9H), 6.82 (td, J=2.0 Hz, J=8.4 Hz, 1H), 6.95 (dd, J=1.6 Hz, J=8.0 Hz, 1H), 7.12 (d, J=2.8 Hz, 1H), 7.27-7.31 (m, 1H), 7.50-7.64 (m, 6H), 7.70 (dt, J=2.4 Hz, J=12.0 Hz, 1H), 7.75 (d, J=2.8 Hz, 1H), 7.96 (s, 1H), 8.71 (t, J=2.0 Hz, 1H), 9.20 (d, J=2.0 Hz, 1H), 9.31 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[CH:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11](C(=O)C)[CH:10]=1)[CH3:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[NH:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCOC(=O)C=CCCc1cn(C(C)=O)c2ccccc12
Reactant: NCc1ccccc1
Product: CCOC(=O)CC(CCc1c[nH]c2ccccc12)NCc1ccccc1
Temperature: 80 °C
Yield: 79.9 %

Procedure:
A mixture of olefin 32 (5.0 g, 17.5 mmol) and benzylamine (7.7 mL, 70 mmol) was heated at 80° C. for 20 hours. The cooled reaction mixture was applied directly to a flash chromatography column (silica, 30% ethyl acetate/hexanes) to give the Micheal adduct 33 (4.9 g) as a viscous yellow oil.
Reaction SMILES: Br[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:21]1[O:23][CH2:22]1>C(Cl)Cl>[CH:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([C:14]=2[CH2:21][CH2:22][OH:23])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: C1CO1
Reactant: Brc1cccc2cc3ccccc3cc12
Agent: [Li]CCCC
Solvent: ClCCl
Product: OCCc1c2ccccc2cc2ccccc12

Procedure:
A solution in methylene chloride (20 ml) of 2-(9--anthryl)ethanol (3.5 g; 15.7 mmoles), which had been obtained by reaction between bromoanthracene and n-butyllithium and subsequent reaction with ethylene oxide was slowly added to an ice-cold solution of phosgene (20 ml; 38.4 mmoles; 20% in toluene). The reaction mixture was kept for 3 hours in an ice-bath and was then allowed to stand at room temperature during the night. Work up by vacuum evaporation of the solvent gave a crystalline residue, which was recrystallized from methylene chloride solution by precipitation with hexane to give 3.36 g (75%) of AEOC as practically colourless crystals, mp 85°-87° C. 270 MHz 1H-NMR in CDCl3 : 4.10 (t, J=8 Hz, 2 H); 4.66 (t, J=8 Hz, 2 H); 7.46-7.61 (m, 4 H); 8.03 (d, J=8 Hz, 2 H); 8.27 (d, J=8.6 Hz, 2 H); 8.43 (s, 1 H, H-10).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14](=[O:16])[CH3:15])([O:3][CH3:4])=[O:2]>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14](=[O:16])[CH3:15])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc(Br)cc(Cl)c1NC(C)=O
Solvent: CCO
Product: COC(=O)c1cccc(Cl)c1NC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
In a hydrogenation apparatus was placed 3.1 g of N-(2-carbomethoxy-4-bromo-6-chlorophenyl)acetamide and 100 mL of ethanol. The apparatus was purged with nitrogen and 0.1 g of 10 percent palladium on charcoal was added. The mixture was agitated under a hydrogen atmosphere at 40 psig for 2 hr at ambient temperature. The mixture was filtered to remove the catalyst, and the solvent was removed from the filtrate under reduced pressure. The product was purified by elution from a silica gel column using a gradient of 9:1 to 1:1 methylene chloride : ethyl acetate as the eluent to give 1.8 g of white solid (m.p. 135°-136° C.). 1H NMR (acetoned d6 +CDCl3) δ7.92 (d with fine coupling, 8.0 Hz, lH), 7.74 (d with fine coupling, 8.0 Hz, 1H), 7.46 (t, 8.0 HZ, 1H), 3.98 (s, 3H, OCH3), 2.55 (s, 3H, COCH3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:12]2[C:16]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[C:23]([F:31])[CH:22]=3)(=[O:20])=[O:19])=[CH:15][C:14]([CH3:32])=[N:13]2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CC(=O)CC(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.[OH-].[NH4+:53]>CN(C=O)C.[Cu]I>[NH2:53][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[C:16]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[C:23]([F:31])[CH:22]=3)(=[O:20])=[O:19])=[CH:15][C:14]([CH3:32])=[N:13]2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)c(F)c2)n(-c2ccc(Br)c3ncccc23)n1
Reactant: [NH4+]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)CC(C)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)c(F)c2)n(-c2ccc(N)c3ncccc23)n1
Temperature: 120 °C
Yield: 70 %

Procedure:
To a stirring solution of N-(1-(8-bromoquinolin-5-yl)-3-methyl-1H-pyrazol-5-yl)-4-t-butyl-3-fluorobenzenesulfonamide (0.052 g, 0.10 mmol) in ammonium hydroxide (1 mL) and DMF (1 mL) was added 2,4-pentanedione (0.006 g, 0.06 mmol), cesium carbonate (Cs2CO3, 0.064 g, 0.20 mmol), and copper(I) iodide (CuI, 0.0095 g, 0.050 mmol). The reaction mixture was heated at 120° C. in microwave for 2 h. After cooling to room temperature, ethyl acetate (100 mL) was added to the reaction mixture and washed with deionized water (20 mL) and brine (2×20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a brown solid (0.032 g, 0.070 mmol, 70%). 1H NMR (400 MHz, CD3OD) δ 8.80 (d, J=3.2 Hz, 1H), 7.53 (dd, J=1.2, 8.4 Hz, 1H), 7.45 (dd, J=4.0, 8.4 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.32 (dd, J=2.0, 8.4 Hz, 1H), 7.22 (dd, J=2.0, 12.0 Hz, 1H), 7.08 (s, 2H), 6.12 (s, 1H), 2.28 (s, 3H), 1.41 (s, 9H); MS: (ES) m/z calculated for C23H25FN5O2S [M+H]+ 454.2. found 454.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:7]1[C:14]([Cl:15])=[N:13][C:11](Cl)=[N:10][C:8]=1[Cl:9]>C(Cl)(Cl)Cl.O>[Cl:9][C:8]1[N:7]=[C:14]([Cl:15])[N:13]=[C:11]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -5 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Morpholine (9.5 mL, 108 mmol)) was added to a solution of cyanuric chloride (20 g, 108 mmol) in chloroform (10 mL) and stirred at −5° C. for 1 hour. Reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 5% ethyl acetate in pet-ether as an eluent to give 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 39% yield).
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[NH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[C:27]3([CH3:31])[C:28]([CH3:30])([CH3:29])[CH:23]([N:24]([C:32]([C:34]4[CH:42]=[CH:41][C:37]5[N:38]=[CH:39][NH:40][C:36]=5[CH:35]=4)=[O:33])[CH2:25][CH2:26]3)[CH2:22][C:21]=2[CH:43]=1.N>C(#N)C.CO>[N:38]1[C:37]2[CH:41]=[CH:42][C:34]([C:32]([N:24]3[CH2:25][CH2:26][C:27]4([CH3:31])[C:28]([CH3:30])([CH3:29])[CH:23]3[CH2:22][C:21]3[CH:43]=[C:17]([CH2:16][NH:15][C:12](=[O:14])[CH3:13])[CH:18]=[CH:19][C:20]=34)=[O:33])=[CH:35][C:36]=2[NH:40][CH:39]=1
Reactant: CC12CCN(C(=O)c3ccc4nc[nH]c4c3)C(Cc3cc(CN)ccc31)C2(C)C
Reactant: CC(=O)OC(C)=O
Agent: N
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCc1ccc2c(c1)CC1N(C(=O)c3ccc4nc[nH]c4c3)CCC2(C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (38 μL) and acetic anhydride (26 μL) are added to a suspension of (9-aminomethyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-(3H-benzoimidazol-5-yl)-methanone (0.10 g) in acetonitrile (2 mL). The resulting mixture is stirred at ambient temperature for 1 h. Then, methanol (1 mL) and concentrated aqueous ammonia solution (0.5 mL) are added and the resulting solution is stirred for another 30 min. The solution is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (water/MeCN) to give the title compound as a white foam-like solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH:14]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][C:20]([OH:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:5][O:6][Si](C)(C)C(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][O:2][N:3]=[C:4]([CH:14]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][C:20]([OH:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:5][OH:6]
Reactant: CON=C(CO[Si](C)(C)C(C)(C)C)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CON=C(CO)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
Treat a solution of the crude oxime from Step 3 (≤12.3 mmol) in THF (400 mL) with TBAF (15.4 mL, 15.4 mmol, 1M in THF) at 0° C. Stir the solution for 2 hours. Quench the reaction with water and extract the aqueous phase with EtOAc (3×100 mL). Dry the combined organic layers over MgSO4, filter and concentrate under reduced pressure to give the crude product as a yellow oil. Purify by silica gel chromatography (column: 7.5 cm×20 cm; pack column in CH2Cl2 and elute using a gradient of 100% CH2Cl2 to 5% CH3 OH(NH3)/CH2Cl2) to obtain 16 g (29.9 mmol, 75% from Example CAA2) of the title compound as a white solid. HRMS (FAB, M+H+): m/e cal'd for [C23H29N2O3Cl2 ]+ : 451.1555, found 451.1553 .
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]([F:13])([F:12])[CH2:10][OH:11].C(OC(C)C)(C)C.C(N(CC)CC)C.Cl>O>[C:1]([O:11][CH2:10][C:9]([Br:8])([F:13])[F:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCC(F)(F)Br
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)OCC(F)(F)Br
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A glass flask equipped with a thermometer, a condenser and a dropping funnel was charged with 271 g (2.24 moles) of pivaloyl chloride, 360 g (2.23 moles) of 2-bromo-2,2-difluoroethanol and 1.5 L of diisopropyl ether, followed by stirring. Then, 318 g (3.14 moles) of triethylamine was added dropwise thereto, in an iced bath. After the termination of the dropping, stirring was conducted for 1 hour at room temperature. Then, the termination of the reaction was confirmed by gas chromatography. With the addition of 300 mL of water, a reaction solution was completely dissolved therein, followed by adding 500 mL of 2N hydrochloric acid thereto. The reaction solution was separated into an organic layer and a water layer, followed by extracting the water layer with 500 ml of diisopropyl ether. Subsequently, the organic layer was rinsed with 500 ml of saturated brine, followed by drying with anhydrous sodium sulfate. Thereafter, a solvent was distilled off, thereby obtaining 485 g (82% yield, 93% purity) of 2-bromo-2,2-difluoroethyl pivalate in the form of a light yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][NH:13][C:14](=O)[CH3:15].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:11][CH2:12][N:13]=[C:14]2[CH3:15]
Reactant: COc1cccc(CCNC(C)=O)c1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc2c(c1OC)CCN=C2C

Procedure:
In close analogy to the procedure described above, N-[2-(2,3-dimethoxy-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:17][NH2:18]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:18][CH3:17])=[O:11])[CH2:7]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 5.6 g (0.02 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was stirred while 5 mL (0.06 mole) of 40% aqueous methylamine was added slowly and stirring was continued for 18 h. The reaction mixture was diluted with 200 mL of ice water, and the solid which formed was collected by filtration (6.9 g). The crude wet solid was recrystallized from ethanol/water to yield 3.65 g (66.3%) of greenish-gray plate-like crystals, mp 158°-159° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:23]=[N:22][N:21]([CH:24]4[CH2:28][CH:27]([OH:29])[CH:26]([OH:30])[CH:25]4[OH:31])[C:13]=3[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si](Cl)(C(C)(C)C)(C)[CH3:33].N1C=CN=C1>CN(C)C=O>[CH3:33][N:10]([CH:8]1[CH2:9][CH:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]1[C:12]2[N:23]=[N:22][N:21]([CH:24]3[CH2:28][CH:27]([OH:29])[CH:26]([OH:30])[CH:25]3[OH:31])[C:13]=2[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(O)C(O)C3O)c2n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCSc1nc(N(C)C2CC2c2ccccc2)c2nnn(C3CC(O)C(O)C3O)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the product of step d) (1.79 g), tert-butyldimethylsilylchloride (1.22 g) and imidazole (1.10 g) in N,N-dimethylformamide (3 ml) was stirred at ambient temperature for 24 hours. Further tert-butyldimethylsilylchloride (1.0 g) was added and the mixture stirred for a further 6 hours. The reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, ethyl acetate: hexane 1:20 as eluant) to afford the sub-title compound (2.43 g).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].N#N.Br[C:20]1[CH:42]=[N:41][C:23]2[N:24]([CH2:39][CH3:40])[C:25]3[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:26]=3[N:27]([CH3:30])[C:28](=[O:29])[C:22]=2[CH:21]=1>CN(C=O)C.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>[CH2:39]([N:24]1[C:23]2[N:41]=[CH:42][C:20]([CH2:3][CH:2]=[CH2:1])=[CH:21][C:22]=2[C:28](=[O:29])[N:27]([CH3:30])[C:26]2[CH:31]=[CH:32][C:33]([C:35]([F:38])([F:37])[F:36])=[N:34][C:25]1=2)[CH3:40]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(C(F)(F)F)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(c1)C(=O)N(C)c1ccc(C(F)(F)F)nc1N2CC
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 103.2 %

Procedure:
Allyltributyltin (98 μL, 0.32 mmol) and Pd(Ph3P)4 (16 mg, 0.02 mmol) were added to a degassed (N2 through solution for 30 min) solution of 8-bromo-5,11-dihydro-11-ethyl-5-methyl-2-(trifluoromethyl)-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (11 mg, 0.27 mmol) in DMF (1.4 mL) at room temperature. The mixture was stirred at 90° C. for 1.5 h then was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 8:2 to 7:3) to give the title compound (101 mg, 99% yield).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[CH2:35]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)[CH2:36][CH2:37][CH3:38].[BH4-].[Na+]>CO.O>[CH2:12]([N:9]1[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C@@H:3]([NH:2][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([O:39][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:41][CH:42]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
2-Amino-1-(4-benzyl-piperazin-1-yl)-(S)-3-phenyl-propan-1-one hydrochloride (500 mg, 1.26 mmol) were dissolved in MeOH (5 mL), DIPEA (359 mg, 2.77 mmol) and 4-n-butoxybenzaldehyde (226 mg, 1.26 mmol) was added and the mixture was heated to reflux for 2 h, cooled again to rt followed by slow addition of sodium borohydride (48 mg, 1.26 mmol) in portions. Stirring was continued for 15 min. Water (1 mL) was added and the solvents were removed under reduced pressure. The residue was taken up in diethylether (5 mL), washed with 10% aq. citric acid (5 mL) and water (5 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give 411 mg (67%) of 1-(4-benzyl-piperazin-1-yl)-2-(4-butoxy-benzylamino)-(S)-3-phenyl-propan-1-one. LC-MS: tR=0.74 min; [M+H]+=486.43.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(N(CC)CC)C>C(Cl)Cl>[NH2:10][C:8]([C:3]1([NH:2][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[Cl:11])[CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:9]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC(=O)C1(N)CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)C1(NC(=O)c2ccccc2Cl)CCCC1
Reaction time: 3 h

Procedure:
To a stirred solution of 1-aminocyclopentanecarboxamide hydrochloride (0.46 g, 2.79 mmol) in DCM (4 mL), cooled to 0° C., were added 2-chlorobenzoyl chloride (0.73 g, 4.19 mmol) and triethylamine (0.97 mL, 6.99 mmol). After stirring for 3 h, the precipitate in the reaction mixture was filtered to give the title compound.