Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:43][CH2:44][C:45]1[C:46]([F:62])=[C:47]([O:52][C:53]2[CH:54]=[C:55]([CH:58]=[C:59]([Cl:61])[CH:60]=2)[C:56]#[N:57])[C:48]([Cl:51])=[CH:49][CH:50]=1>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([NH:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([O:52][C:53]2[CH:54]=[C:55]([C:56]#[N:57])[CH:58]=[C:59]([Cl:61])[CH:60]=2)[C:46]=1[F:62])=[O:9]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1[nH]ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]ccc3Br)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
To a solution of 3-bromo-1H-pyrrole-2-carboxylic acid (0.2 g, 0.684 mmol) in DMF (2 mL) was added HATU (0.48 g, 1.262 mmol), DIPEA (0.270 ml, 1.547 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.39 g, 1.253 mmol). The reaction mixture was stirred at RT overnight. Water (5 ml) and EtOAc (10 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (3×10 mL), the organic layers combined, dried over sodium sulfate, filtered and evaporated. Purification was accomplished by RPHPLC. Further purification by RPHPLC was required. The desired fractions were collected, neutralized with sat. sodium bicarbonate and extracted with EtOAc (3×10 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated to afford 3-bromo-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-pyrrole-2-carboxamide (0.029 g, 8.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.87 (br. s., 1H) 7.96 (t, 1H) 7.83 (s, 1H) 7.46-7.54 (m, 3H) 7.40 (t, 1H) 6.96 (t, 1H) 6.25 (t, 1H) 4.56 (d, 2H). MS: m/z 479.9 (M−1).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]1([F:35])[C:17]([CH3:19])([CH3:18])[O:16][CH2:15][C:14]([NH2:20])=[N:13][C@@:12]1([C:22]1[CH:27]=[C:26]([C:28]#[C:29][Si](C)(C)C)[CH:25]=[CH:24][C:23]=1[F:34])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[NH2:20][C:14]1[CH2:15][O:16][C:17]([CH3:19])([CH3:18])[C:11]([F:35])([F:10])[C@:12]([C:22]2[CH:27]=[C:26]([C:28]#[C:29][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=3)[CH:25]=[CH:24][C:23]=2[F:34])([CH3:21])[N:13]=1
Reactant: N#Cc1ccc(I)nc1
Reactant: CC1(C)OCC(N)=N[C@](C)(c2cc(C#C[Si](C)(C)C)ccc2F)C1(F)F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(C#Cc3ccc(C#N)cn3)ccc2F)C1(F)F
Temperature: 40 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
A dried flask was charged under an atmosphere of argon with a solution of 6-iodo-nicotinonitrile (25 mg, 109 μmol) and (R)-6,6-Difluoro-5-(2-fluoro-5-trimethylsilanylethynyl-phenyl)-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine (50 mg, 131 μmol) in dimethylformamide (368 μl) (solution A). A second dried flask was charged under an atmosphere of argon with dimethylformamide (368 μl), then successively with bis(triphenylphosphine)palladium(II)chloride (5.47 mg, 7.6 μmol), triphenylphoshine (1.14 mg, 4.4 μmol), copper(I)iodide (0.42 mg, 2.1 μmol), triethylamine (55.2 mg, 0.545 mmol), and tetrabutylammoniumiodide (41.1 mg, 109 μmol) were added. The mixture was heated to 40° C., and solution A was added dropwise. The temperature was raised to 60° C. and a solution of tetrabutylammoniumfluoride (1M in tetrahydrofuran; 142 μl) was added dropwise. Stirring was continued for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 50:50 as the eluent. The 6-[3-((R)-3-amino-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenylethynyl]-nicotinonitrile (18 mg, 40% yield) was obtained as a colorless oil. MS (ISP): m/z=413.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27][N:28]1[CH2:33][C@H:32]2[CH2:34][C@@H:29]1[CH2:30][NH:31]2.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:31]3[CH2:30][C@H:29]4[CH2:34][C@@H:32]3[CH2:33][N:28]4[CH3:27])=[O:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CN1C[C@H]2C[C@@H]1CN2
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN1C[C@H]2C[C@@H]1CN2C(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.9 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (26 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 63 as a solid (11 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+]>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].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:17]([C:19]1[N:23]([CH3:24])[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CNS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1C(F)(F)F
Reaction time: 16 h
Yield: 46.8 %

Procedure:
According to general procedure B, 4-bromo-N-methyl-2 (trifluoromethyl)benzenesulfonamide (178 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (83 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-methyl-2-(trifluoromethyl)benzenesulfonamide (90 mg, 47%) was provided after purification. MS (ESI) m/z 343. HPLC purity 99.2% at 210-370 nm, 9.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.[CH3:12][O-:13].[Na+].[OH-].[Na+]>CC#N.CO>[CH3:12][O:13][C:2]1[O:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: CCOC(=O)c1cnc(Cl)o1
Reactant: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: COc1ncc(C(=O)O)o1
Yield: 69.9 %

Procedure:
To a solution of ethyl 2-chlorooxazole-5-carboxylate (510 mg, 2.90 mmol) in anhdryous MeCN (10 mL) and anhydrous MeOH (10 mL) is added NaOMe (628 mg, 11.62 mmol). The crude is stirred at reflux for 2 hrs. To this crude is added additional MeOH. The crude is refluxed for another 4 hrs. The crude is cooled and then concentrated and is redissolved in MeOH (10 mL). To this crude is added 1 N NaOH (10 ml, 10 mmol). The crude is stirred at room temperature for 3 hrs. The crude is quenched with concentrated HCl, PH adjusted to 7 via pH paper indicator. The crude is concentrated to remove MeOH. The crude is diluted in water. The aq. layer is acidified with concentrated HCl and diluted in EtOAc. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated to give 2-methoxyoxazole-5-carboxylic acid (290 mg). This acid is used without further purification. HPLC retention time=0.58 minutes (condition B); MS 144.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:31])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[C:19]([C:28](=[O:30])[CH3:29])=[CH:18]1)=[O:8].[N-:36]=[N+:37]=[N-:38].[Na+].Cl>O.C(O)(C)C.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:31])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[NH:38][N:37]=[N:36][N:27]=3)[CH:24]=2)[C:19]([C:28](=[O:30])[CH3:29])=[CH:18]1)=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(C#N)ccc12
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(-c3nnn[nH]3)ccc12
Temperature: 130 °C

Procedure:
To a suspension of (2S,4R)-1-[2-(3-acetyl-6-cyano-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (prepared as described in Example 616 (45.0 mg, 0.09 mmol) in water (2 mL) and isopropanol (1 mL) at RT were added sodium azide (24.0 mg, 0.360 mmol) and zinc bromide (40.0 mg, 0.180 mmol). The mixture was heated to 130° C. for 10 h in a microwave apparatus (Personnal Chemistry, Biotage). After cooling to RT, a 6N HCl solution was added to the mixture, followed by extraction with EtOAc (3×). The combined organics were washed with brine, dried (phase separator) and concentrated in vacuo. Purification of the residue by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) afforded after lyophilization the title compound as solid. MS (LC/MS): 542.0 [M+H]+; tR (HPLC conditions k): 3.15 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[CH:38])=[CH:33][CH:32]=1.CCN(CC)CC>C1COCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[OH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[C:38][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=2)=[CH:33][CH:32]=1
Reactant: NCc1ccc(I)cc1
Reactant: C#Cc1ccc(CO)cc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NCc1ccc(C#Cc2ccc(CO)cc2)cc1
Reaction time: 8 h

Procedure:
A mixture of 4-iodo-(aminomethyl)-benzene (7.4 mmol), palladium acetate (0.015 mmol), triphenylphosphine (0.18 mmol), and CuI (0.18 mmol) in anhydrous THF (40 mL) is thoroughly degassed by purging under Ar. To this solution under Ar is added 4-hydroxymethylphenylacetylene (7.4 mmol) and Et3N (11 mmol). The mixture was then incubated at RT with stirring overnight. The mixture is diluted with EtOAc (150 mL) and the solids are removed by filtration through Celite. The crude residue obtained from the filtrate is purified by flash column chromatography (silica, 1:1 hexane:Et2O) to give the product as a slightly yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][CH2:29]Br)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][CH2:29][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(CN2CCC(CCCBr)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(CN2CCC(CCCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 57.8 using 3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-propyl-bromide (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][N+:21]=1[O-:29].C(N(CC)CC)C>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][N+:21]=2[O-:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc[n+]([O-])c(NCCCOc2cccc(CN3CCCCC3)c2)c1
Temperature: 0 °C
Yield: 43.8 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine 6.21 g), 2-chloro-4-nitropyridine-N-oxide (4.36 g) and triethylamine (6.32 g) were stirred, in ethanol (30 ml), under reflux for 31/2 hours. The reaction mixture was cooled gradually to 0° C. to yield 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-4-nitropyridine-N-oxide (4.23 g), m.p. 90°-90.5° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Br:13][C:14](=[CH2:28])[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27].[CH2:29]([O:36][C:37]([NH:39][C@H:40]([CH2:44][CH:45]=[CH2:46])[C:41](O)=[O:42])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[Br:13][C:14](=[CH2:28])[CH2:15][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27])[C:41]([C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:44][CH:45]=[CH2:46])=[O:42]
Reactant: C=C(Br)CNCc1ccc(OC)cc1OC
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=C)Br)Cc1ccc(OC)cc1OC
Yield: 58.1 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (55 mg, 0.285 mmol) was added to a solution of 2-bromo-N-(2,4-dimethoxybenzyl)prop-2-en-1-amine (73 mg, 0.256 mmol) and (2R)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid (71 mg, 0.285 mmol) in dichloromethane (5 mL). After 18 h the mixture was concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (77 mg). MS 517 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH:15]([CH2:24][CH3:25])[C:16]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])=[O:17].O>CN(C=O)C>[CH2:22]([O:21][CH2:20][CH2:19][O:18][C:16]([CH:15]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7])[CH2:24][CH3:25])=[O:17])[CH3:23]
Reactant: O=Cc1ccc[nH]1
Reactant: CCOCCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOC(=O)C(CC)n1cccc1C=O
Yield: 62 %

Procedure:
A mixture consisting of pyrrole-2-carboxaldehyde (9.5 g, 0.1 mole), anhydrous potassium carbonate (27.6 g, 0.2 mole) and 2-ethoxyethyl α-bromobutyrate (23.6 g, 0.105), as previously described, were kept under stirring in 20 ml DMF at room temperature for 12 hours. The reaction mixture was carefully poured into water, extracted with ethylacetate and the extracts were dried on sodium sulfate. After evaporation of the solvent, 15.5 g of 1-[1-(2-ethoxyethoxycarbonyl)-propyl]-2-formyl pyrrole were obtained as a brown oil, which was used in the subsequent step without any further purification.
Reaction SMILES: F.[CH3:2][N:3]([CH3:38])[C:4]([C:6]1[N:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:37])[CH2:25][O:26][Si](C(C)C)(C(C)C)C(C)C)[CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=1)=[O:5]>C1COCC1>[CH3:38][N:3]([CH3:2])[C:4]([C:6]1[N:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:37])[CH2:25][OH:26])[CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=1)=[O:5]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: F
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A solution of hydrogen fluoride (70% in pyridine, 3.25 mL) was added to methyl 3-[5-(dimethylcarbamoyl) pyrazin-2-yl]oxy-5-[(2S)-1-tripropan-2-ylsilyloxypropan-2-yl]oxy-benzoate in THF (300 mL) in a PTFE vessel and the resulting solution stirred for 18 hours at room temp. Further hydrogen fluoride solution (70% in pyridine, 3.25 mL) was added and the reaction stirred for an additional 66 hours. The reaction was quenched by the very careful addition of saturated aqueous sodium bicarbonate solution until the solution reached pH 8. The aqueous layer was extracted with ethyl acetate (2×500 mL) and the combined organics dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica eluting with 25 to 100% ethyl acetate in isohexane to afford the product (13.2 g, 98%). 1H NMR δ (CDCl3) 1.32 (3H, d), 1.93 (1H, d), 3.17 (6H, d), 3.74-3.79 (1H, m), 3.91 (3H, s), 4.54-4.60 (1H, m), 6.96 (1H, t), 7.43 (1H, d), 7.51 (1H, d), 8.36 (1H, d), 8.53 (1H, d); m/z 376 (M+H+)
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].Br[C:23]1[CH:24]=[CH:25][C:26]([CH:29]=[O:30])=[N:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH:29]([C:26]1[N:27]=[CH:28][C:23]([C:16]2[CH:17]=[CH:18][C:12]3[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:14][C:13]=3[CH:15]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Reactant: O=Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C=O)nc3)cc2C1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
A mixture of (4-{[(1,1-dimethylethyl)oxycarbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (500 mg, 1.7 mmol), 5-bromopicolinaldehyde (380 mg, 2.0 mmol), cesium carbonate (1.66 g, 5.0 mmol), and dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (125 mg, 0.17 mmol) in dioxane (5.0 mL) and water (1.0 mL) was degassed with nitrogen, and then stirred at 90° C. with microwave irradiation for 30 min. The reaction mixture was cooled to room temperature, and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×), the combined organic layers were washed with brine (1×), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (hexanes/ethyl acetate 4:1) provided 1,1-dimethylethyl 7-(6-formylpyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxylate (580 mg, 96% yield) as a colorless solid. MS (EI) for C20H22N2O4: 355 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][C:3]=1[CH3:13].[Li]C(C)(C)C.C1C[O:22][CH2:21]C1>>[CH:21]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][C:3]=1[CH3:13])=[O:22]
Reactant: C1CCOC1
Reactant: Cc1cc(C(C)(C)C#N)ccc1Br
Agent: [Li]C(C)(C)C
Product: Cc1cc(C(C)(C)C#N)ccc1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
2-(4-bromo-3-methylphenyl)-2-methylpropanenitrile (3.31 g, 13.9 mmol) is dissolved in dry THF (80 mL). The mixture is cooled to −78° C. and tert-BuLi (1.7 M in pentane, 18 mL, 30.6 mmol) is added. After 30 minutes, the reaction is quenched with DMF (10 mL), volatiles are evaporated and the residue purified by normal phase MPLC (SiO2, heptane to heptane/EtOAc 3:1), giving 2-(4-formyl-3-methylphenyl)-2-methylpropanenitrile (1.89 g, 10.2 mmol, 73%) as a colorless liquid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.70 (s, 6H) 2.64 (s, 3H) 7.49 (s, 1H) 7.55 (dd, J=8.01, 2.15 Hz, 1H) 7.86 (d, J=7.81 Hz, 1H) 10.22 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11](=[O:17])[CH:12]=[CH:13][N:14]([CH3:16])[CH3:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:11](=[O:17])[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CN(C)C=CC(=O)c1cc(N)cc2c1OCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCC(=O)c1cc(N)cc2c1OCC2
Yield: 87.2 %

Procedure:
A solution of 1-(5-amino-2,3-dihydrobenzofuran-7-yl)-3-dimethylamino- propene-1-one (D14) (400 mg) in dry tetrahydrofuran (9 ml) was added to a stirred suspension of lithium aluminium hydride (46 mg) in dry tetrahydrofuran (9 ml) at 0° C. under argon. The mixture was stirred at this temperature for 1/4 h then treated sequentially with water (0.046 ml), 10% NaOH (0.068 ml) and water (0.12 ml). After a further 1/4 h stirring at room temperature the mixture was filtered through kieselguhr, and washed with dry tetrahydrofuran, and the solvent was evaporated under reduced pressure to give the title compound as a yellow/orange solid (352 mg, 87%).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)[CH3:2].Cl.[C:17]1([C:23]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]3[CH:27]([CH2:28][NH:29][CH2:30]3)[C:26](=[O:32])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[C:33]1([C:23]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:31]3[CH:27]([CH2:28][N:29]([C:11](=[O:13])[CH2:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]([CH2:1][CH3:2])[CH2:14][CH3:15])[CH2:30]3)[C:26](=[O:32])[CH2:25][CH2:24]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CCN(CC)c1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
N,N'-Carbonyldiimidazole (0.86 g) is added to a solution of 2-diethylaminophenylacetic acid (1.1 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred at +5° C. for 30 minutes and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.73 g) and triethylamine (1.48 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 24 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 3 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (30/80 by volume) and collecting 125 cc fractions. Fractions 12 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (15 cc) and isopropyl ether (50 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-(2-diethylaminophenyl)acetyl]-4-perhydroisoindolone (1.6 g) is obtained in the form of white crystals melting at 160° C.