Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.[CH3:26][O:27][CH2:28][CH2:29][CH2:30][OH:31]>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([O:31][CH2:30][CH2:29][CH2:28][O:27][CH3:26])=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: COCCCO
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: COCCCOc1ccc2c(C(=O)NCC3(O)CCC(F)(F)CC3)c(Cl)ccc2n1

Procedure:
The title compound was synthesized according to the procedure described in example 9 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide and 3-methoxy-propan-1-ol. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (t, J=6.01 Hz, 1H), 8.03 (d, J=9.61 Hz, 1H), 7.77-7.80 (m, 1H), 7.69-7.71 (m, 1H), 7.10 (d, J=9.21 Hz, 1H), 4.68 (s, 1H), 4.45 (t, J=6.41 Hz, 2H), 3.47-3.50 (m, 2H), 3.38-3.39 (m, 2H), 3.25 (s, 3H), 2.01-2.04 (m, 4H), 1.90-2.00 (m, 2H), 1.67-1.72 (m, 4H). m/z: 443.2 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:8]=1)[CH3:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=O)[CH3:17].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:6]2[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=2)[CH2:11][CH2:12]1)[CH3:17]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CCc1cnc(NC2CCNCC2)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3ncc(CC)cn3)CC2)ccc1OC
Temperature: 55 °C
Yield: 38 %

Procedure:
To a solution of (5-ethyl-pyrimidin-2-yl)-piperidin-4-yl-amine (30.9 mg, 0.15 mmol, 1.0 equiv; intermediate C1) and 3-ethoxy-4-methoxy-benzaldehyde (32.4 mg, 0.18 mmol, 1.2 equiv; commercially available) in ethanol (2 mL) was added acetic acid (27.0 mg, 0.45 mmol, 3.0 equiv) and the mixture stirred at 55° C. After 1 h sodium cyano borohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 21.0 mg (38%) of the title compound. MS (ESI): 371.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Br.[NH2:19][CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([CH:25]2[CH2:24][O:23][C:21](=[O:22])[CH:20]2[NH2:19])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1CCOC1=O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Br
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1COC(=O)C1N

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and α-amino-γ-butyrolactone hydrobromide (Aldrich), the title compound was prepared as a solid having a melting point of 174-177° C. The reaction was monitored by tlc on silica gel (Rf=0.52 in 10% methanol/dichloromethane) and purification was by silica gel chromatography.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.[H-].[Na+].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)([O-:20])=[O:19].O>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ccco2)c2ncn(Cc3cccc([N+](=O)[O-])c3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
An ice-cold solution of 6-(2-furyl)1H-purine-2-amine (201 mg, 1 mmol) in DMF (6 mL) was treated with NaH (44 mg, 1.1 mmol), stirred for 30 min, treated with 3-nitrobenzyl bromide (238 mg, 1.1 mmol), stirred at room temperature for 3 h, treated with water and the resulting solid filtered, suspended in methanol, stilled for 30 min, and filtered to give the title compound (201 mg, 60%) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=S)[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][N:23]=[CH:22]1>C(O)C>[C:1]1([CH2:7][N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=[N:29][CH2:28][CH2:27][CH2:26][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCn1ccnc1
Reactant: S=C1c2cccc3cccc(c23)N1Cc1ccccc1
Solvent: CCO
Product: c1ccc(CN2C(=NCCCn3ccnc3)c3cccc4cccc2c34)cc1
Yield: 66.3 %

Procedure:
A mixture of 3.0 g 1-(phenylmethyl)benz[cd]indole-2(1H)-thione (Cc), 1.34 g of 1H-imidazole-1-propaneamine, 10.0 ml ethyl alcohol, and 3.5 g of mercuric acetate is reacted as described in Example 3, giving 2.6 g of the desired product, mp. 90°-93° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CN(CCN)S(C)(=O)=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Product: CN(CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O)S(C)(=O)=O
Yield: 23.7 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and N-(2-aminoethyl)-N-methylmethanesulfonamide (100 mg, 0.657 mmol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-N-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (18 mg, 24% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.31 (br s, 1 H), 8.58 (s, 1 H), 7.49 (s, 1 H), 7.18-7.14 (m, 2 H), 7.05-6.99 (m, 2 H), 4.37 (m, 2 H), 4.14 (s, 2 H), 3.67 (m, 2 H), 3.51 (m, 2 H), 3.41 (m, 2 H), 2.95 (s, 3 H), 2.83 (s, 3 H), 1.83 (m, 2 H); HRMS m/z calcd for C23H28N4O6FS: 507.1714. Found: 507.1712.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].C(N(C(C)C)C(C)C)C.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([C:33]([F:36])([F:35])[F:34])[C:27]([C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=[N:26]1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30]([C:29]2[N:25]([CH3:24])[N:26]=[C:27]([C:37]([F:42])([F:43])[C:38]([F:40])([F:41])[F:39])[C:28]=2[C:33]([F:35])([F:36])[F:34])=[O:31])=[CH:13][C:6]=1[C:7](=[O:8])[NH:9][CH:10]1[CH2:11][CH2:12]1
Reactant: Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
95.3 mg (0.45 mmol) of 5-amino-2-chloro-N-cyclopropylbenzamide, 3.7 mg (0.03 mmol) of N,N-dimethylpyridine-4-amine are dissolved in 2.5 ml of ethyl acetate. The solution is cooled to 0° C. using an ice bath and admixed with 158 μl (0.91 mmol) of N-ethyldiisopropylamine. 100 mg (0.30 mmol) of 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride are suspended in 2.5 ml of ethyl acetate and then added to the cooled reaction solution. The reaction mixture is heated for four hours at 50° C. and then stirred for 16 hours at room temperature. The reaction solution is diluted with 10.0 ml of ethyl acetate. The organic phase is washed three times with 1M hydrochloric acid, twice with 1M sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and filtered and solvent is removed under reduced pressure on a rotary evaporator. This gives 151 mg of N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (97%) as white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][C:5]1([CH3:11])[O:9][C:8](=[O:10])[NH:7][CH2:6]1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>CN(C)C=O>[Cl:3][CH2:4][C:5]1([CH3:11])[O:9][C:8](=[O:10])[N:7]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH2:6]1
Reactant: CC1(CCl)CNC(=O)O1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC(C)(CCl)OC2=O)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 78.2 %

Procedure:
To a mixture was sodium hydride (401 mg, 60% dispersion) in 50 ml of dimethylformamide was added 5-(chloromethyl)-5-methyl-1,3-oxazolidin-2-one (1.00 g, INTERMEDIATE 16) followed by 4-methoxybenzylchloride (1.05 g). The mixture was stirred at 90° C. for 4 h. Excess sodium hydride was quenched by addition of 3 ml of methanol. The sample was then transferred to a Biotage 65i column and purified via column chromatography on a Biotage Horizon eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 50% ethyl acetate in hexanes (over 6 column volumes), and held at 50% ethyl acetate (2 column volumes) to provide the title compound (1.41 g, 78%). Mass spectrum (ESI) 271.9 (M+2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH2:51])[O:46][C:45]=2[CH:52]=1>CN(C=O)C>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH:51][CH2:15][CH2:14][CH2:13][CH2:12][C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:8][CH:7]=3)[O:46][C:45]=2[CH:52]=1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Reactant: COc1ccc2c(c1)OC(CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccc(OC)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
5-Methoxyindole-3-butyric acid (1.0 g, 4.3 mmole), 1-hydroxybenzotriazole hydrate (0.7 g, 5.2 mmole) and 1,3-diisopropylcarbodiimide (1.6 ml, 10.3 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.0 g, 4.3 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as eluant. Evaporation of product-containing fractions gave 1.3 g (74%) of the desired product, (7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-methoxy-1H-indol-3-as an off-white solid.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[C:11]=1[C:12]#[N:13]>O>[OH:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=1[C:12]#[N:13]
Reactant: COc1cccc(OC)c1C#N
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1c(O)cccc1O
Temperature: 210 °C
Yield: 59.9 %

Procedure:
Another potential method utilizes pyridine hydrochloride in place of the boron tribromide. Into a 500 mL 3-neck round bottom flask equipped with stir bar, nitrogen inlet and condenser was charged 2,6-dimethoxybenzonitrile (15.0 g, 91.9 mmol), followed by pyridine hydrochloride (150 g). The mixture was heated to 210° C. for 2 hours and allowed to cool to room temperature. Water was then added to the flask to dissolve the solidified mixture. The aqueous layer was then extracted with ethyl acetate (150 mL) 3 times. The combined organic layer was dried under anhydrous sodium sulfate, and the solvent was removed to yield 7.44 g (60.0%) of a light pink solid, m.p.: 202.8-204.8° C. 1H-NMR (DMSO-d6): 6.39-6.41 (d, 2H, Ar—H), 7.20-7.24 (t, 1H), 10.78 (s, 2H, Ar—O—H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCc1ccc(OC)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1ccc(OC)cc1OCc1ccccc1
Yield: 102 %

Procedure:
Under a nitrogen atmosphere, 18.30 g (120.2 mmol) of 2-ethyl-5-methoxyphenol (2) was dissolved in 150 ml of acetone. To this solution was added 33.24 g (240.5 mmol) of potassium carbonate followed by 15.02 ml (126.3 mmol) of benzyl bromide. The resultant mixture was heated to reflux for 16 hours. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (300 ml) and water (300 ml). The ethyl acetate layer was separated, washed with 1M NaOH (2×200 mL) and brine (1×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield 29.70 g of crude 3-benzyloxy-4-ethyl-1-methoxybenzene (3). Chromatography of the crude product on 400 g of silica gel 60 (EM Science) using 97:3 hexane: ethyl acetate yielded 12.62 g (43%) of 3-benzyloxy-4-ethyl-1-methoxybenzene (3).
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([I:16])[CH:10]=1.[ClH:17]>C(#N)C.[Cu](Cl)Cl>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([Cl:17])=[C:11]([I:16])[CH:10]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Clc1ccc(Br)cc1I
Temperature: 60 °C

Procedure:
tert-Butyl nitrite (3 ml, 25 mmol) is added to a suspension of copper(II) chloride (2.71 g, 20 mmol) in acetonitrile (60 ml) and the mixture is heated with stirring to 60° C. A solution of 4-bromo-2-iodoaniline (5 g, 17 mmol) in acetonitrile (15 ml) is added dropwise, and once the addition is complete the mixture is stirred at 60° C. for 2.5 hours. The mixture is cooled to room temperature, poured into 20% aqueous hydrochloric acid and extracted with diethyl ether. The organic extract is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel to give 4-bromo-1-chloro-2-iodobenzene (4.32 g) as an oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH3:3].[OH:14][C:15]1[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=1>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:14][C:15]2[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=2)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C(=O)Cl)cc1
Reactant: O=c1cc(O)cc[nH]1
Solvent: c1ccncc1
Product: CCCOc1ccc(C(=O)Oc2cc[nH]c(=O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
A 2.14 g quantity of 4-n-propoxybenzoyl chloride was added to a suspension of 1.00 g of 4-hydroxy-2-pyridone in 30 ml of pyridine, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and the concentrate was washed with ethyl acetate and water, thereby producing 1.98 g of the title compound in a yield of 81%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38](=[O:71])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][CH:53]=[C:54]([C:56]2[CH:61]=[CH:60][C:59](B3OC(C)(C)C(C)(C)O3)=[CH:58][CH:57]=2)[N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:59]4[CH:60]=[CH:61][C:56]([C:54]5[NH:55][C:51]([CH:47]6[CH2:48][CH2:49][CH2:50][N:46]6[C:44](=[O:45])[CH:40]([NH:39][C:38]([O:37][CH3:36])=[O:71])[CH:41]([CH3:43])[CH3:42])=[N:52][CH:53]=5)=[CH:57][CH:58]=4)=[CH:20][CH:19]=3)=[CH:15][N:14]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(C(=O)OC(C)(C)C)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 48.1 %

Procedure:
4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-1′-carboxylic acid tert-butyl ester (75 mg, 0.136 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (67.6 mg, 0.136 mmol) under an argon atmosphere. Potassium carbonate (37.5 mg, 0.272 mmol) and Pd(PPh3)4 (15.7 mg, 0.014 mmol) were added, followed by DME (3 mL) and water (0.6 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product (55 mg): LCMS-ESI+: calc'd for C44H57N9O8: 839.9 (M+). Found: 840.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.90-7.81 (m, 10H), 5.58 (m, 1H), 5.43 (m, 1H), 5.25-5.20 (m, 2H), 4.24 (d, J=7.5 Hz, 1H), 4.11 (m, 1H), 3.99 (m, 1H), 3.86 (m, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.46 (d, J=7.2 Hz, 1H), 2.59 (m, 1H), 2.22-2.10 (m, 5H), 1.53 & 1.44 (s, 9H) 1.04-0.89 (m, 12H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)Cc1ccccc1O
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccccc1OCc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (2.72 g, 19.9 mmol) and diisopropyl azodicarboxylate (DIAD, 3.67 g, 18.2 mmol) in THF (30 ml) was added drop wise to a solution of Ethyl 2-(2-hydroxyphenyl)acetate (3 g, 16.6 mmol) and triphenylphosphine (4.76 g, 18.2 mmol) in THF (80 ml). The reaction mixture was stirred at room temperature for 6 hours, diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:24])[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][C:13](Cl)=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(OCC)(=O)C.O>[Cl-].[Na+].O>[CH2:1]([NH:8][C:9](=[O:24])[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][C:13]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)NCc1ccccc1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 5.0 g (14.8 mMol) of N-benzyl-6-chloro-4-o-tolyl-nicotinamide and 25 ml morpholine was heated to 100° C. for 3.5 hours. After cooling to room temperature, extractive work-up with ethyl acetate, water and brine gave 5.7 g (100%) N-benzyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide as a yellow powder.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][CH:6]([NH:13][CH2:14][CH2:15][CH3:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:21](OCC)(OCC)(OCC)[CH3:22]>>[ClH:1].[CH3:21][C:22]1[N:13]([CH2:14][CH2:15][CH3:16])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[N:2]=1
Reactant: CCCNC(Cc1ccccc1N)c1ccccc1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Product: CCCN1C(C)=Nc2ccccc2CC1c1ccccc1

Procedure:
90 ml of Ethanolic hydrogen chloride is added dropwise to a stirred suepnsion of 9.00 g of 2-amino-α-phenyl-N-proylphenethylamine in 90 ml of triethyl orthoacetate. After complete addition, the mixture is refluxed for 2 hours. The ethanol is slowly distilled from the mixture and additional ethanolic hydrogen chloride (50 ml) is added. The mixture is then distilled to a volume of 20-30 ml. 100 ml of ether is added causing precipitation of the hydrochloride salt. The salt is collected, washed with ether (100 ml) and dried to give white crystals, mp 272°-275° C. of 4,5-dihydro-2-methyl-4-phenyl-3-propyl-3H-1,3-benzodiazepine hydrochloride.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18]([NH2:26])(=[S:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]2[S:25][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=3)[N:26]=2)[CH:20]=1
Reactant: NC(=S)c1cccnc1
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(-c2cccnc2)nc1-c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 22.8 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (1.0 g, 3.4 mmol) in 20 mL of tetrahydrofuran was added thionicotinamide (0.46 g, 3.4 mmol). The resulting mixture was stirred at 65° C. for 16 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was triturated with chloroform, taken up in ethyl acetate, washed with saturated aq Na2CO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with ethyl acetate left the title compound as an off-white solid (0.26 g, 23%). MS (ESI) 336.1 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22]>>[CH2:1]([S:8][C:9]1[C:10]([CH3:16])=[C:11]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Br)cccc1SCc1ccccc1
Reactant: O=C1CCCN1
Product: Cc1c(SCc2ccccc2)cccc1N1CCCC1=O

Procedure:
Intermediate 24 (14.08 g, 48 mmol) and pyrrolidin-2-one (4.9 g, 57.6 mmol) were converted to intermediate 25 as described in example 1; 1.5). The crude product (14.6 g) was used without purification in the next step.