Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(=O)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@H:14]([CH3:31])[C@:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(O)(Cn1cncn1)c1cc(F)ccc1F
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 70 °C
Yield: 45 %

Procedure:
A solution of the racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (4.4 g) and (1R)-10-camphorsulfonic acid (2 g) in toluene (40 ml) containing glacial acetic acid (0.6 ml) was warmed up to approximately 70° C., then allowed to cool slowly to 20° C., seeded with the pure enantiomeric salt whereupon the pure enantiomeric salt start to crystallize out. After ca. 2 hrs at this temperature the solid was collected, washed with cold toluene and dried. The crystals were taken with a solvent mixture of methylenechloride/water and after addition of aqueous saturated sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated and the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 2 g (45% yield, 99% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]2[C:18]#[N:19])=[O:7])=[CH:4][CH:3]=1.C(=O)(O)[O-:23].[Na+].OO>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]2[C:18]([NH2:19])=[O:23])=[O:7])=[CH:20][CH:21]=1
Reactant: N#CC1C=Cc2ccccc2N1C(=O)c1ccc(F)cc1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)C1C=Cc2ccccc2N1C(=O)c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
1-(4-Fluorobenzoyl)-1,2-dihydro-quinoline-2-carbonitrile (24.0 g) was dissolved in acetone (500 mL). Solid sodium bicarbonate (15 g) was added. The mixture was stirred for 10 minutes. 30% Hydrogen peroxide solution (300 mL of a 30% solution) was added drop-wise. Stirring was continued for 30 minutes. The mixture was then warmed slowly until a solution formed, then stirred at ambient temperature for 2 hours. The acetone was evaporated under vacuum. The aqueous residue was diluted with water (100 mL), and acidified with 1N HCl. The mixture was extracted with ethyl acetate (500 mL). The organic extract was washed with water (300 mL), dried over anhydrous sodium sulfate, then concentrated. Hexane was added to the precipitation point. The solid was collected and dried to give the title compound as a white solid, m. p. 149-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[N:14]2[C:9]([CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13]2)=[CH:8][C:7]=1[CH3:19])=O.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][C:6]1[N:14]2[C:9]([CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13]2)=[CH:8][C:7]=1[CH3:19]
Reactant: COC(=O)c1ccc2cc(C)c(C(=O)c3ccc(Cl)cc3Cl)n2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(C)c(Cc3ccc(Cl)cc3Cl)n2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
To a solution of methyl 3-(2,4-dichlorobenzoyl)-2-methylindolizine-6-carboxylate (2.34 g) in tetrahydrofuran (47 ml) was dropwise added a borane-dimethylsulfide complex (10.0 M, 6.5 ml) under ice-cooling. The mixture was stirred for 4 hr at room temperature. To this reaction mixture was carefully added dropwise 1N hydrochloric acid (6.5 ml) under ice-cooling, and the mixture was stirred for 30 min at room temperature. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and the resulting product was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the objective compound (490.4 mg) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C@@H:7]([CH2:12][CH2:13][CH3:14])[CH2:6][C@H:5]2[NH:15][CH:16]=[O:17].[C:18](Cl)(=[O:20])[CH3:19].N1C=CC=CC=1>C(Cl)Cl>[C:18]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[C@H:5]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:7]1[CH2:12][CH2:13][CH3:14])(=[O:20])[CH3:19]
Reactant: CCC[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1C(C)=O
Reaction time: 1 h
Yield: 68 %

Procedure:
[(cis)-6-Bromo-2-propyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (for a preparation see intermediate 89) (8.0 g, 26.9 mmol) in DCM (100 mL) was added dropwise at room temperature to a mixture of acetyl chloride (6.7 mL, 94.28 mmol) and pyridine (10.85 mL, 134.7 mmol) in DCM (150 mL). The resulting mixture was stirred at this temperature for 1 h then was washed with 1M NaOH aqueous solution, 1M HCl aqueous solution, a saturated NaHCO3 aqueous solution then brine, was dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue by flash chromatography on silica gel (20:1 DCM/MeOH) gave [(cis)-1-acetyl-6-bromo-2-propyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (6.29 g, 18.5 mmol, 68%) as a light orange solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](=[O:40])[CH2:38][CH3:39])[CH2:31][CH2:30]1.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.CO>[OH:40][CH:37]([CH2:38][CH3:39])[CH2:36][O:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:30][CH2:31]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)CC)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)CC)CC2)c2ncnn12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4′-({5-Oxo-4-[trans-4-(2-oxobutoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.64 g) was dissolved in tetrahydrofuran (3 mL) and methanol (6 mL), and sodium tetrahydroborate (0.060 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 74%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30]C)=[C:26]([CH3:32])[CH:25]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[N:7][CH:8]=1)[CH3:2].B(Br)(Br)Br.C[O-].[Na+]>ClCCl>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:20])([F:21])[F:19])=[CH:15][CH:16]=2)[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH3:32])[CH:25]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(N(CCc2ccc(OC)c(C)c2)Cc2ccc(OC(F)(F)F)cc2)nc1
Agent: BrB(Br)Br
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cnc(N(CCc2ccc(O)c(C)c2)Cc2ccc(OC(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine (1.12 g; 2.53 mmol) in dichloromethane (70 ml) was cooled in an ice bath and treated under nitrogen with boron tribromide (1M solution in dichloromethane; 2.78 ml). Allowed to warm to rt and additional boron tribromide (2.53 ml) was added. Stirred for 2 hr and concentrated. Azeotroped 3× with MeOH, redissolved in MeOH and treated with sodium methoxide (0.14 g; 2.53 mmol). Stirred for 30 minutes and concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, filtered and concentrated to afford 4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-methylphenol as a dark brown oil (0.98 g; 90% crude yield) which was used in subsequent steps without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[NH:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:23][C:24]1[N:25]([CH3:29])[N:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:29][N:25]1[C:24]([CH2:23][O:20][C:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]3[CH:9]=[N:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]=3[N:12]=2)=[N:28][CH:27]=[N:26]1
Reactant: O=c1[nH]c2c(cnn2-c2ccccc2)c2ccccc12
Reactant: Cn1ncnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nc2c(cnn2-c2ccccc2)c2ccccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture of 3,4-dihydro-3-phenyl-5H-pyrazolo[3,4-c]isoquinolin-5-one (0.10 g, 0.38 mmol), 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (0.10 g, 0.57 mmol) and cesium carbonate (0.37 g, 1.14 mmol) in dry DMF (2 ml) was stirred at 60° C. under nitrogen for 3 h. Water (30 ml) was added and the mixture was filtered. The solids were washed with diethyl ether (5 ml) and dried in vacuo to give the title compound (0.10 g, 74%) as an off-white powder, m.p. 149-151° C. Found: C, 66.19; H, 4.46; N, 23.71. C20H16N6O.0.25(H2O) requires C, 66.56; H, 4.61; N, 23.29%. δH (400 MHz; CDCl3) 3.98 (3H, s), 5.82 (2H, s), 7.36 (1H, dd, J=7 and 7), 7.52-7.57 (3H, m), 7.83 (1H, dd, J=7 and 7), 7.94 (1H, s), 8.15-8.20 (3H, m), 8.33 (1H, d, J=8), 8.42 (1H, s); m/z (ES+) 356 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][C:6]#[N:7].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]([CH2:2][CH:3]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][C:6]#[N:7])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCC(CO)CCC#N
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(CCC#N)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 66 h
Yield: 82.7 %

Procedure:
To a mixture of 45.50 g (0.323 mol) of crude 4-(hydroxymethyl)heptanenitrile and 53.5 g of t-butyldimethylsilyl chloride in 450 mL of methylene chloride at 3°-4° C., under argon, was added a solution of 67.5 mL (50.1 g, 0.388 mol) of diisopropylethylamine in 67.5 mL of methylenechloride dropwise over 10 min. 3.94 g (32,2 mmol) of 4-dimethylaminopyridine was then added and after stirring at room temperature for 66 hr, the dark reaction mixture was washed with 150 mL of 2N hydrogen chloride solution, 150 mL of water and 150 mL of saturated brine, dried (MgSO4), filtered, and concentrated. The residue was redissolved in methylene chloride, 180 g of silica gel was added and the solvent was removed under vacuum. The residual powder was placed on top of a 23/8"×9" column of 270 g of silica gel and eluted, sequentially, with 1 L of hexane, 1 L of 1:19 ethyl acetate:hexane and 1 L of 1:9 ethyl acetate:hexane; 500-mL fractions were collected. Fractions 3-7 were combined and concentrated in vacuo, and the residue was distilled to give 68.22 g (82.9%) of 4-(t-butyldimethylsiloxymethyl)heptanenitrile, bp 114°-117° C. (0.9-1.0 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:22][C:15]([C:9]2[C:10]3[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=3[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=2[CH3:18])=[O:16])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Nc3ccccc3)c2nc1OC
Reaction time: 40 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and aniline 80 μL (0.84 mmol). Reaction was continued for 40 hours, and the crude product was eluted through a flash column (3:2 hexanes:ethyl acetate), 180 mg (62%), mp 238-240° C.; 1 H NMR (CDCl3): δ 8.34 (s, 1H), 7.81 (d, 2H, J=8.8 Hz), 7.69 (s, 1H), 7.35 (t, 2H, J=7.6, 8.5 Hz), 7.11 (t, 1H, J=6.3, J=7.3 Hz), 4.17 (s, 3H), 4.02 (s, 3H), 2.58 (s, 3H); MS (APCI): m/z 369 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].C[Al+]C.[F:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH2:17][C:16]3[CH:22]=[C:23]([C:25]([O-])=[O:26])[S:24][C:15]=3[C:14]=2[CH:13]=1>ClCCCl>[F:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH2:17][C:16]3[CH:22]=[C:23]([C:25]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:26])[S:24][C:15]=3[C:14]=2[CH:13]=1
Reactant: C1COCCN1
Reactant: O=C([O-])c1cc2c(s1)-c1cc(F)ccc1OC2
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1cc2c(s1)-c1cc(F)ccc1OC2)N1CCOCC1
Yield: 40 %

Procedure:
To a cooled solution (ice/H2O) of morpholine in DCE was added slowly dropwise 2 equiv. of dimethylaluminum chloride. This reaction was stirred for greater than 30 minutes until reaching ambient temperature. Next the reaction was again cooled (ice/H2O) and 8-fluoro-4H-thieno[3,2-c]chromene-2-carboxylate was added as a solid portion wise. The reaction was allowed to equilibrate to ambient temp and monitored by LC/MS. The completed reaction was quenched with an aqueous solution of Na, K-tartrate (20% wt/wt). This mixture was extracted with EtOAc and the organic was washed with saline and dried (MgSO4). The dried org. was concentrated in vacuo to a residue. This residue was not soluble in DMF and 170bp as a white solid was collected by vacuum filtration, Yield=40% of theoretical. MS: (ESI+)=320.5
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Cl)(=[O:30])=[O:29]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:30])=[O:29]
Reactant: O=S(=O)(CCCCCCCl)NCCCCO
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCCCCO
Yield: 95.6 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and N-(4-hydroxybutyl)-6-chlorohexanesulfonamide (543.6 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(4-hydroxybutyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (1001.2 mg) as a pale yellow oil (95.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[N:10]12[CH2:17][CH2:16][C:13]([C:18]([O:20]CC)=O)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>C1COCC1>[N:10]12[CH2:11][CH2:12][C:13]([C:18]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=3)([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[OH:20])([CH2:14][CH2:15]1)[CH2:16][CH2:17]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: OC(c1cccc(F)c1)(c1cccc(F)c1)C12CCN(CC1)CC2
Temperature: 25 °C
Yield: 76.7 %

Procedure:
A solution of 3-fluorophenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1756 g, 0.958 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.242 g, 76.7%). EI-MS m/z 330(M+H+) Rt (1.45 min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[CH2:35]([O:37][C:38](=[O:42])[C@H:39]([CH3:41])[NH2:40])[CH3:36]>>[CH2:35]([O:37][C:38](=[O:42])[C@@H:39]([NH:40][C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH2:9][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[O:33])=[CH:23][CH:22]=2)=[CH:29][CH:28]=1)=[O:31])[CH3:41])[CH3:36]
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)ccn1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Product: CCOC(=O)[C@H](C)NC(=O)c1ccc(-c2ccc([C@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1

Procedure:
In analogy to example 89, step 2, from 4′-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and L-alanine ethyl ester hydrochloride was prepared the title compound as a light yellow oil, MS (ESI+): m/z=535.3 ([M+H]+).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=2)[O:4]1.CCN(C(C)C)C(C)C.Cl[C:32]1[C:37]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:36]([CH3:46])[N:35]=[CH:34][N:33]=1>CN1C(=O)CCC1>[F:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][C:37]2[C:32]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([B:5]5[O:4][C:3]([CH3:21])([CH3:2])[C:7]([CH3:8])([CH3:9])[O:6]5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)=[N:33][CH:34]=[N:35][C:36]=2[CH3:46])=[CH:44][CH:43]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CNCCO3)OC1(C)C
Reactant: Cc1ncnc(Cl)c1Cc1ccc(F)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(N2CCOc3ccc(B4OC(C)(C)C(C)(C)O4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 120 °C
Yield: 79.5 %

Procedure:
To a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (1.4 g, 4.5 mmol) and DIPEA (6.4 mL, 37 mmol) in NMP (24 mL) was added and 4-chloro-5-(4-fluorobenzyl)-6-methylpyrimidine (reagent preparation 5) (1.7 g, 7.3 mmol). The resulting mixture was heated (120° C.) for 12 h and then partitioned between ethyl acetate (100 mL) and 1N aqueous hydrochloric acid (50 mL). The organic layer was washed with additional 1N aqueous hydrochloric acid (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Column chromatography on silica (0-30% ethyl acetate/hexanes) provided 4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1.7 g, 47% yield) as a white foam. MS (EI) for C27H31BFN3O3: 476 (MH+).
Reaction SMILES: [CH:1]([C:4]1([CH3:17])[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:6][C:5]1=[O:16])([CH3:3])[CH3:2].C([Li])CCC.C[O:24][C:25](=O)[C:26]([N:28]([CH3:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].O>O1CCCC1>[CH:1]([C:4]1([CH3:17])[C:5](=[O:16])[NH:6][C:7]([C:9]2[C:14]([C:25](=[O:24])[C:26]([N:28]([CH3:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:8]1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C2=NC(=O)C(C)(C(C)C)N2)nc1
Reactant: COC(=O)C(=O)N(C)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)C(=O)N(C)c2ccccc2)c1
Temperature: -70 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To a stirred solution of 2.5 g(0.011 mole) of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2 -yl)-5-methyl pyridine in 100ml of anhydrous tetrahydrofuran cooled to -70° C. under the presence of nitrogen was added dropwise a 9.68 ml of 2.5 molar n-butyllithium, thus maintaining temperature below -65° C. The solution was stirred at -70° C. for 3 hr and a solution 1.96 g of N-methyl-N-phenyl oxamic acid methyl ester(3.4 g, 0.016 mole) in 10 ml of anhydrous tetrahydrofuran was added dropwise while maintaining temperature below -65° C. After stirring another hour at -70° C., the solution was poured into water and extracted with methylene chloride. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography to produce 1.76 g of pale yellow solid(m.p.=153°~156° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([O:49][Si:50]([CH:57]([CH3:59])[CH3:58])([CH:54]([CH3:56])[CH3:55])[CH:51]([CH3:53])[CH3:52])=[C:45]([Cl:60])[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([O:49][Si:50]([CH:54]([CH3:56])[CH3:55])([CH:57]([CH3:58])[CH3:59])[CH:51]([CH3:53])[CH3:52])=[C:45]([Cl:60])[CH:44]=2)[N:36]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1Cl)(C(C)C)C(C)C
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)cc1Cl)(C(C)C)C(C)C
Yield: 89 %

Procedure:
A mixture of Intermediate E (145 mg, 0.40 mmol) and [5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporated herein by reference, 251 mg, 0.420 mmol) in 1,4-dioxane (4 mL) and DIPEA (110 μL, 0.63 mmol) was stirred at 90° C. for 5.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-12% MeOH in DCM, to give the title compound (288 mg, 89%). LCMS (Method 3): Rt 3.85 min, m/z 811 [MH+].