Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:48]=[CH:47][C:34]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=2[NH2:46])=[O:36])=[CH:33][CH:32]=1>>[NH2:46][C:39]1[CH:40]=[C:41]([O:44][CH3:45])[CH:42]=[CH:43][C:38]=1[NH:37][C:35]([C:34]1[CH:47]=[CH:48][C:31]([CH2:30][NH:29][C:26]([C:22]2[C:23]3[C:18](=[CH:17][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)=[O:27])=[CH:32][CH:33]=1)=[O:36]
Reactant: COc1ccc(NC(=O)c2ccc(CN)cc2)c(N)c1
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1ccc(NC(=O)c2ccc(CNC(=O)c3cccc4cc(Oc5ncnc6cc(OC)c(OC)cc56)ccc34)cc2)c(N)c1
Yield: 81.9 %

Procedure:
The title compound (51.6 mg, 82% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-amino-4-methoxyphenyl)benzamide (32.5 mg, 0.12 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 630 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[C:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[C:13]([F:23])=[CH:12][N:11]=1.[F:24][CH2:25][C:26](OCC)=[O:27]>O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.C1COCC1>[Br:9][C:10]1[N:11]=[C:12]([C:26](=[O:27])[CH2:25][F:24])[C:13]([F:23])=[C:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:15]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)ncc1F
Reactant: CCOC(=O)CF
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)CF)c1F
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 93.7 %

Procedure:
To a 3-neck 500-mL round bottomed flask was added THF (180 mL). The solvent was cooled to −78° C. and lithium diisopropylamide, (Aldrich; 40.3 mL, 81 mmol, 2.0 M solution in tetrahydrofuran/heptane/ethylbenzene) was added over 2 min. To the solution was added 2-bromo-5-fluoro-4-(triethylsilyl)pyridine (11a, synthesized according to procedure in WO 2012/095469 A1; 18.0 g, 62.0 mmol) in 5 mL THF over 5 min. The temperature was not allowed to go above −70° C. during the addition. After 50 min, ethyl fluoroacetate (Aldrich; 7.79 mL, 81 mmol) was added over 3 min. The temperature was not allowed to go above −60° C. during the addition. The solution was stirred at −78° C. for 10 min and then the cold bath was removed and the solution was allowed to warm to −40° C. At that point the solution was poured into a solution of 1 N HCl/10% NH4Cl (1:1, 200 mL). The solution was extracted with EtOAc (3×200 mL) and the combined extracts were washed with brine (100 mL), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 20% EtOAc/hexane) afforded 1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethanone (20.35 g, 58.1 mmol, 94% yield) as a yellow oil. MS m/z=350.0 [M+H]+. Calculated for C13H18BrF2NOSi: 349.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][O:15][CH3:16].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[Sn](CCCC)(CCCC)CCCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][O:15][CH3:16]
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccc(-c3ccco3)cc21
Temperature: 100 °C
Yield: 67.5 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (1.24 g, 4.4 mmol) and PdCl2(PPh3)2 (200 mg, 0.28 mmol) and 2-furyltributyltin (2 g, 5.6 mmol) in N,N-dimethylformamide (20 mL) is degassed and heated at 100° C. for 1 hour. Upon cooling to room temperature, the product precipitated out. After filtration, the precipitate is washed with Et2O and dried to provide the desired product (800 mg, 68%). MS (ESI): 270.1 (M+1)+1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.C(N)(=O)C1C=CC=CC=1.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:43]3[CH:44]=[CH:45][C:40]([C:39]([F:50])([F:49])[F:38])=[CH:41][CH:42]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: NC(=O)c1ccccc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3ccc(C(F)(F)F)cc3)C2=O)cc1
Yield: 85 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-(4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-(trifluoromethyl)phenyl boronic acid instead of phenyl boronic acid to obtain the title compound (85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.CS(O)(=O)=O.[CH2:14](O)[CH2:15]C>>[CH2:1]([O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1)[CH2:14][CH3:15]
Reactant: CCCO
Reactant: COC1=CC(=O)NC1
Agent: CS(=O)(=O)O
Product: CCCOC1=CC(=O)NC1

Procedure:
A mixture of 4-methoxy-3-pyrrolin-2-one (3 g), 1-propanol (3.5 ml) and methanesulfonic acid (0.2 g) was refluxed for 2 hours in the presence of 3A molecular sieves. Solvent was removed from the mixture, and the residue chromatographed on silica gel, eluting with 2% methanol in methylene chloride, to give 4-n-propoxy-3-pyrrolin-2-one.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[CH2:19][CH2:20][CH3:21])=[N:5][N:6]=1.[C:22]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:27])[CH2:23][C:24]([O-])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][S:7][C:4]2[S:3][C:2]([NH:1][C:24](=[O:25])[CH2:23][C:22]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:27])=[N:6][N:5]=2)=[C:10]([CH2:19][CH2:20][CH3:21])[C:11]=1[OH:18])(=[O:17])[CH3:16]
Reactant: COc1ccc(COC(=O)CC(=O)[O-])cc1
Reactant: CCCc1c(CSc2nnc(N)s2)ccc(C(C)=O)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(CSc2nnc(NC(=O)CC(=O)OCc3ccc(OC)cc3)s2)ccc(C(C)=O)c1O

Procedure:
To a solution of 0.14 g of 2-amino-5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazole obtained in Example 5 and 0.15 g of mono-p-methoxybenzyl malonate in 3 ml of pyridine were added 0.15 g of dicyclohexylcarbodiimide and a catalytic amount of p-toluenesulfonic acid. The resultant mixture was stirred at room temperature for 6 hours. During the stirring, 0.15 g each of mono-p-methoxybenzyl malonate and dicyclohexylcarbodiimide were supplemented to the system. After completion of the reaction, ethyl acetate was added to the system. After insoluble matters were filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in chloroform. The solution was washed with, in sequence, 1N hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and water and then, dried over anhydrous magnesium sulfate. The solvent was then removed by distillation. The resultant residue was subjected to silica gel column chromatography followed by elution with a mixture of chloroform-methanol (4:1) The eluate was recrystallized from isopropyl alcohol to give 0 04 g of p-methoxybenzyl 3-[[ 5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]amino]-3-oxopropionate.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[B:6]([O:15][CH:16](C)C)([O:11]C(C)C)OC(C)C.[CH2:19]1[CH2:23]O[CH2:21][CH2:20]1>>[CH3:5][CH:4]1[CH2:16][O:15][B:6]([OH:11])[C:23]2[CH:19]=[CH:20][CH:21]=[CH:2][C:3]1=2
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Product: CC1COB(O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 250 mL round bottom flask, 3.2054 g (10.2330 mmol, 1.0 eq) of the protected alcohol was dissolved in 83 mL of reagent-grade THF under N2 atmosphere. The solution was then cooled to −78° C. using a dry ice/acetone bath. 4.50 mL (11.2563 mmol, 1.1 eq) of the n-BuLi (2.5 M in hexanes) was added dropwise to the solution. The reaction was allowed to stir for 30 min while maintaining lowered temperature. 3.54 mL (15.3495 mmol, 1.5 eq) of the triisopropyl borate was added to the reaction slowly at −78° C. Upon complete addition of the triisopropyl borate, the reaction was allowed to gradually warm to room temperature overnight, maintaining inert atmosphere. The following morning, the reaction was quenched by the slow addition of 20 mL of 6M HCl (aq). The reaction was allowed to stir for 1 h. The reaction solution was then diluted with 50 mL of EtOAc and poured into 50 mL of H2O. The layers were separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine, and dried over Na2SO4. The solution was decanted and the solvent was removed under reduced pressure. The oily material was then taken up in 25 mL of DCM and stirred together with 25 mL of 10% NaOH solution. The layers were separated and the aqueous layer was neutralized with 2N HCl. The aqueous layer was then re-extracted with EtOAc (3×30 mL) and the organic layer was washed with brine (1×50 mL) and dried over Na2SO4. The solvent was then removed under reduced pressure, yielding a colorless oil. LCMS (m/e): 177 (M+H); 1H NMR (400 MHz, acetone-d6) δ ppm 1.22-1.28 (m, 3H) 3.82-3.92 (m, 1H) 4.14 (dd, J=10.84, 3.95 Hz, 1H) 7.15-7.31 (m, 2H) 7.35-7.48 (m, 1H) 7.75 (d, J=7.17 Hz, 1H).
Reaction SMILES: [CH2:1](OC1C=CC(NC2(N)C3C(=CC=C(C4O[C:28]([CH:31]5[O:35][CH2:34][CH2:33][O:32]5)=CC=4)C=3)N=CN2)=CC=1)[C:2]1[CH:7]=C[CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH3:5][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1].[C:31]([O:32][CH2:33][CH3:34])(=[O:35])[CH3:28]
Reactant: NC1(Nc2ccc(OCc3ccccc3)cc2)NC=Nc2ccc(-c3ccc(C4OCCO4)o3)cc21
Agent: Cl
Solvent: C1CCOC1
Product: CCCC(C)C
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 4-(4-benzyloxy-phenylamino)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine (1.0 g, 2.1 mmol) was dissolved in THF (20 ml) and hydrochloric acid (2N, 10 ml) was added. The reaction was stirred at room temperature for 1 hr. The precipitate which formed was collected by filtration and washed with acetone, then partitioned between ethyl acetate, triethylamine and water. The organic phase was washed with water, dried (magnesium sulphate) and the solvent was removed under vacuum. Trituration with iso-hexane/ethyl acetate gave the product as an orange solid (610 mg, 69%); δH [2H6]-DMSO 10.05 (1H, b, NH), 9.62 (1H, s, CHO), 8.95 (1H, s, 5-H), 8.48 (1H, s, 2-H), 8.24 (1H, d, 7-H), 7.80 (1H, d, 8-H), 7.70 (1H, d, furan 4-H), 7.59 (2H, d, 2′-H, 6′-H), 7.48-7.25 (6H, m, 5×Ph-H, furan 3-H), 7.02 (2H, m, 3′-H, 5′-H), 5.09 (2H, s, CH2); m/z 422 (M+1)+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17](O)[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=[CH:15][CH:16]=1>>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]([F:7])[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Reactant: CCN(CC)S(F)(F)F
Product: CC(C)(C)OC(=O)NCCC(F)c1cccc(Br)c1
Temperature: -78 °C

Procedure:
Diethylaminosulphur trifluoride (DAST) is added under an inert atmosphere to a cold (−78° C.) solution of alcohol 39. The reaction mixture is stirred at −78° C. until no starting material is seen by TLC. The reaction mixture is partitioned between water and EtOAc, and aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine and dried over anhydrous MgSO4. Purification by flash chromatography gives tert-butyl 3(3-bromophenyl)-3-fluoropropylcarbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CO[C:17]1[CH:18]=[C:19]([CH2:25][C@H:26](N)C)[CH:20]=[CH:21][C:22]=1OC.C1(CC(=O)C)C=CC=CC=1.[H][H]>[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:14][CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:17][CH:18]=2)[CH3:26])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C[C@H](C)N)cc1OC
Reactant: COc1ccc(C[C@@H](C)N)cc1OC
Reactant: [H][H]
Agent: [Ni]
Agent: CC(=O)Cc1ccccc1
Product: COc1ccc(CC(C)NC(C)c2ccccc2)cc1OC

Procedure:
Weinges et al., Chem. Z., 94, 728 (1970), reported on a stereospecific synthesis of (S)-1-(3,4-dimethoxyphenyl)-2-aminopropane and (R)-1-(3,4-dimethoxyphenyl)-2-aminopropane in which initial reductive amination of the achiral 1-phenylpropan-2-one with either (R)- or (S)-α-phenethylamine in the presence of hydrogen and Raney nickel under high pressure produced 1-[1-(3,4-dimethoxyphenyl)prop-2-ylamino]1-phenylethane. Hydrogenolysis of this product then yielded (S)-1-(3,4-dimethoxyphenyl)-2-aminopropane or (R)-1-(3,4-dimethoxyphenyl)-2-aminopropane, respectively.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:29]3[CH:30]=[CH:31][C:32]4[C:36]([CH:37]=3)=[N:35][N:34]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=4)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][C@@H:19]4[CH2:21][C@H:16]3[CH2:17][N:18]4C(OC(C)(C)C)=O)[N:6]2[N:5]=[CH:4][N:3]=1.Cl>CO.O1CCOCC1>[CH2:38]([N:34]1[CH:33]=[C:32]2[C:36]([CH:37]=[C:29]([C:8]3[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]4[CH2:20][C@@H:19]5[CH2:21][C@H:16]4[CH2:17][NH:18]5)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:30]=[CH:31]2)=[N:35]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2CCCCc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncnn2c(CCCCN3C[C@@H]4C[C@H]3CN4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of tert-butyl (1S,4S)-5-{-4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]butyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate in MeOH (1 mL) was added 4M HCl in dioxane (0.5 mL). The mixture was stirred at rt for 2 h. Additional 4M HCl in dioxane (0.5 mL) was added and the mixture continued to stir at rt for 16 h. The mixture was concentrated and the residue was partitioned between saturated, aqueous NaHCO3 (20 mL) and EtOAc (20 mL). The layers were separated and the organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water to obtain 36 mg (62%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.88 (s, 1 H), 7.79 (d, 1 H), 7.57 (s, 1 H), 7.28-7.39 (m, 5 H), 7.13 (d, 1 H), 6.58 (s, 1 H), 5.64 (s, 2 H), 3.51 (s, 1 H), 3.25-3.47 (m, 2 H), 2.97 (d, 1 H), 2.87 (t, 2 H), 2.73 (dd, 1 H), 2.66 (dd, 2 H), 2.37-2.45 (m, 1 H), 2.33 (d, 1 H), 1.59-1.77 (m, 3 H), 1.35-1.52 (m, 3 H); ES-MS m/z 493.27 [M+H]+, HPLC RT (min) 1.89.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[CH3:17].Br[C:34]1[CH:39]=[N:38][C:37]([Br:40])=[CH:36][N:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:40][C:37]1[N:38]=[CH:39][C:34]([C:21]2[CH:20]=[CH:19][C:18]([N:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=3[CH3:17])[C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[N:35][CH:36]=1
Reactant: Cc1ccc(N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c2ccc(C)cc2C)c(C)c1
Reactant: Brc1cnc(Br)cn1
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: C1COCCO1
Solvent: O
Product: Cc1ccc(N(c2ccc(-c3cnc(Br)cn3)cc2)c2ccc(C)cc2C)c(C)c1
Temperature: 80 °C

Procedure:
A mixture of N-(2,4-dimethylphenyl)-2,4-dimethyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)aniline (Compound 17) (6.0 g, 14 mmol), 2,5-dibromopyrazine (7.74 g, 30 mmol), Pd(PPh3)4 (0.5 g, 0.43 mmol), K2CO3 (4.14 g, 30 mmol) in dioxane/water (80 mL/17 mL) was degassed and heated at about 80° C. overnight. The resulting mixture was poured into ethyl acetate (200 mL), washed with brine, dried over Na2SO4, then loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 9:1 to 6:1 to 7:3. The desired yellow fraction was collected, and a yellow solid (Compound 18) was obtained after removal of solvents (3.83 g, 60% yield).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18]OS(C)(=O)=O)[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[S:32]>>[O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:29]4[CH:30]=[CH:31][N:27]([CH3:26])[C:28]4=[S:32])[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Reactant: CN1CCNC1=S
Product: Cn1ccn(C[C@H]2CN(c3ccc(C4=CCOCC4)c(F)c3)C(=O)O2)c1=S
Yield: 9.2 %

Procedure:
Essentially the procedure of Example 37 was used, but starting with (5R)-3-(4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyloxazolidin-2-one (300 mg, 0.81 mM), and 1-methylimidazolidin-2-thione (100 mg, 0.88 mM) and heating the reaction at 60° for 1.5 hours. Chromatography on two columns gave the desired product (29 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@@H:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]1SC=CN=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(S(OC)(=O)=[O:38])(F)F.[BH4-].[Na+].O>CC#N.[Hg](Cl)Cl>[Si:1]([O:8][C@H:9]([CH2:24][O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:27])[CH3:28])[C@@H:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH2:11][OH:38])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](c1nccs1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: COS(=O)(=O)C(F)(F)F
Agent: Cl[Hg]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CO)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
A solution of tert-butyl (1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propylcarbamate (6.150 g, 12.2 mmol) in 120 mL MeCN was treated with 4A mol. sieves and was allowed to stir at room temperature for 10 minutes. Methyl trifluoromethylsulfonate (1.62 ml, 14.7 mmol) was added, and the reaction mixture was allowed to stir for an additional 30 minutes. The reaction mixture was then concentrated in vacuo. The crude residue was dissolved in 100 mL MeOH, cooled to 0° C., and treated with NaBH4 (1.39 g, 36.7 mmol). The reaction mixture was allowed to warm to RT and stir for an additional 20 minutes. The reaction mixture was then concentrated, diluted with EtOAc, filtered through celite and again concentrated in vacuo. The residue was dissolved in 100 mL ACN and 20 mL water and was treated with mercury(II)chloride (3.32 g, 12.2 mmol). After stirring for 30 minutes, an additional portion of NaBH4 (1.39 g, 36.7 mmol) was added, and the reaction mixture was allowed to stir for another 30 minutes. The reaction mixture was quenched with saturated NaHCO3 solution and diluted with EtOAc. The crude reaction mixture was then washed with water then brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude residue was forced through a short plug of silica eluting with ether. The filtrate was again concentrated in vacuo yielding tert-butyl (2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-hydroxybutan-2-ylcarbamate (5.33 g, 96.9% yield) with minor impurities.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][C:22]=1O.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:21][C:22]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc(-c2ccccc2)cc1Cl)C(F)(F)F
Reaction time: 0.5 h

Procedure:
6.7 mL (40.32 mmol) of trifluoromethanesulfonic acid anhydride dissolved in 5 mL dichloromethane is added dropwise between −10° C. to −5° C. to a solution of 7.5 g (36.65 mmol) of 3-chlorobiphenyl-4-ol and 6.1 mL (44 mmol) of triethylamine in 100 mL of dichloromethane. Then the mixture is stirred for 30 minutes. The reaction solution is then extracted with water, the organic phase is separated off and filtered through an Alox frit. The filtrate is concentrated by evaporation. Yield: 12 g (97% of theory); C13H8ClF3O3S (M=336.72); calc.: molecular ion peak (M+H)+: 336/338 (Cl); found: molecular ion peak (M+H)+: 336/338 (Cl); Rf value: 0.7 (silica gel, petroleum ether/ethyl acetate (5:1)).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=O)[CH2:3]1.[N+:20]([O-])([O-])=[O:21].[Na+].[OH2:25]>C(O)(=O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]=[C:4]([C:14](=[O:25])[C:15](=[N:20][OH:21])[O:17][CH2:18][CH3:19])[CH2:3]1
Reactant: CCOC(=O)C=C1CN(C)C(=O)c2ccccc2N1
Reactant: O=[N+]([O-])[O-]
Reactant: O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=NO)C(=O)C1=Nc2ccccc2C(=O)N(C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
32.2 g (0.124 mol) of ethyl (1,3,4,5-tetrahydro-4-methyl-5-oxo-2H-1,4-benzodiazepin-2-ylidene)acetate are dissolved in 300 ml of acetic acid and treated at room temperature with 12.8 g (0.186 mol) of sodium nitrate. The mixture is stirred at room temperature for a further 10 minutes, then poured into 1 liter of water and extracted three times with 200 ml of chloroform each time. The combined chloroform phases are washed with 100 ml of water, dried over magnesium sulphate and evaporated. The residue is recrystallised from ethyl acetate. There is obtained ethyl 4,5-dihydro-4-methyl-5-oxo-3H-1,4-benzodiazepine-2-glyoxylate α-oxime of melting point 173°-174° C.