Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][C:5]([CH2:6][C@@H:7]([CH2:11][C:12](=[O:33])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[N:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=5[C:22]=4[NH:21][C:20]3=[O:32])[CH2:15][CH2:14]2)[C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:40].[O:41]1[CH2:46][CH2:45][CH:44]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1>>[NH2:1][C:2]1[C:35]([C:36]([F:39])([F:37])[F:38])=[CH:34][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:23]4[CH:24]=[N:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=5[C:22]=4[NH:21][C:20]3=[O:32])[CH2:17][CH2:18]2)=[O:33])[C:8]([N:50]2[CH2:49][CH2:48][N:47]([CH:44]3[CH2:45][CH2:46][O:41][CH2:42][CH2:43]3)[CH2:52][CH2:51]2)=[O:10])=[CH:4][C:3]=1[Cl:40]
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)O)cc1C(F)(F)F
Reactant: C1CN(C2CCOCC2)CCN1
Product: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 7i from 80 mg (0.14 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl]-butanoic acid and 26.0 mg (0.15 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[C:8]2[CH2:15]O.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.C(OCC)C>[Cl:19][CH2:15][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:11]=[N:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cncc(CO)c2c1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1ccc2cncc(CCl)c2c1

Procedure:
The hydrochloride of the compound obtained in Step B (1.09 g; 0.005 mol) is suspended in 50 ml of chloroform. Thionyl chloride (2.80 ml; 0.04 mol) is added and then the reaction mixture is heated at reflux for 24 hours with stirring. After evaporation under reduced pressure, the residue obtained is taken up in ethyl ether. The precipitate formed is suction-filtered off and recrystallised from acetonitrile to yield the title compound in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2Br)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:32][N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]1=[O:42].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(#N)C>[C:1]([C:4]1[C@@H:5]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[C:36]2[CH:37]=[CH:38][N:33]([CH3:32])[C:34](=[O:42])[CH:35]=2)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Cn1ccc(B(O)O)cc1=O
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)[C@@H]1c1ccc(C#N)cc1-c1ccn(C)c(=O)c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
4-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-3-bromo-benzonitrile (intermediate 4)(300 mg, 0.61 mmol) and (1-methyl-2-oxo-4-pyridyl)boronic acid (121 mg, 0.79 mmol) are suspended in acetonitrile (9 mL) and are degassed with a stream of argon. Potassium carbonate solution (2 mol/L, 914 μL, 1.83 mmol) and 1.1-bis(diphenylphosphino)-ferrocendichloropalladium(II), complex with dichloromethane (1:1) (9.95 mg, 0.012 mmol) are added and the reaction is shaken at 75° C. overnight. The reaction mixture is filtrated over a layer of silica gel and basic aluminum oxide 1:1 and purified by reversed phase HPLC. Yield: 142 mg; ESI mass spectrum [M+H]+=521; Retention time HPLC: 0.99 min (HPLC method Z018_S04).
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:27])[C@H:12]([CH3:26])[NH:13][C:14](=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1.Cl.[CH2:29]([O:31][C:32](=[O:36])[C@H:33]([CH3:35])[NH2:34])[CH3:30]>CCOC(C)=O>[CH2:29]([O:31][C:32](=[O:36])[C@H:33]([CH3:35])[NH:34][C:11](=[O:27])[C@H:12]([CH3:26])[NH:13][C:14](=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[CH3:30]
Reactant: CCOC(=O)[C@H](C)N
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure Z and using N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (from Example D8 above) and L-alanine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=193-195° C.). The reaction was monitored by tlc (Rf=0.4 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15](Cl)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2cc(Cl)c(F)cc2c1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3Cc2ccccc2)CC1

Procedure:
1.65 g (0.005 mol) of 1-benzyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 2.5 cm3 of 1-methylpiperazine and 12 cm3 of pyridine were heated under reflux for 9 hours. The reaction product was isolated as indicated in Example 35 and purified by recrystallisation from methylcellosolve (20 cm3). 1 g of 1-benzyl-6-fluoro-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 266° C., was obtained.
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:9]2[C:8](=[O:18])[N:7]([CH3:19])[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:10]1[C:9]2[C:8](=[O:18])[N:7]([CH3:19])[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=[C:2]1[N:10]1[CH2:9][CH:4]2[CH2:23][CH:24]1[CH2:2][NH:3]2
Reactant: Cn1c(=O)c2c(nc(Cl)n2-c2ccccc2Cl)n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(nc(N3CC4CC3CN4)n2-c2ccccc2Cl)n(C)c1=O
Temperature: 150 °C
Reaction time: 3 h

Procedure:
2,5-(Diaza-bicyclo[2.2.1]heptane)-2-carboxylic acid tert-butyl ester (50 mg) and 8-chloro-7-(2-chlorophenyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (10 mg) were mixed, and the mixture was stirred at 150° C. for 3 hours. The residue was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 5.10 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH3:11][C:12]([CH3:14])=O.ICC=C.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:14]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH:12]=[CH2:11]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)=O
Agent: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=CCOc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-nitrophenol (5.2 g, 0.037 mol) in acetone (100 mL, 1 mol) at 0° C. was added 3-iodo-1-propene (3.8 mL, 0.041 mol) and potassium carbonate (5.7 g, 0.041 mol). The reaction mixture was stirred for 1 h at 0° C. then warmed to room temperature overnight. The reaction mixture was worked up by diluting the reaction with water and washing with dichloromethane. The organic phase was washed with a 10% HCl solution, water and brine then dried over magnesium sulfate, filtered and concentrated in vacuo to a greenish-brown oil. Purification of the reaction mixture was accomplished using ISCO chromatography on silica gel (350 g column) using hexane-ethyl acetate (0-100%). The major fractions were combined and concentrated in vacuo to give product, 1-allyloxy-2-nitrobenzene, as a light yellow-green oil (5.4 g, 81%). 1H NMR (CDCl3, 400 MHz) δ 7.83 (d, 1H, J=8.09 Hz), 7.51 (t, 1H, J=8.08 Hz), 7.08 (d, 1H, J=8.33 Hz), 7.03 (t, 1H, J=8.08 Hz), 6.04 (m, 1H), 5.49 (d, 1H, J=17.2 Hz), 5.32 (d, 1H, J=10.6 Hz), 4.69 (d, 2H, J=5.05 Hz).
Reaction SMILES: ClC(N(C)C)=C(C)C.[C:9]([NH:17][C:18]([NH:20][C:21]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:25]([CH2:26]O)[CH2:24][N:23]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:22]1)=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:9]([NH:17][C:18]1[S:19][CH2:26][CH:25]2[CH2:24][N:23]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:22][C:21]2([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:20]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(NC(=S)NC1(c2ccccc2)CN(C(=O)OCc2ccccc2)CC1CO)c1ccccc1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC1=NC2(c3ccccc3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine (17.9 mL, 135 mmol) is added to a 0° C. solution of racemic benzyl 3-(benzoylcarbamothioylamino)-4-(hydroxymethyl)-3-phenyl-pyrrolidine-1-carboxylate (51 g, 104 mmol) in dichloromethane (459 mL) and stirred at room temperature for 2 hours. A saturated solution of sodium hydrogen carbonate (300 mL) is added and the layers are separated. The organic layer is dried over magnesium sulfate, the solution concentrated. The crude product is purified over silica gel eluting with dichloromethane to 5% ethyl acetate/dichloromethane to give the title compound (31 g, 63%). ES/MS (m/e): 372 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=O)[CH:5]=[CH:6][CH:7]=1.[Cl-].[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH:23]=[CH:10][CH:9]=[CH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=CC=Cc1cccc(Cl)c1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1cccc(C=CC=Cc2ccccc2OCc2ccccc2)c1
Yield: 94 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, the whole of this 3-(3-chlorophenyl)-2-propenal was reacted with 6.9 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 2.89 g of 1,8-diazabicyclo[5,4,0]undec-7-ene in 100 ml of acetonitrile. The crude product, extracted as described in the first part of Preparation 3, was purified as described in the first part of Preparation 3, to give 4.13 g (yield 94%) of 1-(2-benzyloxyphenyl)-4-(3-chlorophenyl)butadiene as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1(=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1>C(Cl)Cl.[Ti].Cl[Ti](Cl)(Cl)Cl>[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8]1
Reactant: O=C1CCc2ccccc21
Reactant: C1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti]
Solvent: ClCCl
Product: C1=C(N2CCCCC2)c2ccccc2C1
Yield: 72.9 %

Procedure:
According to the general method for titanium catalyzed enamine formation of Example 7, dry piperidine (51.4 g, 600 mmol) was treated with TiCl4 (14.35 g, 75.7 mmol) in 400 mL of CH2Cl2 at 0° C. 1-Indanone (10.0 g, 75.6 mmol) was added at this temperature and the reaction mixture was brought to 25° C. 1H NMR analysis of a worked-up aliquot revealed complete conversion to product. Solvent was removed by rotary evaporation and the resulting dark oil and TiO2 residue was triturated with 300 mL of hexane. The solution was filtered through dry Celite and evaporated to afford crude product (20 g dark oil). The product was distilled through a 6″ Vigreaux column to afford pure product (11.01 g, 55.1 mmol) in 73 percent yield as a light yellow oil (98 area percent enamine by GC analysis): bp=143° C. @ 1 mm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:34]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:34])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:11]2=[N:10]1
Reactant: BrBr
Reactant: Cc1ccc(O)c(-n2nc3ccc(C(C)(C)C)cc3n2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2(2′hydroxy 5′-bromomethyphenyl)-5-tert-butylbenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-butylbenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 6.274 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-tert-butylbenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-butylbenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-butylbenzotriazole was 6.8 g (84%)
Reaction SMILES: C(NCC1SC([B:10]([OH:12])[OH:11])=CC=1)C.[CH2:13]([CH:15]([CH2:47][CH3:48])[CH2:16][NH:17][CH2:18][C:19]1[S:23][C:22](C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=[CH:21][CH:20]=1)[CH3:14].C(C1SC(B(O)O)=CC=1)=O.[BH3-]C#N.[Na+].C(C(CC)CN)C>CO>[CH2:13]([CH:15]([CH2:47][CH3:48])[CH2:16][NH:17][CH2:18][C:19]1[S:23][C:22]([B:10]([OH:12])[OH:11])=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCNCc1ccc(B(O)O)s1
Reactant: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: CCC(CC)CN
Agent: O=Cc1ccc(B(O)O)s1
Agent: [BH3-]C#N
Solvent: CO
Product: CCC(CC)CNCc1ccc(B(O)O)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The {5-[(ethylamino)methyl]-2-thienyl}boronic acid used to prepare 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide was prepared as follows: A solution of (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol) in MeOH (0.5 mL) and a solution of NaCNBH3 (40 mg, 0.64 mmol) in MeOH (0.5 mL) were added to (2-ethylbutyl)amine (32 mg, 0.32 mmol) in a 2-dram vial. The vial was capped and the reaction was stirred at room temperature for 20 h. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of nitrogen to give 48 mg of crude (5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)boronic acid.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=[C:15]=[S:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)[NH:27][NH2:28])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15](=[S:16])[NH:27][NH2:28])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Reactant: CC(C)(C)OC(=O)NN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)NN
Reaction time: 2 h
Yield: 118.9 %

Procedure:
A mixture of Example 1a (1 g, 3.51 mmol) and tert-butylcarbazate (465 mg, 3.51 mmol) in DCM (10 mL) was stirred at rt for 2 h. Trifluoroacetic acid (2 mL) was added and mixture was stirred for 2 h. The solvent was removed and the residue was dissolved in EtOAc (15 mL), washed with saturated sodium bicarbonate solution, dried (anh. MgSO4), filtered and evaporated to give the title compound (1.32 g) as a brown solid. (M+H)+=317.
Reaction SMILES: [CH2:1]([Si:3]([CH2:20][CH3:21])([CH2:18][CH3:19])[O:4][C@@H:5]([C:9]([CH3:17])=[CH:10][C:11]1[N:12]=[C:13]([CH3:16])[S:14][CH:15]=1)[CH2:6][CH:7]=C)[CH3:2].C[N+]1([O-])CC[O:26]CC1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.C1C=CC=CC=1.[Os](=O)(=O)(=O)=O.O>[CH2:1]([Si:3]([CH2:20][CH3:21])([CH2:18][CH3:19])[O:4][C@@H:5]([C:9]([CH3:17])=[CH:10][C:11]1[N:12]=[C:13]([CH3:16])[S:14][CH:15]=1)[CH2:6][CH:7]=[O:26])[CH3:2]
Reactant: C=CC[C@@H](O[Si](CC)(CC)CC)C(C)=Cc1csc(C)n1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Product: CC[Si](CC)(CC)O[C@H](CC=O)C(C)=Cc1csc(C)n1
Reaction time: 12 h

Procedure:
Osmium tetraoxide (1 wt % in THF, 20.3 mL) is added to a mixture of (4R)-4-(triethylsilyloxy)-5-methyl-6-(2-methylthiazol-4-yl)-1,5-hexadiene (13.5 g), H2O (21 mL), and N-methylmorpholine N-oxide (50% in THF, 10 mL, 0.048 mol) in tert-butanol (155 mL) at 0° C. After the resulting mixture is stirred for 12 hours, Na2SO3 (10 g) and water (5 mL) are added. The resulting solution is stirred at 25° C. for 30 minutes and then extracted with ether. The combined extracts are washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography on SiO2 provides a 1:1 diastereomeric mixture of the diol as a colorless, viscous oil. Lead tetraacetate (19.1 g) is added portionwise over 5 minutes to a suspension of the diol (18.0 g) and Na2CO3 (8.67 g) in 500 mL of benzene at 0° C. After stirring for 15 minutes, the mixture is filtered through a SiO2 pad to afford the aldehyde product. The product is directly subjected to the next reaction.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=O)[CH:26]([CH3:32])[CH2:25]2.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:27]3[C:28]4[C:24](=[CH:23][C:22]([F:21])=[CH:30][CH:29]=4)[CH2:25][CH:26]3[CH3:32])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CC1Cc2cc(F)ccc2C1=O
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CC1Cc2cc(F)ccc2C1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-5-fluoro-2-methyl-indan-1-one using decaborane yielded a mixture of isomers of the title compound as a white solid. MS (ESI): m/z=427.3 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([Br:33])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:34][Si:35]([CH2:38][CH2:39][O:40][CH2:41]Cl)([CH3:37])[CH3:36]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:41][O:40][CH2:39][CH2:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([Br:33])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1Br
Reactant: C[Si](C)(C)CCOCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1Br
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To a mixture of compound 34B (0.815 g, 1.5 mmol) and SEMCl (0.318 mL, 1.8 mmol) in THF (6 mL) was added TEA (0.65 mL, 4.5 mmol) at rt. The reaction mixture was stirred for 20 minutes, concentrated under reduced pressure, and purified by column chromatography on silica gel eluting with 3:1/hexanes:EtOAc to provide 0.95 g of the desired product as a mixture of two inseparable isomers: MS (ESI(+)): m/z 657 (M+H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=[O:10])=[CH:3][CH:2]=1.[CH3:26][N:27](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C.C(Cl)Cl>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([NH:27][CH3:26])=[O:10])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a solution of (S)-3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoic acid (300 mg, 0.88 mmol) in DMF (1.5 mL) and DCM (1.5 mL) was added HATU (401 mg, 1.05 mmol) and triethylamine (0.37 mL, 2.64 mmol) followed by methylamine (0.46 mL, 0.91 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with sat NaHCO3 and extracted with EtOAc. The organic layer was washed with water (8 times), brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by TLC preparation plates using 3% 2N Ammonia in MeOH in DCM to give (S)-tert-butyl 3-(biphenyl-4-yl)-1-(methylamino)-1-oxopropan-2-ylcarbamate (111 mg). HPLC retention time=1.66 minutes (condition B); MS (m+1)=355.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 9H) 2.66 (d, J=4.8 Hz, 3H) 3.01 (d, J=6.3 Hz, 2H) 4.18-4.41 (m, 1H) 5.08 (br. s., 1H) 5.93 (d, J=4.3 Hz, 1H) 7.19 (d, J=8.1 Hz, 2H) 7.22-7.29 (m, 1H) 7.35 (t, J=7.6 Hz, 2H) 7.44 (d, J=8.1 Hz, 2H) 7.48 (d, J=7.3 Hz, 2H).