Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[C:28]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].C(OC(=O)CSC1SC(N)=NC=1)C>>[C:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)C1CCC(NC2CCCCC2)CC1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via (4-tert-butyl-cyclohexyl)-cyclohexyl-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=1>>[C:31]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:11](=[O:13])[CH2:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:19]([F:20])([F:22])[F:21])[CH:5]=2)[CH2:14][C:15]([F:16])([F:17])[F:18])=[CH:25][CH:26]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Product: CC(=O)Nc1ccc(NC(=O)CN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and N-(4-aminophenyl)acetamide: MS (APCI) m/z 459 (M+1).
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:17]=1[N:18]1[CH2:25][CH:24]2[CH:20]([CH2:21][N:22]([CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23]2)[CH2:19]1)=[O:11])C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>CO>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:17]=1[N:18]1[CH2:25][CH:24]2[CH:20]([CH2:21][N:22]([CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23]2)[CH2:19]1)=[O:11]
Reactant: CC(C)COC(C)ONC(=O)c1cccnc1N1CC2CN(Cc3ccc4ccccc4c3)CC2C1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO)c1cccnc1N1CC2CN(Cc3ccc4ccccc4c3)CC2C1
Reaction time: 6 h
Yield: 5.8 %

Procedure:
To N-(1-isobutoxyethoxy) 6-(5-naphthalen-2-ylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)pyridine-5-carboxamide (0.199 g, 0.4 mmol) was added TFA:DCM:MeOH (8 ml, 1:2:2). The solution was stirred for 6 h and then concentrated under vacuum. The residue was suspended in MeOH and poured into EtOH (250 ml). The mixture was washed with 1:1 saturated sodium bicarbonate/1M NaOH (100 ml), and water (50 ml). The organic fraction was dried (Na2SO4), concentrated and purified by reverse phase HPLC to yield the title compound (9 mg, 5%). m/z 389.25 [M+H]+; 1H NMR (300 MHz, CD3OD) δ: 2.64 (2H, d, J=5.3 Hz), 2.90-3.07 (4H, m), 3.37-3.58 (4H, m), 3.89 (2H, s), 6.46 (1H, d, J=8.9 Hz), 7.33-7.44 (3H, m), 7.70-7.80 (5H, m), 8.37 (1H, d, J=2.2 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[C:8]([NH:15][C@H:16]([CH:24]1[CH2:26][O:25]1)[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O>C1COCC1>[C:8]([NH:15][C@@H:16]([CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH:24]([OH:25])[CH2:26][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C1CO1
Reactant: Cc1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(O)CCc1ccccn1
Reaction time: 1 h

Procedure:
220 μl of 2-picoline (2 eq) are deprotonated in analogy to Example (6c). Then 300 mg of Boc-2-cyclohexyl-1(S)-oxiran-2(R,S)-ylethylamine in THF are added dropwise at -60° C. After 1 h, H2O is added, and the mixture is extracted 3 times with EA. The organic phases are dried with Na2 so4 and then concentrated, and the title compound is isolated by chromatography on SiO2 with EA/H 2:1 as eluent.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([O:30]CC)=O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:30])[N:27]=2)[CH2:22]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: C1CCNCC1
Agent: C[Al](C)C
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCCCC3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.00 g, 2.14 mmol) (obtained as described in Reference Example 2(1)) in benzene (50 ml) was added a solution of 0.67M piperidine-trimethylaluminium in benzene (7.3 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux for 5 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (50 ml) and ethyl acetate (100 ml) were added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 2 hours. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (607 mg, yield 56%) as a pale brown solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[N:43][NH:44][CH:45]=2)O1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.S([O-])([O-])(=O)=O.[Mg+2]>[Cr].CCOC(C)=O.CCCCCC>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([C:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:3]=[C:2]2[C:41]1[CH:42]=[N:43][NH:44][CH:45]=1)([O-:13])=[O:12]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cr]
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 38.2 %

Procedure:
To a vial containing 3-bromo-5-nitro-1-trityl-1H-indazole (1.45 g, 3.00 mmol), 4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-1H-PYRAZOLE (0.873 g, 4.50 mmol) [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.245 g, 0.300 mmol) and Potassium phosphate (1.59 g, 7.50 mmol) in a mixture of 1,4-Dioxane (25 mL, 320 mmol) Water (12 mL, 670 mmol) was degassed under an atmosphere of Nitrogen. This r×n mixture was heated at 80° C. overnight under an atmosphere of Nitrogen. TLC (20% EtOAc/hexane) showed starting material. MS showed (M+H) at 472. The r×n was diluted with EtOAc and Water (50/50 mL) and filtered through Celite. The org. layer was washed with water, dried over Magnesium sulfate (2 g, 20 mmol) and rotavap to give a crude, 2.2 g. The crude was chrom. (30% EtOAc/Hexane) on Biotage (40 L) to obtain the product (fraction 2), M+H at 472, 5-nitro-3-(1H-pyrazol-4-yl)-1-trityl-1H-indazole (0.54 g; Yield=38%)
Reaction SMILES: [O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[O:16][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([O-:22])=O)=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:47]1([CH2:52][CH2:53][NH2:54])[CH2:51][CH2:50][CH2:49][CH2:48]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[O:16][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:54][CH2:53][CH2:52][N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:22])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: NCCN1CCCC1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc(-c2cccc(C(=O)[O-])c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccccc2/C1=C\c1ccc(-c2cccc(C(=O)NCCN3CCCC3)c2)o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (E)-3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoate (20 mg, 0.06 mmol) and HOBt (16 mg, 0.14 mmol) in NMP (0.5 mL) was added EDCI (22 mg, 0.12 mmol). The reaction was stirred at rt for 10 min and then added 2-(pyrrolidin-1-yl)ethanamine (0.05 mL) followed by DIEA (0.05 mL). The reaction mixture was stirred at rt for 1 h and diluted with H2O (10 mL). The mixture was extracted with EtOAc (3×20 mL), dried over Na2SO4 and concentrated. The crude was purified by RHPLC to give (E)-3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide. LCMS (ES): m/z 463 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:18]=[N:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=3)[C:6]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)O1.[F-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.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(O)C.C1(C)C=CC=CC=1>[CH3:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:35]4[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=4)=[CH:26][C:6]=3[N:7]([C:17]3[CH:18]=[N:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=3)[CH2:8][C@@H:9]([CH3:16])[C:10]2=[N:14][N:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc([N+](=O)[O-])nc1)C[C@H]2C
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: [Cs+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc([N+](=O)[O-])nc1)C[C@H]2C
Temperature: 110 °C
Yield: 51.3 %

Procedure:
A mixture of (R)-8-bromo-1,4-dimethyl-6-(6-nitropyridin-3-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (42 mg, 0.1 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (27 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol), potassium fluoride (5.8 mg, 0.1 mmol) and cesium carbonate (49 mg, 0.15 mmol) in a mixed solution of toluene (2 mL), ethanol (1 mL) and water (0.2 mL) was heated at 110° C. for 1.5 hours under microwave (pressure: 3.0 bar, equipment power: 150 W). The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product (R)-5-(1,4-dimethyl-6-(6-nitropyridin-3-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2-amine (22 mg, 51%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:14]([N:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: N#CC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 119.3 %

Procedure:
A round-bottomed flask was charged with Boc-D-tert-leucine (300 mg, 1.3 mmol) and azetidine-3-carbonitrile hydrochloride (231 mg, 1.95 mmol). DMF (6 ml) was added followed by N,N-diisopropylethylamine (0.68 ml, 3.9 mmol) and HATU (543 mg, 1.43 mmol). The light yellow solution was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 458 mg of [(R)-1-(3-cyano-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester as a light yellow oil.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][O:10][C:11]1[C:16]([NH2:17])=[CH:15][C:14](B2OC(C)(C)CC(C)(C)O2)=[CH:13][N:12]=1.Br[C:29]1[CH:30]=[C:31]([NH:44][C:45]([C:47]2[N:48]=[C:49]([CH2:52][N:53]3[CH2:58][C@H:57]([CH3:59])[O:56][C@H:55]([CH3:60])[CH2:54]3)[S:50][CH:51]=2)=[O:46])[C:32]2[C:36]([CH:37]=1)=[N:35][N:34]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)[CH:33]=2.O>O1CCOCC1.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[NH2:17][C:16]1[CH:15]=[C:14]([C:29]2[CH:30]=[C:31]([NH:44][C:45]([C:47]3[N:48]=[C:49]([CH2:52][N:53]4[CH2:58][C@H:57]([CH3:59])[O:56][C@H:55]([CH3:60])[CH2:54]4)[S:50][CH:51]=3)=[O:46])[C:32]3[C:36]([CH:37]=2)=[N:35][N:34]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[CH:33]=3)[CH:13]=[N:12][C:11]=1[O:10][CH3:9]
Reactant: C[C@@H]1CN(Cc2nc(C(=O)Nc3cc(Br)cc4nn(C5CCCCO5)cc34)cs2)C[C@H](C)O1
Reactant: COc1ncc(B2OC(C)(C)CC(C)(C)O2)cc1N
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn(C4CCCCO4)nc3c2)cc1N
Temperature: 140 °C
Yield: 62 %

Procedure:
Tripotassium phosphate (910 mg, 4.29 mmol), chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (105 mg, 0.143 mmol) and 2-(methyloxy)-5-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-3-pyridinamine (453 mg, 1.715 mmol) were weighed to a 20 ml microwave vial. N-[6-Bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (764 mg, 1.429 mmol) was dissolved in 1,4-dioxane (10 mL) and added, followed by water (2.000 mL). The reaction was heated at 140° C. for 20 min. The reaction mixture was passed through a 10 g silica cartridge, eluting with methanol. The solvent was evaporated to dryness and the residue was partitioned between DCM 200 ml and water 200 ml. The DCM was collected and eluted through a hydrophobic frit, then evaporated to dryness. The residue was purified by chromatography on silica gel (100 g cartridge), eluting with 0-25% methanol in DCM over 40 mins, then on a further silica gel 100 g cartridge, eluting with 0-100% ethyl acetate in cyclohexane over 40 mins and then 0-25% methanol in DCM over 20 mins to afford the title compound (512 mg).
Reaction SMILES: CC1C=CC(C)=CC=1C(CC#N)=O.COC(OC)(OC)CCC.C(OC(=O)C)(=O)C.[C:31]([C:33]([C:40](=[O:49])[C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:42]=1[CH3:48])=[CH:34][CH:35](OC)[CH2:36][CH3:37])#[N:32].C(N(CC)CC)C.[Cl:57][C:58]1[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[C:60]([Cl:68])[C:59]=1[NH:69][NH2:70]>C(OCC)(=O)C>[NH2:32][C:31]1[N:69]([C:59]2[C:60]([Cl:68])=[CH:61][C:62]([C:64]([F:65])([F:66])[F:67])=[CH:63][C:58]=2[Cl:57])[N:70]=[C:34]([CH2:35][CH2:36][CH3:37])[C:33]=1[C:40](=[O:49])[C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:42]=1[CH3:48]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCC(C=C(C#N)C(=O)c1cc(C)ccc1C)OC
Agent: CCCC(OC)(OC)OC
Agent: Cc1ccc(C)c(C(=O)CC#N)c1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1cc(C)ccc1C

Procedure:
A solution of 0.52 g (3.0 mmol) of 2,5-dimethylbenzoylacetonitrile, 0.45 g (3.0 mmol) of trimethylorthobutyrate and 0.632 g (0.58 mL, 6.2 mmol) of acetic anhydride in 5.0 mL of ethyl acetate was refluxed overnight and then cooled. The solvents were removed in vacuo and the residues were dissolved in 10 mL of ethanol. One-half of this solution, containing 1.5 mmol of 1-cyano-1-(2,5-dimethylbenzoyl)-3-methoxy-1-pentene was mixed with 0.7 mL (0.51 g, 5.0 mmol) of triethylamine and 0.37 g (1.50 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine and refluxed for 2.5 hours. The reaction mixture was cooled and partitioned between dilute hydrogen chloride and ethyl acetate. The organic phase was washed with water and then dried with brine and with magnesium sulfate. The solvent was evaporated to give an oil which was chromatographed on silica gel by the flash method eluting with 4:1 hexane/ethyl acetate to give the title compound as an amorphous foam. Anal. Calcd. for C22H20ON3CL2F3, 469.0935. Found: 469.0889.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:4]=1[NH:18][C:19](=[O:24])[O:20][CH:21]([CH3:23])[CH3:22].[H-].[Na+].I[CH3:28].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:14])([CH3:15])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:4]=1[N:18]([CH3:28])[C:19](=[O:24])[O:20][CH:21]([CH3:22])[CH3:23]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)C
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N(C)C(=O)OC(C)C
Yield: 134.5 %

Procedure:
To isopropyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (0.298 mmol, 0.10 g) in tetrahydrofuran (1 ml) at room temperature were subsequently added sodium hydride (60% dispersion in mineral oil, 0.350 mmol, 0.014 g) and iodomethane (0.803 mmol, 0.05 ml). After 1 hour aqueous ammonium chloride solution was added and extracted with dichloromethane (three times). The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to yield isopropyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl(methyl)carbamate (0.14 g) which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:7][CH3:8])[C@H:4]([OH:6])[CH3:5].C(=O)(O)[O-].[Na+].C([BH3-])#N.[Na+].[CH:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:24]([NH:2][C@H:3]([CH2:7][CH3:8])[C@H:4]([OH:6])[CH3:5])[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CC[C@@H](N)[C@@H](C)O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Product: CC[C@@H](NCc1ccccc1)[C@@H](C)O
Reaction time: 1 h

Procedure:
To a solution of (2R,3R)-3-aminopentan-2-ol hydrochloride (1.00 g, 7.2 mmol) in DCM (20 mL) at rt was added sodium bicarbonate solution (604 mg, 7.2 mmol dissolved in 3.0 mL of water), dropwise. The reaction mixture was stirred for 1 hour, and the solvent was evaporated under reduced pressure. The residue and sodium cyanoborohydride (600 mg, 10.7 mmol) were added to a solution of benzyaldehyde 877 mg, 8.6 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. 30.0 mL water was added to this mixture, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the residue on a silica gel column (0 to 50% EtOAc/hexanes) afforded (2R,3R)-3-(benzylamino)pentan-2-ol. MS APCl calc'd for C12H19NO [M+H]+ 194. found 194.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][OH:18])=[O:14].ClC(Cl)(Cl)C(=N)O[CH2:34][CH:35]=[CH2:36].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][O:18][CH2:36][CH:35]=[CH2:34])=[O:14]
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesulfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95°-97° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([S:7]([CH3:10])(=[O:9])=[O:8])[NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:17](I)[CH3:18]>CN(C=O)C.CCOC(C)=O>[CH2:17]([N:5]1[CH:6]=[C:2]([I:1])[CH:3]=[C:4]1[S:7]([CH3:10])(=[O:9])=[O:8])[CH3:18]
Reactant: CS(=O)(=O)c1cc(I)c[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cc(I)cc1S(C)(=O)=O
Yield: 10 %

Procedure:
A solution of 4-iodo-2-methanesulfonyl-1H-pyrrole (0.14 g, 0.52 mmol) in DMF was treated with Cs2CO3 (0.84 g, 2.58 mmol) and ethyl iodide (0.161 g, 1.03 mmol). The reaction mixture was diluted with EtOAc and washed sequentially with water and brine. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo. Chromatography of the resultant residue (silica gel, 10%-30% EtOAc-hexanes as eluent) yielded an oil; 1H NMR (400 MHz, CDCl3) δ: 1.47 (t, 3H, J=7.3 Hz), 3.09 (s, 3H), 4.26 (q, 2H, J=7.3 Hz), 6.90 (m, 1H), 6.95 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:3]1=[O:24].[CH2:25]([O:27][C:28](=[O:51])[C@H:29](OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH3:26].CN1CCOCC1>C(OCC)(=O)C.CCCCCC>[CH2:25]([O:27][C:28]([C@@H:29]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:18][CH:19]=2)[C:3]1=[O:24])[CH2:30][CH2:31][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:51])[CH3:26]
Reactant: CC(C)(C)c1ccc(CN2C(=O)C(N)CCc3ccccc32)cc1
Reactant: CCOC(=O)[C@@H](CCC1CCCCC1)OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CCCCCC
Product: CCOC(=O)[C@H](CCC1CCCCC1)N[C@@H]1CCc2ccccc2N(Cc2ccc(C(C)(C)C)cc2)C1=O

Procedure:
The reaction of 3.55 g of 3-amino-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one with 2.5 g of (R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-cyclohexylbutyric acid ethyl ester and 1.03 ml of N-methylmorpholine yields the two diastereoisomeric esters 3-(S)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one and 3-(R)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one, Rf values (eluant ethyl acetate/hexane 1:2) non-polar component 0.42, polar component 0.26.