Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Br:25])[CH:24]=1.[CH3:26][CH2:27]CCCC>CS(C)=O>[Br:25][C:23]1[CH:24]=[C:19]([N:6]2[CH2:7][CH2:8][C:3]([CH3:2])([C:9]([O:11][CH2:26][CH3:27])=[O:10])[CH2:4][CH2:5]2)[CH:20]=[N:21][CH:22]=1
Reactant: CCCCCC
Reactant: Brc1cncc(Br)c1
Reactant: CC1(C(=O)O)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(C)CCN(c2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
To a solution of 4-methylpiperidine-4-carboxylate hydrochloride (3.6 g, 21.10 mmol) in DMSO (5 mL) was added Cs2CO3 (1.63 g, 5 mmol) at rt. The resulting mixture was stirred at rt for 10 min followed by addition of 3,5-dibromopyridine (1.0 g, 4.20 mmol). The reaction was heated up to 150° C. for 48 h. After completion (by TLC), the reaction mixture was poured into 100 mL of ice-cold water and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 20.0% EtOAc:hexane to obtain a viscous liquid product (0.2 g, 14% yield). MS: 327.08 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[CH3:10][C:11]([CH3:16])([CH3:15])[C:12](N)=[O:13].N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[CH3:10]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CC(C)(C)C(N)=O
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Product: CC(C)(C)C(=O)N[Si](C)(C)C
Yield: 125.4 %

Procedure:
7.7 ml (37 mmoles) of hexamethyldisilazane were added to 5.0 g (49.5 mmoles) of α,α-dimethylpropionamide and 10 mg (0.05 mmole) of saccharin in 15 ml of refluxing tolune over 15 minutes and after refluxing for 45 minutes, the evolution of ammonia had stopped completely. Evaporation and drying in vacuo yielded 8.04 g (98%) of N-trimethylsilyl-α,α-dimethylpropionamide melting at 101°-105.5° C. According to NMR analysis, the purity of the product was 92%.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[CH2:4]1.[CH:11]([O:13][CH2:14][CH3:15])=[CH2:12].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:11]([O:13][CH:14]([O:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[CH2:4]1)[CH3:15])[CH3:12]
Reactant: CC1(C)C[C@H](CO)NC1=O
Reactant: C=COCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(C)OC[C@H]1CC(C)(C)C(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.1 %

Procedure:
To a solution of (R)-5-hydroxymethyl-3,3-dimethyl-pyrrolidin-2-one (4.0 g, 28 mmol), prepared as described in Tetrahedron 1998, 54 10295-10307, and ethyl vinyl ether (4 mL, 42 mmol) in chloroform (26 mL), was added a catalytic amount of trifluoroacetic acid (0.056 mL), and the reaction mixture was stirred for four hours at room temperature. The solution was then washed with a saturated solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The crude oil obtained after evaporating the solvent, was purified by chromatography on silica gel using hexane:ethyl acetate 1:1 as a solvent, giving 2.6 g of (R)-5-(1-ethoxy-ethoxymethyl)-3,3-dimethyl-pyrrolidin-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:33]([O:37][C:38]([NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]1[CH:53]=[CH:52][C:51]([CH2:54]O)=[CH:50][CH:49]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:54][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[CH2:41][NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])=[CH:53][CH:52]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)NC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
To a solution of 60 mg (0.15 mmol) of 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]butanamide (Step D) in 0.5 mL of dry dimethylformamide under nitrogen was added 6.4 mg (0.16 mmol) of 60% sodium hydride/oil dispersion. After stirring for 15 minutes, a solution of 60 mg (0.15 mmol) of 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step I) in 0.5 mL of dimethylformamide was aded by cannula. The flask which originally contained the methanesulfonate ester was rinsed with 0.5 mL of dimethylformamide which was added to the reaction mixture. After stirring at room temperature for two hours, the reaction mixture was diluted with 75 mL of ethyl acetate, washed with 20 mL of water and 20 mL of saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (60:40) to afford 89 mg (96%) of the product as a white foam. FAB-MS: calculated for C42H48N4O6 704; found 705 (M+H). 1H NMR (200 MHz, CDCl3); 1.31 (s, 3H), 1.32 (s, 3H), 1.37 (s, 9H), 1.76 (s, 1H), 2.30-2.62 (m, 5H), 4.15 (d, 5 Hz, 2H), 4.40-4.60 (m, 2H), 4.85 (d, 14 Hz, 1H), 4.95 (d, 10 Hz, 1H), 5.04 (d, 10 Hz, 1H), 5.18 (d, 14 Hz, 1H), 5.65 (s, 1H), 6.70 (d, 6 Hz, 1H), 7.10-7.42 (m, 17H).
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[Br:26][C:27]1[C:28]([NH2:38])=[N:29][NH:30][C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.NC1C=CNN=1>O1CCCC1>[Br:26][C:27]1[C:28]([NH:38][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[NH:5][C:4]2=[O:13])=[N:29][NH:30][C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1Nc2ccc(Cl)cc2/C1=C/O
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1=CNc1n[nH]c(-c2ccccc2)c1Br

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 4-bromo-5-phenyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one (0.1820 gms.) is reacted with 0.4511 gms. of 4-bromo-5-phenyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (3.0 mL).
Reaction SMILES: Cl[P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4](Cl)[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[C:15]([C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]=1[OH:33])([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[C:15]([C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]=1[O:33][P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4]([O:33][C:20]2[C:21]([C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:22][C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:24][C:19]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)N1P(Cl)N(C(C)(C)C)P1Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(C)(C)C)c(OP2N(C(C)(C)C)P(Oc3c(C(C)(C)C)cc(C(C)(C)C)cc3C(C)(C)C)N2C(C)(C)C)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-di-tert-butyl-1,3,2,4-diazadiphosphetidine, 2,4,6-tri-tert-butylphenol and triethylamine to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7](NCC=C)[CH:8]=C.C(N(CC)[C:17]([C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:32]([N:34]([CH2:37]C)[CH2:35][CH3:36])=[O:33])=[CH:26][CH:27]=3)[C:22](=[O:39])[C:21]=2[CH:20]=1)=[O:18])C>>[N:1]1([C:17]([C:19]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25]([C:32]([N:34]5[CH2:37][CH2:8][CH2:7][CH2:36][CH2:35]5)=[O:33])=[CH:26][CH:27]=4)[C:22](=[O:39])[C:21]=3[CH:20]=2)=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)C(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)N(CC)CC)ccc1-2
Reactant: C=CCNCC=C
Reactant: C1CCNCC1
Product: O=C1c2cc(C(=O)N3CCCCC3)ccc2-c2ccc(C(=O)N3CCCCC3)cc21

Procedure:
Substituting an equivalent molar amount of piperidine or diallylamine in lieu of the diethylamine above, results in the formation of 2,7-bis(piperidinocarbonyl)fluoren-9-one m.p. 255.5°C; and N,N,N',N'-tetraallyl-9-oxo-fluorene-2,7-dicarboxamide, m.p. 94.5°-95.5°C,
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[O:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:12]=2)[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[N:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1.N12CCCN=C1CCC[CH2:36][CH2:35]2>N1C=CC=CC=1>[CH2:35]([N:22]([C:2]1[N:6]([CH2:7][C:8]2[O:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:12]=2)[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[N:3]=1)[CH:23]1[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]1)[CH3:36]
Reactant: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(Cn2c(N(CC)C3CCN(C(=O)OCC)CC3)nc3ccccc32)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 2-chloro-1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazole (9.50 g, 31.2 mmol) and ethyl 4-aminopiperidine-1-carboxylate (5.4 g, 31 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.6 mL, 37.4 mmol), and pyridine (90 mL). Heat to reflux. After 18 hours, cool to ambient temperature and evaporate in vacuo to give ethyl (1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9](=[O:23])[C@@H:10]([NH2:22])[C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])[CH3:12].[OH:24][CH2:25][C@@H:26]1[CH2:28][C@H:27]1[C:29]#[C:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([C:41](O)=[O:42])[CH:35]=[CH:34]2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:18]([O:17][C:15]([NH:14][C:11]([CH3:13])([CH3:12])[C@H:10]([NH:22][C:41]([C:36]1[CH:35]=[CH:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([C:30]#[C:29][C@@H:27]3[CH2:28][C@H:26]3[CH2:25][OH:24])[CH:32]=2)[CH:37]=1)=[O:42])[C:9]([O:8][CH3:7])=[O:23])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H](N)C(C)(C)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc2cc(C#C[C@@H]3C[C@H]3CO)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H](NC(=O)c1ccc2cc(C#C[C@@H]3C[C@H]3CO)ccc2c1)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a stirring suspension of (S)-methyl-2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate oxalate (6.3, 1.6 g, 4.9 mmol) and 6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthoic acid (6.2, 1.0 g, 3.8 mmol) in ACN (10 mL) at 0° C. was added triethylamine (2.1 mL, 15 mmol), followed by the portionwise addition of a solution of HATU (3.0 g, 7.9 mmol) in ACN (10 mL) and the reaction mixture was stirred at 0° C. for 75 min. The reaction was concentrated under reduced pressure to yield a residue, which was partitioned between MTBE and water. The organic layer was washed with 1M citric acid, water, saturated sodium bicarbonate (2×), saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamido)-3-methylbutanoate (6.4), which was carried through to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28]SC3C=CC=CC=3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.[C:39]1(C)[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=O)=[CH:41][CH:40]=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:45]([C:42]3[CH:41]=[CH:40][CH:39]=[CH:44][CH:43]=3)(=[O:47])=[O:48])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CSc2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CS(=O)(=O)c2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfanyl)methyl]-1,4-dihydro-3-quinolinecarboxamide (0.08 gm) from Example No. 76 in dichloromethane (4 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.03 gm) followed by m-chloroperoxybenzoic acid (˜85%) (0.06 gm). The mixture is stirred for 1 hr. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by recrystallization from acetonitrile to afford 0.07 gm of the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]([NH:15][NH2:16])=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([NH:10][NH2:11])=[O:9].C(N[CH:21]([CH3:23])[CH3:22])(C)C.[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:24]([NH:11][NH:10][C:8](=[O:9])[C:7]1[CH:12]=[C:3]([CH2:2][OH:1])[CH:4]=[C:5]([C:13]([NH:15][NH:16][C:24]([C:22]2[CH:21]=[CH:23][CH:42]=[CH:37][CH:38]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:14])[CH:6]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)NC(C)C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NNC(=O)c1cc(CO)cc(C(=O)NN)c1
Solvent: CN(C)C=O
Product: O=C(NNC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc(CO)cc(C(=O)NNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 2.5 h

Procedure:
To a solution of 2.0 g (8.92 mmol) of dihydrazide 2 in 20 ml of DMF was added 9.1 ml (53.5 mmol) of diisopropylamine and 5.6 g (19.6 mmol) of trityl chloride. The mixture was stirred for 2.5 hours, concentrated, and crystallized in 100 ml ethyl acetate. The product was filtered, washed with cold ethanol, dried under low vacuum at 40° C. for 18 h o yield 5.2 g (82%) of 3: 1H-NMR (DMSO-d6,) 9.36 (d, J=7.4 Hz, 2H), 7.47–7.17 (m, 33H), 6.12 (d, J=7.4 Hz, 2H), 5.28 (t, J=5.7 Hz, 1H), 4.41 (d, J=5.7 Hz); 13C-NMR 165.4, 144.3, 142.5, 132.6, 128.5, 127.7, 126.8, 124.6, 73.4, 62.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:16]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>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>[CH3:16][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cnc(C(F)(F)F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnc(C(F)(F)F)c(C)c1
Yield: 33.6 %

Procedure:
To a solution of methyl 5-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate (1173 mg, 4.13 mmol) in 1,4-dioxane (25 ml) stirred under N2 was added K2CO3 (1712 mg, 12.39 mmol), trimethylboroxine (0.866 ml, 6.19 mmol) and tetrakis(triphenylphosphine)palladium (0) (239 mg, 0.206 mmol). The reaction mixture was stirred heating under reflux for 24 h. HPLC showed starting material remaining, more tetrakis(triphenylphosphine)palladium (0) was added until starting material was not detected by HPLC. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography using a 40 g Merck silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded methyl 5-methyl-6-(trifluoromethyl)-3-pyridinecarboxylate (304 mg, 32%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:8])[CH:6]=[O:7])(=[O:3])[CH3:2].C(OCCC(O)=O)(=[O:11])C.C(OC(=O)C)(=O)C.C(O)(=O)C(C)O>>[C:1]([O:4][CH:5]([CH3:8])[C:6]([OH:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(=O)O
Reactant: CC(=O)OC(C)C=O
Agent: CC(O)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(C)C(=O)O

Procedure:
α-Acetoxypropionaldehyde and β-acetoxypropionic acid were identified by elemental analysis, molecular weight, and nuclear magnetic resonance studies. An authentic sample of α-acetoxypropionic acid was prepared by the addition of acetic anhydride to lactic acid [A. Golomb and P. D. Ritchie, J CHEM SOC, 838 (1962)]. The corresponding aldehyde could not be prepared by an independent method.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1.[OH-].[Na+].C(O)C>CC(O)=O>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:12][C:7]=2[N:6]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(OCC(=O)OCC)ccc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(OCC(=O)O)ccc2S(=O)(=O)C1
Yield: 79.2 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-(ethoxycarbonylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 3; 110 mg, 0.24 mmol) and sodium hydroxide (100 mg, 2.5 mmol) were added to ethanol (5 ml, 95%). The mixture was refluxed for 1 h. AcOH (0.30 ml) was added and the reaction mixture was evaporated under reduced pressure. The residue was extracted with DCM/water. The DCM layer was separated, dried and evaporated under reduced pressure. The residue crystallised when treated with hexane. 82 mg (79%) of the title compound was obtained. NMR (500 MHz): 0.7-0.9 (m, 6H), 1.1-1.7 (m, 8H), 3.1-3.25 (m, 2H), 3.6-3.8 (br d, 2H), 4.6 (s, 2H), 6.9-7.1 (m, 5H), 7.2-7.3 (m, 2H),
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[CH3:32][N:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH:40]=O)[N:35]=[CH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].[Cl:61]CCl>>[ClH:61].[ClH:61].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:40][CH2:39][CH2:38][C:36]2[N:35]=[CH:34][N:33]([CH3:32])[CH:37]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cn1cnc(CCC=O)c1
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(C[C@@H]2CN(CCCc3cn(C)cn3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Product: Cl
Reaction time: 4 h

Procedure:
Under nitrogen atmosphere, to a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (315 mg) and 3-(1-methyl-1H-imidazol-4-yl)propanal (98 mg) in dichloromethane (6 ml) was added sodium triacetoxyborohydride (225 mg) and'stirred at room temperature. After 4 hours, aqueous sodium bicarbonate solution was added to the mixture and the mixture was stirred for several minutes. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using dichloromethanemethanol (10:1) as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(1-methyl-1H-imidazol-4-yl)propyl]piperazine dihydrochloride (187.1 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][N:19](CC4C=CC=CC=4)[CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.O.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:21][CH2:20][NH:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCNC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A mixture of N-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.359 g, 0.96 mmol), prepared as described in Example 2, ammonium formate (0.304 g, 4.82 mmol) and palladium (10% wt. on activated carbon, 40 mg) in MeOH (5 mL) was stirred at r.t. for 1 h and then at 60° C. for 2 h. The mixture was cooled to r.t. and filtered over celite. The filtrate was concentrated under reduced pressure to give a white solid which was dissolved in water. The mixture was extracted twice with a 3:1 mixture of chloroform:isopropanol. The combined organic extracts were dried over sodium sulfate and concentrated to dryness to give 0.26 g of the title compound which was used directly without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>O1CCOCC1.O>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([O:1][C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: OCCc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Oc1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-Hydroxyphenyl)ethanol (400 mg, 2.90 mmol) was dissolved in a mixture of 4 ml of dioxane and 4 ml of water, and sodium hydrogencarbonate (2.43 g, 29 mmol) was added followed by acetic anhydride (2.96 g, 29 mmol) with ice cooling. The mixture was stirred overnight at room temperature and then partitioned between 2 N hydrochloric acid and EA. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the crude title compound which was used without further purification.