Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].[Cl:13][CH2:14][O:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[Cl-:13].[CH3:1][N:2]([CH3:12])[C:3]([O:5][C:6]1[CH:7]=[N+:8]([CH2:14][O:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: CCCCCC(=O)OCCl
Reactant: CN(C)C(=O)Oc1cccnc1
Product: CCCCCC(=O)OC[n+]1cccc(OC(=O)N(C)C)c1
Product: [Cl-]
Reaction time: 3 h
Yield: 80.2 %

Procedure:
3-Dimethylcarbamoyloxypyridine (1.66 g) and chloromethylhexanoate (2.0 g) were heated to 90° C. with stirring for 3 hours. The reaction mixture was treated in a similar manner as described in Example 1 to give 2.65 g of 3-(dimethylcarbamoyloxy)-1-(hexanoyloxymethyl)-pyridinium chloride as colorless powdery crystals. It was impossible to precisely measure the melting point because of high hygroscopicity. The structure was determined by N.M.R.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])[C:10]1=[O:29].Cl[C:31](OC1C=CC([N+]([O-])=O)=CC=1)=[O:32].Cl.Cl.[O:45]=[C:46]1[NH:54][C:49]2=[N:50][CH:51]=[CH:52][CH:53]=[C:48]2[N:47]1[CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>O1CCCC1.C(Cl)(Cl)Cl>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][C:25]([OH:28])([CH3:26])[CH3:27])[C:10](=[O:29])[C@H:9]([NH:8][C:31]([N:58]2[CH2:59][CH2:60][CH:55]([N:47]3[C:48]4[C:49](=[N:50][CH:51]=[CH:52][CH:53]=4)[NH:54][C:46]3=[O:45])[CH2:56][CH2:57]2)=[O:32])[CH2:15][CH2:14]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(O)CN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(O)CN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
Triethylamine (0.054 mL, 0.389 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)azepan-2-one (54 mg, 0.173 mmol) and 4-nitrophenyl chloroformate (40 mg, 0.199 mmol) in tetrahydrofuran (15 mL) at 0° C. After 30 min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (151 mg, 0.519 mmol), triethylamine (1.04 mmol) and chloroform (15 mL) were added and the mixture allowed to warm to ambient temperature. The reaction was then heated to 50° C. for 2 h, concentrated, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1.5%→11% methanol/dichloromethane) gave the title compound (70 mg). MS 557.2653 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J=4.8 Hz, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.1 (m, 2H), 7.0-6.9 (m, 2H), 6.17 (d, J=5.1 Hz, 1H), 4.84 (dd, J=10.9, 5.0 Hz, 1H), 4.5 (m, 1H), 4.3 (br dd, 2H), 4.02 (dd, J=10.1, 15.1 Hz, 1H), 3.76 (d, J=14.1 Hz, 1H), 3.42 (d, J=15.1 Hz, 1H), 3.31 (d; J=14.1 Hz, 1H), 3.15-2.95 (m, 4H), 2.3-1.9 (m, 8H), 1.26 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([NH2:18])=[O:17])[CH2:2][CH3:3].[CH3:19][C:20]([CH3:22])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:19][C:20]1([CH3:22])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16](=[O:17])[NH:18]1
Reactant: CCCNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Temperature: 70 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
A mixture of 3-(propylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.130 g, 0.500 mmol), acetone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 2 days at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 12 g silica gel, hexane to ethyl acetate), then washed with ethyl acetate to afford the title compound (0.094 g, 62%) as a yellow solid:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][C:6]1[NH:7][CH:8]=[N:9][C:10]=1[Cl:11].C(N(CC)C(C)C)(C)C.ClCCl.[CH3:25][Si:26]([CH3:33])([CH3:32])[CH2:27][CH2:28][O:29][CH2:30]Cl>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][C:6]1[N:7]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:33])([CH3:32])[CH3:25])[CH:8]=[N:9][C:10]=1[Cl:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)CCc1[nH]cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1c(Cl)ncn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.40 g of 3-(5-chloro-3H-imidazol-4-yl)-propionic acid methyl ester, 0.5 mL of N,N-diisopropylethylamine, 15 mL of dichloromethane and 0.4 mL of 2-(trimethylsilyl)ethoxymethyl chloride was stirred at room temperature for 24 h. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography eluting with ethyl acetate gave 0.8 g of 3-[5-chloro-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-propionic acid methyl ester as an oil.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:48]([OH:53])(=[O:52])[C:49]([OH:51])=[O:50]>C(OCC)(=O)C>[C:48]([OH:53])(=[O:52])[C:49]([OH:51])=[O:50].[N:20]1[CH:21]=[CH:22][CH:23]=[N:24][C:19]=1[N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1/[CH:1]=[CH:2]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Clc1ncccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: C(=C/c1nc2ccccc2n1-c1ncccn1)\c1ccccc1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-Chloropyrimidine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate-hexane yielded the titled compound. MW: 388.39; mp: 167.0-168.0° C.; 1H-NMR (DMSO-d6) δ: 9.09 (2H, dd, J=5.1, 0.7), 8.13-8.07 (1H, m), 7.91 (2H, s), 7.76-7.70 (2H, m), 7.76 (1H, d, J=7.3 Hz), 7.63 (1H, td, J=4.8, 0.7 Hz), 7.41 (1H, d, J=7.7 Hz), 7.46-7.30 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][C:18]=1[NH:23][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][N:9]=1)=[O:13]
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Reactant: COc1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(NC(=O)c2n[nH]c3ncc(Br)cc23)c1
Temperature: 45 °C

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid Compound 1c (200 mg, 0.826 mmol), 4-methoxy-benzene-1,2-diamine Compound 19a (114 mg, 0.826 mmol), HATU (314 mg, 0.826 mmol) and DIPEA (213 mg, 1.652 mmol) in DMF (10 mL) was stirred and heated to 45° C. overnight. The mixture was diluted with AcOEt (60 mL) and washed with water. The organic layer was separated, dried and evaporated to give a brown solid residue. The residue was recrystallized with AcOEt/hexane mixture to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (2-amino-5-methoxy-phenyl)-amide Compound 19b (221 mg, 74% yield) as a light brown powder. MS m/z 362 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[C:23](=O)[CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:27]([NH2:29])[CH3:28].C([BH3-])#N.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH:23]([NH:29][CH2:27][CH3:28])[CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCN
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C(C)=O)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNC(C)c1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Temperature: 60 °C

Procedure:
(2′-Acetyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.222 g, 0.61 mmol), ethylamine (2M in THF; 0.46 mL, 0.91 mmol), sodium cyanoborohydride (0.058 g, 0.91 mmol), and acetic acid (0.05 mL, 0.91 mmol) were combined in MeOH (2.2 mL) and heated to 60° C. overnight. Analytical LCMS showed starting material remained, so the reaction was stirred at 60° C. over the weekend. Once minimal starting material was seen by analytical LCMS, the mixture was cooled to room temperature and neutralized with saturated aqueous NaHCO3. The solution was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].Cl.[F:25][C:26]([F:38])([F:37])[C:27]1[N:28]=[CH:29][C:30]2[CH2:36][CH2:35][NH:34][CH2:33][C:31]=2[N:32]=1.C(Cl)CCl.CN1CCOCC1>C(#N)C>[CH3:23][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[CH2:9][C:10]([N:34]1[CH2:35][CH2:36][C:30]2[CH:29]=[N:28][C:27]([C:26]([F:38])([F:25])[F:37])=[N:32][C:31]=2[CH2:33]1)=[O:12])=[O:6])[CH3:3]
Reactant: FC(F)(F)c1ncc2c(n1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2cnc(C(F)(F)F)nc2C1)Cc1cc(F)c(F)cc1F
Temperature: 5 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A 1-L round bottom flask was charged with 15.5 g (46.5 mmol) of (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]4-(2,4,5-trifluorophenyl)butanoic acid and 160 mL of acetonitrile. To the resultant suspension was added 14.5 g (60.5 mmol) of amine hydrochloride from Step B. The mixture was cooled to 5° C. and 12 g (62.8 mmol) of EDC and 6.9 mL (62.8 mmol) of N-methylmorpholine were added. After 2 h, the reaction was judged to be complete by LC-MS analysis. The mixture was partitioned between 100 mL of water and 160 mL of ethyl acetate. The organic phase was washed sequentially with 100 mL of saturated aqueous sodium bicarbonate solution and 100 mL of brine, dried over sodium sulfate, and concentrated in vacuo. Purification by Biotage flash chromatography (silica gel, 30–60% ethyl acetate/hexane) gave 20.3 g of the title compound as a white foam. LC-MS 419.4 (M+1-BOC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([CH3:38])[CH:30]=2)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:27]=[C:26]([O:28][C:29]5[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([CH3:38])[CH:30]=5)[N:25]=[CH:24][N:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)ccc1[N+](=O)[O-]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc([N+](=O)[O-])c(C)c4)ncn3)CC1)C(=O)N2

Procedure:
0.69 g (2.51 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.66 g (2.48 mmol) 4-chloro-6-(3-methyl-4-nitrophenoxy)pyrimidine and 1.0 mL (5.81 mmol) DIPEA in 1.0 mL DMF were stirred overnight at 40° C. The reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH2:9][O:8][C@@H](C(C)(C)C)[N:6]1C(OC(C)(C)C)=O)=[O:4].Cl>CO>[CH3:1][O:2][C:3](=[O:4])[C@@:5]([NH2:6])([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH2:9][OH:8]
Reactant: COC(=O)[C@@]1(Cc2cccc(Cl)c2)CO[C@@H](C(C)(C)C)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@](N)(CO)Cc1cccc(Cl)c1
Yield: 95 %

Procedure:
Under N2, to a solution of crude of 11 (1 mmol) in dried MeOH (5 mL) was added dropwise conc.HCl (2 mL) over 1 hr then stirred for overnight. After concentration, the residue was basified with NaHCO3 at 0° C. The mixture was extracted with CH2Cl2 (5×20 mL). The combined extraction were dried over MgSO4, filtered and concentrated. The crude was submitted to silica gel column chromatography (CH2Cl2:MeOH:NH4OH=500:9:1-100:9:1) to give 12 (95%, from 10). [α]D −3.6 (c 1.45, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 2.75 (d, J=13 Hz, 1H), 3.05 (d, J=13 Hz, 1H), 3.56 (d, J=10 Hz, 1H), 3.73 (s, 3H), 3.87 (d, J=10 Hz, 1H), 7.02 (m, 1H), 7.13 (m, 1H), 7.22-7.27 (m, 2H). 13C NMR (CDCl3, 75 MHz) δ 41.5, 52.4, 63.6, 67.7, 127.4, 128.0, 129.8, 129.9, 134.3, 137.5, 175.3; IR (film): 3359, 3300, 3180, 1736, 1083 cm−1; Mass (ESI) 244.02 ([MH]+).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](Cl)=[O:24].O>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)=[O:24])[CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)C=Cc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(C=Cc1cccc(Cl)c1)N1CCc2ccccc21
Temperature: 5 °C
Reaction time: 48 h
Yield: 86.1 %

Procedure:
Triethylamine (9.2 ml) was added at room temperature to a solution of indoline (20 g) in DCM (200 ml) and the mixture was cooled till 5° C. A solution of m-chlorocinnamoyl chloride (40 g) in DCM (100 ml) was added dropwise and the mixture was stirred at room temperature for 48 hours. Water was added, the organic layer was decanted, washed with water, dried, filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/ethyl acetate 90/10), yielding 41 g (73%) of 1-[3-(3-chlorophenyl)-1-oxo-2-propenyl]-2,3-dihydro-1H-indole (interm. 37).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([I:10])[CH:9]=1)[CH:5]=O.[F:12][C:13]([F:22])([F:21])/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[C:4]2[C:3]=1[O:11][CH:14]([C:13]([F:12])([F:22])[F:21])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1cc(I)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Temperature: 100 °C
Yield: 37.7 %

Procedure:
To 18 g (63.7 mmole) of 3-chloro-2-hydroxy-5-iodobenzaldehyde in 16 mL of DMF was added 14.3 mL (16.1 g, 95.6 mmole) of ethyl trifluorocrotonate and 9.69 g (70 mmole) of K2CO3. The mixture was heated to 100° C. for 2 h. The mixture was allowed to cool, treated with 300 mLs of H2O and extracted three times with Et2O. The combined extracts were washed with water and filtered through a silica plug (4.5×6 cm). The silica was washed with methylene chloride and combined filtrates concd to give 10.39 g of a yellow solid. Recystalization in hexanes gave 6.64 g (24.1%) of a crystalline, yellow solid: 1H NMR (CDCl3/400 MHz) 1.35 (t, 3H, J=7.1 Hz), 4.33 (m, 2H), 5.81 (q, 1H, J=6.6 Hz), 7.44 (d, 1H, J=2.0 Hz), 7.62 (s, 1H), 7.66 (d, 1H, J=2.0 Hz); 19F NMR (CDCl3/400 MHz) −79.0 (d, 3F, J=6.8 Hz); 13C NMR (CDCl3/100 MHz) 13.1, 60.8, 70.4 (q, J=33.7 Hz), 82.6 (C-I), 117.7, 121.2, 121.8, 121.9 (q, J=287.2 Hz), 133.6, 134.9, 139.9, 147.9, 162.0; MS (ESI+) 433 (M+1, 100); HRMS (EI) m/z calcd for (C13H9O3IClF3) 431.9237, found 431.9221.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH2:12][CH2:11][C@H:7]1[C:8](O)=[O:9])=[O:5].C(=O)=O.CC(C)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([C@H:13]2[N:6]3[C@@H:7]([C:8](=[O:9])[S:1][CH2:2][CH2:3][C:4]3=[O:5])[CH2:11][CH2:12]2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc([C@H]2CC[C@@H](C(=O)O)N2C(=O)CCS)cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc([C@@H]2CC[C@@H]3C(=O)SCCC(=O)N32)cc1OC
Reaction time: 0.08 h

Procedure:
The compound produced in Example 2 is dissolved in about 500 milliliters methylene chloride and the solution is chilled under nitrogen to 15° C. in a dry ice-acetone mixture. 4-Dimethylaminopyridine is added and the mixture is stirred for five minutes. A slight excess of dicyclohexylcarbodiimide dissolved in methylene chloride is added with stirring. The chilled source is removed after 15 minutes and the solution is stirred overnight at room temperature. The volume of the reaction mixture is reduced on a rotary evaporator under reduced pressure to about 100 milliliters. A precipitate is removed by filtration and the filter residue is washed several times with methylene chloride. The filtrate and combined washings are washed successively with 1 N HCl, saturated aqueous NaHCO3, water and saline and the solution is dried over MgSO4. Evaporation of the methylene chloride with a rotary evaporator under reduced pressure yields the title compound.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])=[O:16])([O:3][CH3:4])=[O:2].Br[CH2:26][CH2:27][CH2:28][C:29]#[N:30]>>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:26][CH2:27][CH2:28][C:29]#[N:30])=[O:16])([O:3][CH3:4])=[O:2]
Reactant: N#CCCCBr
Reactant: COC(=O)CCCCCCCCCCC(=O)Nc1ccccc1O
Product: COC(=O)CCCCCCCCCCC(=O)Nc1ccccc1OCCCC#N

Procedure:
When (44) and 4-bromobutyronitrile are reacted under the conditions of step (A), above, (45) is obtained as a waxy solid. Conversely, reacting (44) with ethyl 4-bromobutyrate as in step (A) yields (8).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]/[CH3:22].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:12][C@H:9]1[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]2[S:4][CH:3]=[C:2](/[CH:20]=[CH:21]\[CH3:22])[C:11]=2[O:10]1
Reactant: C/C=C\B(O)O
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C/C=C\c1csc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixed solution of tert-butyl (2S)-8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (599 mg) obtained in Example 12, steps 1-4, cis-propenylboronic acid (192 mg), dichlorobis(triphenylphosphine)palladium (60 mg) and potassium carbonate (713 mg) in DME-water (1:1, 20 mL) was stirred at 85° C. for 4 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→15% ethyl acetate/hexane) to give the title compound (399 mg, 75%) as a colorless oil.
Reaction SMILES: [C:1]([O:9][CH:10]([C:17]#[N:18])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20]C1C=CC(C(Cl)=O)=CC=1>>[CH3:19][O:20][C:5]1[CH:4]=[CH:3][C:2]([C:1]([O:9][CH:10]([C:17]#[N:18])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:8])=[CH:7][CH:6]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: N#CC(OC(=O)c1ccccc1)c1ccncc1
Product: COc1ccc(C(=O)OC(C#N)c2ccncc2)cc1

Procedure:
The title compound was prepared using the same procedure Lantos, I. et al. (J. Med. Chem. 1984, 27, 72-75) employed to prepare 1-cyano-1(4-pyridyl)-methyl benzoate, except using 4-methoxybenzoyl chloride: 1H NMR (CDCl3): d 8.81 (d, 2H); 8.10 (d, 2H); 7.57 (d, 2H); 7.01 (d, 2H); 6.74 (s, 1H); 3.93 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C)C(O)=[N+](C)C.[NH2:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:7][C@@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:9]([NH:37][C:38]2[S:39][CH:40]=[CH:41][N:42]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)C(O)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step A, 144 mg; 0.5 mmol), O-benzotriazol-1-yl-N,N,N′,N′, -tetramethyluronium hexafluorophosphate (BOP, 268 mg; 0.55 mmol) and 2-aminothiazole (50 mg; 0.5 mmol) in dry methylene chloride (3 mL) at room temperature was added N,N-diisopropylethylamine (0.20 mL; 1.15 mmol) dropwise. The mixture was allowed to stir for 1 h. The mixture was then diluted with methylene chloride and washed with water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue. Flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 30% ethyl acetate/hexanes) provided 150 mg (81%) of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as an off white foam: EI-HRMS m/e calcd for C20H23N3O2S (M+) 369.1511, found 369.1511.