Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][NH:26][C:27]4=O)[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15].C([O-])(O)=O.[Na+]>ClCCCl>[Br:3][C:27]1[C:28]2[C:23](=[C:22]([C:19]3[N:18]=[C:17]([C:9]4[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[C:7]([Cl:6])[CH:8]=4)[O:21][N:20]=3)[CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:25][N:26]=1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(=O)[nH]ccc34)no2)cc1Cl
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Br)nccc34)no2)cc1Cl
Reaction time: 8 h
Yield: 33 %

Procedure:
Phosphorus oxybromide (3.9 g) was added to a suspension of 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1(2H)-isoquinolinone (D39; 2.6 g) in 1,2-dichloroethane (300 ml) at room temperature. The resulting suspension was heated under reflux and stirred overnight. The reaction mixture was poured into cold sat. aq. NaHCO3 and the organic layer was separated. The aqueous layer was extracted with DCM (100 ml). The organic fractions were combined and dried over anhydrous sodium sulphate. The dried solution was filtered and the filtrate was concentrated to give the title compound (1 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4](=[O:14])[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C(=O)C(Cl)=C(Cl)[C:36](=[O:37])[C:35]=1C#N)#N>C(OC(C)C)(=O)C>[C:36]([O:14][C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH:11]=[C:2]([CH3:1])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:37])[CH3:35]
Reactant: COc1ccc2c(c1)CC(C)C(c1ccccc1)C2=O
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)C
Product: COc1ccc2c(OC(C)=O)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A round-bottomed flask was charged with 3-methyl-6-(methyloxy)-2-phenyl-3,4-dihydro-1(2H)-naphthalenone (5) (3.8 g, 14.3 mmol), Isopropyl acetate (70 mL), and p-toluene sulfonic acid (1.4 g, 7.14 mmol). The reaction mixture was refluxed for 16 h under N2. Reaction mixture was cooled to room temperature and DDQ (9.74 g, 43 mmol) was introduced to the reaction mixture and refluxed for an additional 3 h. Reaction mixture was concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography using hexanes:EtOAc (19:1 to 9:1) as an eluent to afford 4.10 g (94%) of the title compound (6). 1H NMR (400 MHz, CDCl3): δ 7.64 (d, J=12.0 Hz, 1H), 7.55 (br s, 1H), 7.43 and 7.39 (dd, J1=16.0 Hz, J2=8.0 Hz, 2H), 7.38 and 7.34 (m, 1H), 7.26-7.24 (m, 2H), 7.14-7.11 (m, 2H), 3.92 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: [N+:1]([CH:3]([CH3:11])[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])#[C-:2].C(N(CCCC)C1C=CC=CC=1)CCC>>[CH3:11][C:3]1[N:1]=[CH:2][O:5][C:4]=1[O:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [C-]#[N+]C(C)C(=O)OCCCC
Agent: CCCCN(CCCC)c1ccccc1
Product: CCCCOc1ocnc1C
Yield: 98.7 %

Procedure:
Example 5 was repeated, except that a mixture of 11.8% by weight of n-butyl α-isocyanopropionate and 88.2% by weight of N,N-dibutylaniline were added continuously via the inlet (A). 4-Methyl-5-n-butoxyoxazole was obtained in a yield of 98.7% via the top take off B and the amine via the side stream take off D.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[C:9]#N.Cl.[OH2:21].[OH-:22].[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[C:9]([OH:22])=[O:21]
Reactant: O
Reactant: N#CC(c1ccccc1Cl)N1CCc2sccc2C1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 100 °C

Procedure:
To 100 mg (0.3466 mmole) (±)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl) acetonitrile was dissolved in 2 mL t-butanol and add 1.5 mL HCl was added. The reaction mixture was refluxed for 9 hrs at 100° C. In the end, after the completion of reaction, water was added and pH was brought to 4 with 10% KOH solution. The product was extracted with 5 mL dichloromethane and proceeded as given in the earlier example. The yield was 40 mg (38%).
Reaction SMILES: [CH:1]12[CH2:11][CH:7]([C:8](=[O:10])[CH2:9]1)[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1.[CH3:12][Mg]Cl.O>O1CCCC1>[CH3:12][C:8]1([OH:10])[CH2:9][CH:1]2[CH2:11][CH:7]1[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1
Reactant: C[Mg]Cl
Reactant: O=C1CC2CC1C1CCCC21
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)CC2CC1C1CCCC21

Procedure:
Tricyclo [5.2.1.02,6] decan-8-one (15.0 g) in tetrahydrofuran (THF, 50 ml) is slowly added into CH3MgCl (9.7 g) in THF and the reaction mixture is stirred completely. Tetrahydrofuran (THF, 100 ml) with 5% of water is added into the reaction mixture. Then 100 ml of water is added to the reaction mixture. The reaction mixture is extracted by ether. The organic extract is concentrated in vacuo to yield 8-methyl-tricyclo [5.2.1.02,6] decan-8-ol (formula (X)) as white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:8]([CH:22]=O)=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]1[CH2:24][C@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1.[CH3:30][NH:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:30][N:31]([CH2:22][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]1([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]1=3)[CH2:19][CH2:18][O:17]4)[C:2](=[O:1])[N:3]2[CH2:24][C@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[CH3:32]
Reactant: O=Cc1cccc2c1C1(COc3cc4c(cc31)CCO4)C(=O)N2C[C@H]1CCCO1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN(C)Cc1cccc2c1C1(COc3cc4c(cc31)CCO4)C(=O)N2C[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To a stirred solution of 2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-4′-carbaldehyde (0.10 g, 0.26 mmol) and dimethylamine (0.19 mL, 0.38 mmol) in dichloroethane was added sodium triacetoxyborohydride (0.10 g, 0.46 mmol) at 0° C. The mixture was stirred at ambient temperature for 18 h, and quenched with water. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (methanol/ethyl acetate, 5/100) to afford 4′-[(dimethylamino)methyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.05 g, 46%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.29-7.20 (m, 1H), 7.07 (d, J=7.9 Hz, 1H), 6.98 (t, J=7.0 Hz, 1H), 6.45-6.39 (m, 1H), 6.38 (s, 1H), 5.07 (dd, J=8.8, 2.1 Hz, 1H), 4.88 (d, J=8.8 Hz, 1H), 4.52 (t, J=8.6 Hz, 1H), 4.33-4.21 (m, 1H), 3.98-3.62 (m, 4H), 3.33 (dd, J=13.2, 3.3 Hz, 1H), 3.03-2.88 (m, 2H), 2.80 (d, J=13.2 Hz, 1H), 2.09-1.63 (m, 10H); MS (ES+) m/z 421.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8](O)[CH2:7]1.C(N(S(F)(F)[F:27])CC)C>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([F:27])[CH2:7]1
Reactant: COC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(CC1CCC(F)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionic acid methyl ester (prepared as in Example 36, 180 mg, 0.56 mmol) in methylene chloride (0.28 mL) was treated with diethylaminosulfur trifluoride (0.11 mL, 0.85 mmol). The resulting mixture was stirred at 25° C. for 18 h. At this time, the reaction was diluted with water (50 mL). This solution was extracted with methylene chloride (3×30 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(3-fluoro-cyclopentyl)-propionic acid methyl ester (71.2 mg, 39.3%) as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]CO)=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH:14]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=[O:32].[Cs+].[Cs+]>C(#N)C>[OH:32][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:12][CH2:13][C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(CCBr)NC(=O)OCc1ccccc1
Reactant: OCCc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)[C@H](CCOc1ccc(CO)cc1)NC(=O)OCc1ccccc1
Yield: 81.7 %

Procedure:
The mixture constituted by 690 mg of 4-hydroxybenzenethanol, 1.72 g of ethyl 4-bromo-2-[[(phenylmethoxy)carbonyl]amino]butanoate and 1.63 g of Cs2CO3 in 100 ml of acetonitrile is heated under reflux or 45 minutes, the solid is filtered, washed with dichloromethane then the filtrate is evaporated under reduced pressure until 2.6 g of crude product is obtained which is purified by chromatography on a silica column (Kieselgel 60; 40-63 μm) eluting with a dichloromethane/methanol mixture 9/5. 1.58 g of expected product is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[C:49]1([SH:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[C:49]1([S:55][C:2]2[CH:3]=[C:4]([CH:8]([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Sc1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Sc5ccccc5)c4)c3)ncnc21
Yield: 80.1 %

Procedure:
To the 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.130 g, 0.000248 mol) from Example 429 Step 2, in dry 1,4-dioxane (1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). The solution was degassed with nitrogen, followed by addition of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.007 g, 0.00001 mol), is(dibenzylideneacetone)palladium(0) (0.0036 g, 0.0000062 mol), and benzenethiol (0.025 mL, 0.00025 mol). Again the solution was purged with nitrogen. The reaction mixture in a sealed tube was heated to reflux for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The crude product was triturated with hexane-ethyl acetate 9:1 to yield 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (110 mg, 80%). LC/MS (M+H)+: m/z=554.2.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:23]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C:32]1=O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(OC)C=CC=CC=1.[Pd]>[C:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:1][C@@H:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(-c2cccc(NC)c2)cc1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Agent: [Pd]
Solvent: COc1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(-c2cccc(NC)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Yield: 55.8 %

Procedure:
5.7 g (22.1 mmol) of ethyl (S)-2-amino-3-(3′-methylaminobiphenyl-4-yl)propionate and 5.8 g (28.7 mmol) of 2-benzoylcyclohexanone are dissolved in 10 ml of anisole. 0.6 g of 10% palladium-on-charcoal are added and the reaction medium is then refluxed using a Dean-Stark apparatus for 16 h. The cooled reaction medium is filtered through celite, rinsed with ethyl acetate and concentrated. The residue obtained is purified by chromatography on a column of silica and eluted with a 7/3 heptane/ethyl acetate mixture. 5.9 g of desired product are isolated with a 49% yield.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][C:7](=[O:9])[O:6][CH:5]1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH3:21])[CH:14]=[C:13]2[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34])([OH:3])=[O:2].C(N(CC)CC)C.[CH2:42]([NH2:45])[CH2:43][CH3:44]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([CH:4]([CH2:8][C:7](=[O:9])[NH:45][CH2:42][CH2:43][CH3:44])[CH:5]([C:10]1[CH:11]=[C:12]2[C:19](=[CH:20][CH:21]=1)[N:15]([CH2:16][CH2:17][CH3:18])[CH:14]=[C:13]2[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34])[OH:6])([OH:3])=[O:2]
Reactant: CCCN
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C3OC(=O)CC3C(=O)O)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCNC(=O)CC(C(=O)O)C(O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC

Procedure:
A solution of methyl 4-[5-(3-carboxy-2,3,4,5-tetrahydro-5-oxofuran-2-yl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.89 g), triethylamine (2.1 g), and propylamine (1.5 g) in methylene chloride (15 ml) was stirred and heated under reflux for 22 hr. The cooled mixture was diluted with ethyl acetate, washed (1M hydrochloric acid (twice), water (3 times), brine), dried (MgSO4), and evaporated to give methyl 4-[5-(2-carboxy-1-hydroxy-3-(propylcarbamoyl)propyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.82 g, 82%, as a mixture of diastereomers) as an off-white foam: partial NMR (300 MHz, DMSO-d6): 0.80(m, 6H, 2×CH3, both isomers), 3.83(s, 3H, OCH3, both isomers), 3.92(s, 3H, OCH3, both isomers), 4.71(d, 0.5H, CHOH, isomer A), 5.05(d, 0.5H, CHOH, isomer B), 7.64(t, 0.5H, NH isomer A/B), 7.75(t, 0.5H, NH isomer B/A).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: N#Cc1cccc(F)c1
Product: N#Cc1cccc(N2CCCCC2)c1

Procedure:
According to a similar manner to that in Reference Example 17, the title compound was synthesized from 3-fluorobenzonitrile and piperidine.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.N1C=CC=CC=1.Cl>>[F:1][C:2]1[C:7]([CH:8]=[CH:15][C:16]([OH:18])=[O:17])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
20 g (42 mmol) of pentafluoro-benzaldehyde, 21.23 g (2 eq.) of malonic acid, and 0.85 g (0.1 eq.) of piperidine were added to 24 g (3 eq.) of pyridine and stirred at room temperature for about 1 hour. After heating it to 80° C., the mixture was stirred for 12 hours. After the reaction, the resulting solution was cooled down to room temperature and was slowly added with 1M HCl until it was titrated to about pH 4. The resulting powder was filtered and washed with water, and then dried in a vacuum oven. (Yield: 13%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1I.C(N(CC)CC)C.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:27]#[C:26][C:23]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccccc1I
Reactant: C#Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C#Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-iodo-benzoic acid methyl ester (1.31 g, 5.00 mmol) in DMF (10 ml) are added bis(triphenylphosphine)-palladium(II)-chloride (351 mg, 0.50 mmol), copper(I) iodide (28.5 mg, 0.15 mmol), triethylamine (2.08 ml, 15.0 mmol) and 1-bromo-4-ethynyl-benzene (905 mg, 5.00 mmol). The resulting dark brown solution is flushed with nitrogen, heated to 80° C. and stirred in a closed reaction vial at this temperature for 16 hours. The reaction mixture is allowed to cool to room temperature and partitioned between water and dichloromethane. The organic phase is washed with 1 N HCl, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 2-(4-bromo-phenylethynyl)-benzoic acid methyl ester as brown oil; HPLC/MS 3.46 min (B), [M+H] 315/317.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1F)[CH:10]=[O:11].C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>C(OCC)(=O)C.O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)[CH:10]=[O:11]
Reactant: c1c[nH]cn1
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(-n2ccnc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a DMF (20 mL) solution of 3-chloro-4-fluorobenzaldehyde (500 mg), potassium carbonate (1.20 g) and imidazole (275 mg) were added one by one, and the reaction solution was agitated at 80° C. overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent: ethyl acetate→ethyl acetate:methanol=10:1), and 548 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:19][CH3:20])=[N:10][CH:9]=1
Reactant: CCC(Br)C(=O)Nc1ncc(Cc2ccccc2Cl)s1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)N1CCCCC1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing piperidine (170 mg, 2.0 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (31 mg, 0.082, 82%). ESI-MS m/z calc. 377.1, found 378.2 (M+1)+ Retention time 2.21 minutes.
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[CH:4][C:5]([F:14])=[C:6]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:7]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C1(C)C=CC=CC=1.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>[F:14][C:5]1[CH:4]=[C:3]([F:15])[C:2]([C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)=[CH:7][C:6]=1[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: OB(O)c1ccncc1
Reactant: CN(C)S(=O)(=O)c1cc(Br)c(F)cc1F
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: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)c1cc(-c2ccncc2)c(F)cc1F
Temperature: 90 °C

Procedure:
5-Bromo-2,4-difluoro-N,N-dimethyl-benzenesulfonamide (400 mg) and 4-pyridine-boronic acid (165 mg) was dissolved in toluene (5 ml) and abs EtoH (5 ml). To the mixture was then added Na2CO3 (200 mg) and Pd(PPh3)4 (79 mg) under an atmosphere of Argon. The resulting mixture was heated to 90° C. for 18 h. Then CH2Cl2 was added and the organic phase was washed with water and dried (MgSO4), filtered and evaporated to dryness. The residue was then used without any further purification. (MS m/z (rel. intensity, 70 eV) 298 (M+, 77), 256 (36), 191 (bp), 190 (98), 143 (74).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[N:4]=1.[Br:10][CH:11](Br)C1C=CC=C(F)N=1>>[Br:10][CH2:11][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[N:4]=1
Reactant: Fc1cccc(C(Br)Br)n1
Reactant: Fc1cccc(CBr)n1
Product: Fc1cccc(CCBr)n1

Procedure:
Fractions 2 and 3 were >96% pure 2-bromomethyl-6-fluoropyridine and were therefore combined. Fraction 4 was composed of a 1:1 mixture of 2-bromomethyl-6-fluoropyridine and 2-dibromomethyl-6-fluoropyridine. The nmr spectra was consistent with the proposed structure for Fractions 2 and 3.
Reaction SMILES: C(N1CC[O:6][CH2:5][CH2:4]1)C.C(OC(=O)C)(=O)C.[CH2:16]([O:23][C:24](=[O:68])[C@H:25]([CH2:64][CH:65]([CH3:67])[CH3:66])[NH:26][C:27](=[O:63])[C@H:28]([C:59]([CH3:62])([CH3:61])[CH3:60])[NH:29][C:30](=[O:58])[C@H:31]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH3:57])[NH:32][C:33](=[O:49])[C@@H:34]([CH:46]([CH3:48])[CH3:47])[NH:35][C:36](=[O:45])[C@H:37]([CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH2:38])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH2:16]([O:23][C:24](=[O:68])[C@H:25]([CH2:64][CH:65]([CH3:67])[CH3:66])[NH:26][C:27](=[O:63])[C@H:28]([C:59]([CH3:62])([CH3:61])[CH3:60])[NH:29][C:30](=[O:58])[C@H:31]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH3:57])[NH:32][C:33](=[O:49])[C@@H:34]([CH:46]([CH3:47])[CH3:48])[NH:35][C:36](=[O:45])[C@H:37]([CH2:39][O:40][C:41]([CH3:42])([CH3:44])[CH3:43])[NH:38][C:5](=[O:6])[CH3:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCN1CCOCC1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)COC(C)(C)C)C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](C(=O)N[C@@H](Cc1ccccc1C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 ml of N-ethylmorpholine and 0.37 ml of acetic anhydride were added in sequence to a solution of 1.95 g of N-[N-[N-[N-(O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 70 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 1 hour and was then washed in sequence with 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous magnesium sulphate and evaporated. Chromatography of the residue on silica using 5% methanol in dichloromethane for the elution gave afforded 1.45 g of N-[N-[N-[N-(N-acetyl-O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester; MS: m/e 780.6 [M+H]+.