Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=O)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:7]=[C:8](/[CH:9]=[CH:22]/[CH:23]=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1cccc(-n2cccn2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1cccc(-n2cccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(1H-pyrazol-1-yl)-benzaldehyde (prepared as described in Reference Example 3) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 199 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:21]=[C:20]([CH2:22][N:23]3[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]3)[C:19]=2[CH:30]=1.[CH3:31][Si:32]([CH3:35])([CH3:34])Cl>CCCCCC.O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:21]=[C:20]([CH2:22][N:23]3[CH2:28][CH2:27][C:26]([O:29][Si:32]([CH3:35])([CH3:34])[CH3:31])=[CH:25][CH2:24]3)[C:19]=2[CH:30]=1
Reactant: COc1ccc2c(c1)C(CN1CCC(=O)CC1)=C2
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COc1ccc2c(c1)C(CN1CC=C(O[Si](C)(C)C)CC1)=C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
17.4 ml of n-butyllithium in hexane are added at 0°-5° to a solution of 2.81 g of diisopropylamine in 30 ml of dry tetrahydrofuran. The whole is stirred at room temperature for 30 minutes, is again cooled to -15° and a solution of 6.13 g (25 mmol) of 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidin-4-one in 30 ml of tetrahydrofuran is added. After 15 minutes, a solution of 3.05 g (28 mmol) of trimethylchlorosilane in 15 ml of tetrahydrofuran is added dropwise. The whole is stirred overnight at room temperature, filtered and concentrated to dryness by evaporation in vacuo. 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-4-trimethylsilyloxy-1,2,5,6-tetrahydro-pyridine is thus obtained in the form of a light-yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].O[NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH2:28][OH:29])=[CH:25][C:24]=2[CH:30]=1)=[NH:19].[CH2:31](N=C=NCCCN(C)C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CS(C)=O.O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([CH:28]([OH:29])[CH3:31])=[CH:25][C:24]=4[CH:30]=3)[N:17]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Reactant: CCN=C=NCCCN(C)C
Reactant: N=C(NO)c1ccc2oc(CO)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(-c3ccc4oc(C(C)O)cc4c3)no2)cc1OCC
Temperature: 120 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A mixture of 3,4-diethoxybenzoic acid (0.21 g; 1 mmol), the product of Step C (0.2 g; 0.97 mmol) and hydrochloride salt of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (0.22 g; 1.15 mmol) in anhydrous dimethylsulfoxide (DMSO) (2 ml) was stirred for 20 min at ˜40° C. under N2. To it 1M tetra-n-butylammonium fluoride (TBAF) in terahydrofuran (THF) (0.4 ml) was added and the resulting mixture was stirred for 1 h at ˜120° C., then overnight at room temperature. The solvents were removed in vacuo and the residue was partitioned between EtOAc (15 ml) and H2O (5 ml). The organic phase was washed with brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.13 g; 34%), as greyish solid. 1H-NMR (CDCl3) 8.36 (d, 1H, J=3 Hz); 8.09 (dd, 1H, J=3, 9 Hz); 7.79 (dd, 1H, J=3, 9 Hz); 7.68 (d, 1H, J=3 Hz); 7.55 (d, 1H, J=9 Hz); 6.98 (d, 1H, J=9 Hz); 6.73 (s, 1H); 4.8 (s, 2H); 4.2 (m, 4H); 2.02 (s, 1H); 1.51 (m, 6H);
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8]>>[N:1]1([CH2:8][CH2:7][C:6]([OH:10])=[O:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C=CC(=O)O
Reactant: c1nc[nH]n1
Product: O=C(O)CCn1cncn1

Procedure:
In a manner analogous to that described in Example (8a), 2.8 g of 1,2,4-triazole are reacted with 2.88 g of acrylic acid to form the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[NH:63]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:64][C:65](O)=[O:66].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:63]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:64][C:65]([NH:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12])=[O:66]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
At 0° C. the solution of 930 mg (1.01 mmol) of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 15 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 200 mg (1.14 mmol) of Boc-Gly-OH, 150 mg (1.11 mmol) of 1-hydroxybenzotriazole and 235 mg (1.14 mmol) of dicyclohexylcarbodiimide in 40 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 12 h and TLC (chloroform/methanol, 10:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 100 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 50 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated. The residue was purified on sinica gel chromatography (CHCl3/CH3OH, 30/1) to provide 770 mg (73%) of the title compound as a glassy mass. Mp 82–84° C., FAB-MS (m/e) 1038.6[M+H]+, 1061.7[M+Na]+.
Reaction SMILES: [Br:1][C:2]1[C:3](C)=C(C=[CH:8][CH:9]=1)C#N.[CH3:11][Mg]Br.Cl.[CH2:15]1[CH2:19][O:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[C:9]([CH3:8])=[C:16]([C:17](=[O:18])[CH3:11])[CH:15]=[CH:19][CH:3]=1
Reactant: C[Mg]Br
Reactant: Cc1c(Br)cccc1C#N
Reactant: C1CCOC1
Agent: Cl
Product: CC(=O)c1cccc(Br)c1C
Temperature: 47.5 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
3-Bromo-2-methylbenzonitrile (810 mg, 4.13 mmol) was stirred in THF (5 mL) at 0° C. under argon, and methylmagnesium bromide (1.6 mL, 4.8 mmol) (3.0 M solution in Et2O). The reaction was stirred at 45-50° C. for 2 h. The reaction was cooled to 0° C. and 6 N HCl (5 mL) was added carefully. The reaction mixture was stirred at 40-50° C. for 2 h. After cooling, the mixture was extracted with Et2O (2×). The organic layers were washed with H2O, brine, dried over MgSO4, filtered and concentrated to give Intermediate 12A (600 mg, 2.82 mmol, 68.2% yield) as yellowish oil. LCMS=1.27 min [M+1]=211.9, 213.9 (Method B).
Reaction SMILES: C1(CO[CH2:9][CH2:10][NH:11][C:12](=[O:30])[CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19](OCC3C=CC=CC=3)=[CH:18][CH:17]=2)C=CC=CC=1.[C:31]([NH:41][C@H:42]([C:49]([OH:51])=O)[CH2:43][C:44]1[N:48]=[CH:47][NH:46][CH:45]=1)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].C(N[C@@H](C(O)=O)CC1N=CNC=1)(O[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=O>>[C:35]1([CH2:34][O:33][C:31]([NH:41][C@H:42]([C:49]([N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:20][CH:21]=2)[CH2:13][C:12]([NH:11][CH2:10][CH2:9][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[O:30])=[O:51])[CH2:43][C:44]2[N:48]=[CH:47][NH:46][CH:45]=2)=[O:32])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(CNCc1ccc(OCc2ccccc2)cc1)NCCOCc1ccccc1
Reactant: O=C(N[C@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Product: O=C(CN(Cc1ccc(-c2ccccc2)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)NCCCc1ccccc1

Procedure:
According to Example 10, Step 4, by substituting the compound from Step 1 above for N-[2-(phenylmethoxy)ethyl]-N2 -[[4-(phenylmethoxy)phenyl]methyl]glycinamide and CBZ-histidine for CBZ-D-histidine, the title compound was obtained as a white foam; ES-MS 646 (m+1).
Reaction SMILES: C=O.[Cl:3][C:4]1[N:5]=[C:6]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:7]2[N:13]=[C:12]([CH2:14][NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH:11]=[CH:10][C:8]=2[N:9]=1.[C:27]([BH3-])#N.[Na+].CO>C(Cl)Cl.C(OCC)(=O)C>[Cl:3][C:4]1[N:5]=[C:6]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:7]2[N:13]=[C:12]([CH2:14][N:15]([CH3:27])[CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: [BH3-]C#N
Reactant: CC(C)(O)CNCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CN(Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1)CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Paraformaldehyde (20 mg, 1.5 eq) was added to a solution of 1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylamino)-2-methylpropan-2-ol (0.16 g) in DCM (2.5 mL). The reaction was stirred for 5 minutes before addition of sodium cyanoborohydride (1.2 eq). Methanol (1 mL) was added to the reaction mixture which was then stirred overnight at room temperature. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 0.12 g of 1-(((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-2-methylpropan-2-ol as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:21])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH:13][C:14]([CH3:16])=[O:15])=[CH:8][C:7]=1[O:17]C(=O)C)#[N:2].[CH2:22]([NH:24][CH2:25][CH2:26]N)[CH3:23]>C(=S)=S>[CH2:22]([N:24]1[CH2:25][CH2:26][N:2]=[C:1]1[CH2:3][NH:4][C:5](=[O:21])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH:13][C:14]([CH3:16])=[O:15])=[CH:8][C:7]=1[OH:17])[CH3:23]
Reactant: CC(=O)Nc1cc(OC(C)=O)c(C(=O)NCC#N)cc1Cl
Reactant: CCNCCN
Solvent: S=C=S
Product: CCN1CCN=C1CNC(=O)c1cc(Cl)c(NC(C)=O)cc1O

Procedure:
143 g of N-(cyanomethyl) 2-acetoxy 4-acetamino 5-chlorobenzamide was introduced into a one liter balloon flask provided with sealed agitator, a reflux condenser on which there was disposed a bubble counter containing vaseline oil, a thermometer and a dropping funnel. Thereafter, 123 g of N-ethyl ethylene diamine were rapidly added dropwise. The reaction was exothermic. The temperature rose to 110° C. and the amount of gas evolved was substantial. A thick solution was obtained. The solution was heated to temperature of 120° and then, after 25 minutes of heating, drops of carbon disulphide were added and the temperature was then maintained at 120° for a further period of 20 minutes until the gas ceased to be evolved.
Reaction SMILES: [Cl:1][C:2]1[C:3](C(N)=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19](=[O:34])[N:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:21]=[CH:22][C:23]=2OCC)=[O:17])=[CH:11][C:10]=1[F:35].O.[C:40]([OH:43])(=O)[CH3:41].C(O)(=O)C.IC1C=CC=CC=1.CC#[N:57]>CCOC(C)=O>[NH2:57][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:34])[N:20]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[CH:21]=[CH:22][C:23]=3[O:43][CH2:40][CH3:41])=[O:17])=[CH:11][C:10]=2[F:35])[CH:6]=[CH:5][N:4]=1
Reactant: CC#N
Reactant: CC(=O)O
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2Cl)c(F)c1
Solvent: O
Solvent: Ic1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(N)c2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a mixture of 3-chloro-4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide (13.9 g, 25.7 mmol) in EtOAc (200 mL), MeCN (200 mL), and water (100 mL) at 0° C. was added iodobenzene diacetate (9.93 g, 30.8 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The resulting precipitate was filtered and washed with ethyl acetate. The combined filtrates were washed with saturated aqueous sodium bicarbonate solution and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. This residue and the original precipitate were combined and purified by flash chromatography (SiO2, 0-2% methanol/chloroform gradient elution) to give N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (9.8 g, 74%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.57 (s, 1H), 7.83-7.79 (m, 2H), 7.67 (d, 1H, J=5.6 Hz), 7.41-7.38 (m, 3H), 7.36-7.22 (m, 3H), 6.44 (d, 1H, J=7.6 Hz), 6.36 (br s, 2H), 5.86 (d, 1H, J=6.0 Hz), 4.18 (q, 2H, J=7.2 Hz), 1.23 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 513.09 (M+H)+.
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][NH:8]3)=[CH:4][C:3]=2[O:2]1.Br[CH2:26][C:27](Br)=[O:28].[NH2:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1>>[CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][N:8]3[CH2:26][C:27]([NH:30][CH:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][CH2:32]3)=[O:28])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Br)CBr
Reactant: NC1CCc2ccccc21
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3c(c1)OCO3)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc3c(c1)OCO3)N(CC(=O)NC1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].[Br:9][C:10]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[CH:27]([C:32]2[CH:37]=[C:36]([Cl:38])[C:35]([Cl:39])=[C:34]([Cl:40])[CH:33]=2)[C:28]([F:31])([F:30])[F:29])[CH:22]=[CH:21][C:11]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:13].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:9][C:10]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[CH:27]([C:32]2[CH:33]=[C:34]([Cl:40])[C:35]([Cl:39])=[C:36]([Cl:38])[CH:37]=2)[C:28]([F:31])([F:29])[F:30])[CH:22]=[CH:21][C:11]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])[CH2:17][CH2:16]1)=[O:13]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: O=C(O)CC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)CC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02 g, 0.16 mmol) in CH2Cl2 (10.0 mL), (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), PYBOP (0.09 g, 0.17 mmol), and DIPEA (0.06 g, 0.48 mmol) were added at ambient temperature. The reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was diluted with CH2Cl2. The combined CH2Cl2 layer was washed with 3N HCl and saturated NaHCO3 solution, the separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% MeOH in CH2Cl2) to afford the title compound as a off white gummy material (0.035 g, 29. %).
Reaction SMILES: [OH-].[K+].[CH:3]1[CH2:7]C=[CH:5][CH:4]=1.[CH3:8][C:9]([CH:11]=[CH2:12])=O.[CH3:13]O>>[CH3:8][C:9]1[CH:5]=[CH:4][C:3](=[CH2:7])[C:11]=1[CH:12]=[CH2:13]
Reactant: C1=CCC=C1
Reactant: CO
Reactant: C=CC(C)=O
Agent: [K+]
Agent: [OH-]
Product: C=CC1=C(C)C=CC1=C
Reaction time: 15 h

Procedure:
Into a glass reactor equipped with a dropping funnel and nitrogen inlet is charged methanol (240 ml) containing potassium hydroxide (1.2 moles). The solution is cooled to 10°-15° C. and freshly distilled cyclopentadiene (2 moles) is added. The solution is cooled to -5° to 5° C. and methylvinylketone (2 moles) is added dropwise during 23/4 hours. After addition, cooling is removed and the solution is stirred for about 15 hours. Then an equal volume of distilled water is added and the organic layer is extracted with chloroform. The organic layer is separated, dried and the chloroform evaporated leaving a red viscous oil, which is vacuum distilled to give the product, methyl vinyl fulvene.
Reaction SMILES: [C:1]([C:4]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.Br[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:24](=[O:25])[O:23]1>CC(C)=O>[C:1]([C:4]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:5]1[C:6]([O:8][CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:24](=[O:25])[O:23]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)C1(O)C=CC=CC1C(=O)O
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)C1(O)C=CC=CC1C(=O)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Yield: 84.4 %

Procedure:
o-Acetylsalicylic acid (18 g) and triethylamine (21 ml) were stirred at a temperature of 20°-25° C. for 30 minutes in 500 ml of acetone. When dissolution was completed, 3-bromophthalide (32 g) was added and the mixture refluxed 2 hours. The reaction mixture was then cooled to 20°-25° C. and poured into distilled water (500 ml). The resulting mixture was extracted with 200 ml of dichloromethane twice, discarding the acetone layer. After the organic solution was washed with 200 ml portions of distilled water twice, 5 g of anhydrous sodium sulfate were added and the mixture filtered. After filtration the organic filtrate was evaporated, the residue was taken up with previously warmed methanol. Decolorizing carbon (1 g) and filtering aid (1 g) were added. The methanolic solution was filtered, and the filtrate was cooled, first to room temperature, and subsequently in an ice/water bath. The solid precipitate was collected by filtration, and dried under vacuum at 40° C. to obtain a yield (83.9%; 26.2 g) of crude phthalidyl o-acetylsalicylate (m.p. 85° C.-88° C.).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH2:13]([CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C:14]#[CH:15]>>[CH2:13]([CH:16]1[CH2:21][CH2:20][N:19]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][CH3:12])=[O:3])[CH2:18][CH2:17]1)[C:14]#[CH:15]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccccc1OC(=O)Cl
Product: C#CCC1CCN(C(=O)Oc2ccccc2OC)CC1

Procedure:
2-(methoxy)phenyl chloroformate (5.00 g, 26.8 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.60 g, 20.6 mmol) according to general procedure 1. Yield=5.03 g, 89%. m/z MH+=274.04. HPLC rt=8.7 min.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1C=CC=CC=1>[CH2:12]1[CH2:13][O:10][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: O=Cc1cccc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1cccc2c1OCCO2
Temperature: 135 °C
Yield: 49 %

Procedure:
12.04 g of 2,3-dihydroxybenzaldehyde was dissolved in 120 ml of dry DMF. To this solution, 9.0 ml of 1.2-dibromoethane, 12.1 g of anhydrous potassium carbonate and 1.1 g of cupric oxide were added. The reaction solution was refluxed under heating for three hours on a hot water bath at 135° C. The reaction solution was diluted with 700 ml of benzene and then washed with 500 ml of water. The aqueous layer was separated and extracted with benzene (500 ml×2 times). The extracted organic layers were combined to the previously separated organic layer, the combined organic layer was dried over anhydrous magnesium sulfate. The inorganic salt was removed by filtration, and the reaction solution was concentrated under reduced pressure to obtain a brown syrup. This syrup was purified by silica gel column chromatography (n-hexane/acetone=5/1). The eluted solution was concentrated under reduced pressure, and the residue was recrystallized from n-hexane/acetone to obtain 7.0 g of the above identified compound as white crystals (melting point: 63-64° C.) (yield: 49%). The mother solution was concentrated and dried to obtain 3.2 g of the above identified compound as crude syrup (yield: 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]2([C:21]#[N:22])[CH2:10][C@@H:9]2[CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH2:21][NH2:22])[CH2:10][C@@H:9]2[CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@]1(c2cccc(Cl)c2)C[C@@H]1CCOCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NC[C@]1(c2cccc(Cl)c2)C[C@@H]1CCOCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of (1R,2R)-1-(3-chlorophenyl)-2-{2-[(phenylmethyl)oxy]ethyl}cyclopropanecarbonitrile (1.26 g, 4.0 mmol) in diethyl ether at 0° C. was treated with 2 equivalents of LAH (1M in diethyl ether). After 1.5 hours at 0° C., water was added dropwise until no further evolution of gas was observed. The aluminum salts were filtered off and washed with diethyl ether. Evaporation of the diethyl ether afforded the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.5 (dd, J=5.9, 4.8 Hz, 1H) 1.0 (dd, J=8.9, 4.7 Hz, 1H) 1.2 (m, 1H) 1.4 (s, 2H) 1.8 (m, 2H) 2.9 (m, 2H) 3.6 (m, 2H) 4.6 (s, 2H) 7.2 (m, 3H) 7.3 (m, 2H) 7.4 (m, 4H).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:10]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][CH:7](O)[C@@H:6]1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:45])=O>ClCCl>[CH2:1]([O:4][C@H:5]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:10]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][CH:7]([Cl:45])[C@@H:6]1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCO[C@H]1[C@@H](OCc2ccccc2)[C@@H](COCc2ccccc2)OC(O)[C@@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCO[C@H]1[C@@H](OCc2ccccc2)[C@@H](COCc2ccccc2)OC(Cl)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
Compound Y (505 mg, 1.03 mmol) in dry dichloromethane (8 ml) was treated with N,N-dimethylformamide (0.55 ml) and oxalyl chloride (0.55 ml) at room temperature for 45 minutes. The mixture was diluted with ice-cold toluene (40 ml), then quickly washed with ice-cold water (6 ml) and ice-cold, saturated, aqueous sodium hydrogencarbonate (6 ml), dried (Na2SO4) and concentrated to give crude Z in quantitative yield.