Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][C@@H:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:22][C@@H:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69 b) and (S)-methyl 2-amino-3,3-dimethylbutanoate hydrochloride (CAN 63038-27-7) as starting materials. MS (EI): m/e=412.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCCC#CC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCC#CC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hexynoic acid was allowed to react with 3-pyridine butanamine according to procedure B and the product was purified by chromatography on silica gel to give 6-(4-acetyl-3-hydroxy- 2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]-2-hexynamide, the title compound, mp 84°-86° (from hexane) in 42% yield.
Reaction SMILES: [C:1]([N:4]([CH:6]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]([CH3:18])[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[CH2:8][CH2:7]1)[CH3:5])(=[O:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[C:1]([N:4]([CH:6]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[CH2:18])[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[CH2:8][CH2:7]1)[CH3:5])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)C1CCc2ccccc2C(C)c2ccccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: C=C1c2ccccc2CCC(N(C)C(C)=O)c2ccccc21

Procedure:
5-(N-Acetyl-N-methylamino)-12-methyl-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene (10.5 g., 34 mmole), dichlorodicyanobenzoquinone (9.5 g. of 98%, 41 mmole) and 750 ml. of benzene were combined and heated at reflux under nitrogen for 3.5 hours. The mixture was cooled, washed four times with 1 M sodium hydroxide solution and twice with water, dried over potassium carbonate, treated with about 0.5 g. of decolorizing carbon, filtered, and evaporated in vacuo to give 10.5 g. of brown oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:18][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[O:20])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:25]([CH3:33])[CH:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:3]=1.[ClH:34].[N:35]1([CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:34].[CH3:17][C:14]1([CH3:16])[C:13]2[CH2:12][CH2:11][N:10]([CH2:18][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[O:20])[CH2:9][C:8]=2[C:7]2[C:2]([O:1][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:3][C:4]([CH:25]([CH3:33])[CH:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:5][C:6]=2[O:15]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Temperature: 6 °C
Reaction time: 8 h

Procedure:
A mixture of 1.14 g. (0.0025 mole) of {[10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridin-2-yl]acetyl}urea, 0.52 g. (0.0025 mole) of 4-piperidinobutyric acid hydrochloride, 0.54 g. (0.0026 mole) of dicyclohexylcarbodiimide, and 170 ml. of dried methylene chloride was stirred at room temperature for 26 hours. The reaction mixture was cooled at approximately 6° C. overnight and was filtered to remove dicyclohexylurea. The filtrate was evaporated in vacuo and the residue was dissolved in 3 ml. of methylene chloride and 12.5 ml. of cyclohexane. After standing overnight in the cold room (approximately 6° C.), the solid was filtered and recrystallized from methylene chloride-ether, giving 1.1 g. of the product, m.p. 167°-170°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[CH3:13][CH:14]([NH:18][C:19](=[O:21])[CH3:20])[C:15](=O)[CH3:16]>B(F)(F)F.CCOCC.C1C=CC=CC=1>[CH3:16][C:15]1([CH:14]([NH:18][C:19](=[O:21])[CH3:20])[CH3:13])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:12]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: CC(=O)NC(C)C(C)=O
Reactant: OCCc1c[nH]c2ccccc12
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(=O)NC(C)C1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A mixture of indole-3-ethanol (16.1 g), benzene (1200 ml), N-(1-methyl-2-oxopropyl)-acetamide[12.7 g, described by A. Triebs and W. Sutter, Chem. Ber. 84, 96(1951)] and boron trifluoride-etherate (5 drops) is refluxed using a water separating condenser for 60 minutes. After cooling, the mixture is washed with concentrated sodium bicarbonate, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel using chloroform. The eluates are evaporated to give a residue of the title compound as a 1:1 mixture of diastereoisomers:
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[O:30])[N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11](=[O:29])[CH:12]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:32][C:33]([Mg]Cl)([CH3:36])[CH2:34]C.[Cl-].[NH4+]>C1COCC1>[CH3:32][C:33]([CH3:36])([CH3:34])[C:3](=[O:2])[C:4]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11](=[O:29])[CH:12]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:30]
Reactant: CCC(C)(C)[Mg]Cl
Reactant: COC(=O)C(=O)N1CCCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 0.38 g (0.90 mmol) of 5 in anhydrous THF (5 mL) was added dropwise at −78° C. a 1.0M solution of 1.9 mL (1.90 mmol) of 1,1-dimethylpropyl magnesium chloride in THF, and the mixture was stirred for 3 hours at −78° C. The solution was poured over saturated ammonium chloride (50 mL) and extracted with EtOAc (2×100 mL). The organic phase was dried (MgSO4) and evaporated to a clear oil which was subject to column chromatography (EtOAc/Hexanes, 1:4) to yield 0.31 g (74.5%) of 6 as a clear oil. TLC Rf=0.8 (EtOAc/Hexanes, 1:4) 1H NMR (CDCl3, 400 MHz): δ 0.94 (t, 3H, J=7.5 Hz); 1.24 (s, 3H); 1.28 (s, 3H); 1.42–2.06 (m, 11H); 2.36 (d, 1H, J=13.0 Hz); 2.61–2.89 (dt, 1H, J=3.2, 12.9 Hz); 3.42 (brt, 1H, J=12.8 Hz); 5.08 (ddd, 1H, J=5.2,7.2,12.3); 5.32 (d, 1H, J=5.4 Hz); 7.16–7.32 (m, 10H); Anal. (C30H39NO3) C, H, N.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>>[OH:23][CH2:22][C:16]1[N:15]=[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:24]=[CH:25][C:2]([C:32]5[CH:31]=[N:30][N:29]([CH2:28][C:27]([CH3:43])([OH:44])[CH3:26])[CH:33]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=1
Reactant: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1ccc(-c3cnn(CC(C)(C)O)c3)cc1OCC2

Procedure:
Following the procedures as Example 182, Suzuki reaction of (5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-yl)methanol and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol provided 273. LCMS: Rt=2.33 min, [M+H]=464
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:24]([S:32][CH3:33])=[N:25][C:26]([CH3:31])=[CH:27][C:28]=2[S:29][CH3:30])=[O:21])[CH2:15][CH2:14]1.B1([O-])O[O:35]1.O.O.O.O.[Na+]>C(O)(=O)C>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:24]([S:32][CH3:33])=[N:25][C:26]([CH3:31])=[CH:27][C:28]=2[S:29]([CH3:30])=[O:35])=[O:21])[CH2:17][CH2:18]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(C)cc(S(C)=O)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Reaction time: 3 h
Yield: 7.1 %

Procedure:
To a solution of 2-[4-[2-(benzimidazol-2ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (1.00 g, 1.99 mmol) in acetic acid (20 ml) was dropped a solution of sodium perborate tetrahydrate (321 mg, 2.09 mmol) in acetic acid (30 ml), and the mixture was stirred for 3 hours. The reaction solution was concentrated in vacuo and the resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol 15:1) to provide 73 mg (yield 7%) of 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[4-methanesulfinyl-6-methyl-2-(methylthio)-3-pyridyl]acetamide as pale yellow oil. IR (KBr) cm−1: 3375, 2496, 1672, 1553, 1122. 1H-NMR (CD3OD) δ: 2.45 (3H, s), 2.51 (3H, s), 2.52-2.64 (8H,m), 2.70 (2H, t, J=6.8 Hz), 2.72 (3H, s), 3.04 (1H, d, J=16.1 Hz), 3.13 (1H, d, J=16.1 Hz), 3.30 (2H, t, J=6.8 Hz), 7.04-7.10 (2H, m), 7.32 (1H, s), 7.33-7.38 (2H, m), 7.78 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:20][C:14]4[NH:15][C:16](=O)[N:17]=[CH:18][C:13]=4[C:12]=3[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:16]1[N:17]=[CH:18][C:13]2[C:12]([C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[CH:3]=[CH:4]4)[O:20][C:14]=2[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(-c2c(-c3ccc4c(ccn4C)c3)oc3[nH]c(=O)ncc23)cc(OC)c1OC
Product: COc1cc(-c2c(-c3ccc4c(ccn4C)c3)oc3nc(Cl)ncc23)cc(OC)c1OC

Procedure:
The product of example 4 (200 mg, 0.46 mmol) was heated in freshly distilled P(O)Cl3 (10 ml) to 90° C. for 3 hours and then solvents were removed under vacuum. The residue was dissolved in CH2Cl2 and washed with aqueous NaHCO3 and evaporated. The residue was purified by silica gel column chromatography using increasing gradient of CH2Cl2 in hexane to pure CH2Cl2. Yield (40%); 1H NMR (300 MHz, CDCl3) δ: 3.77 (s, 6H, 2×OMe), 3.79 (s, 3H, OMe), 3.94 (s, 3H, OMe), 6.49 (d, J=3.0 Hz, 1H), 6.71 (s, 2H), 7.08 (d, J=3.0 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 7.53 (dd, J=9.0, 1.2 Hz, 1H), 8.05 (d, J=1.2 Hz, 1H), 8.72 (bs, 1H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3.C1(C#C)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>>[CH2:1]1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Solvent: C#Cc1ccccc1
Product: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reaction time: 0.07 h

Procedure:
A 10.0 gram (75.6 mmol) amount of dicyclopentadiene was added to a 20 ml scintillation vial. A 5.0 milligram (7.2 μmol) amount of RuClH(H2)(PCy3)2 was added. Five equivalents of phenylacetylene and hexachloroethane per equivalent of RuClH(H2)(PCy3)2 were added via the addition of 0.5 mls of 72 mM solution of phenylacetylene and hexachloroethane, respectively. The ring-opening polymerization of dicyclopentadiene was observed by a rapid thickening of the solution to a rubbery viscous material. After 4 minutes, the material was a rubbery solid. After 24 hours, the material was a hard rubbery solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:26])([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>C(O)C>[CH3:14][C:4]1[CH:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:23])([F:24])([F:25])[F:26])=[CH:18][CH:17]=2)[N:7]2[N:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[N:5]=1
Reactant: Cc1cc(Cl)n2nc(C(C)C)nc2n1
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: CCO
Product: Cc1cc(Nc2ccc(S(F)(F)(F)(F)F)cc2)n2nc(C(C)C)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of Intermediate 18 (0.042 g, 0.199 mmol) in ethanol (5 mL), 4-aminophenylsulfur pentafluoride (MANCHESTER, 0.044 g, 0.199 mmol) was added and the mixture was stirred at room temperature overnight. Solvent was removed in vacuo and the crude mixture was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 75:25 to 25:75%) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]1=[O:21].C([O-])(=O)C.[Na+].[Br:27]Br>C(O)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:15](=[O:16])[C:14]([Br:27])=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]1=[O:21]
Reactant: BrBr
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c(C(F)(F)F)c(Br)c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Yield: 41 %

Procedure:
3.6 g of 3-(2,4,6-trichlorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and 4.1 g of sodium acetate were added to 30 ml of acetic acid, followed by dropwise addition of 6.4 g of bromine with stirring at room temperature. The resulting solution was stirred at 110° C. for 5 hours and then the solvent was distilled away under reduced pressure. The residue was extracted with 100 ml of ethyl acetate, and the obtained organic layer was washed with water and dried. Then the solvent was distilled away to obtain a crude product. This crude product was washed with isopropyl ether and dried to obtain 1.8 g of the objective compound.
Reaction SMILES: CC1C=CC(C)=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:13](Cl)=O.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=C)=[CH:23][CH:22]=1.CN1CCOCC1>CC([O-])=O.CC([O-])=O.[Pd+2].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.CCOC(C)=O>[F:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Solvent: Cc1ccc(C)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Fc1ccc(C=Cc2cc(F)cc(F)c2)cc1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 80.3 %

Procedure:
A 25 mL round bottom flask was charged with p-xylene (10 mL), Pd(OAc)2 (11.3 mg, 0.05 mmol), 1,3-bis-(2,6-diisopropylphenyl) imidazolinium chloride (21.4 mg, 0.05 mmol), 3,5-difluorobenzoyl chloride (0.89 g, 5 mmol), 4-fluorostyrene (0.74 g, 6 mmol), and N-methyl morpholine (0.69 g, 6 mmol). The mixture was stirred at 120° C. for 3.5 h under nitrogen atmosphere. Then it was cooled to room temperature and EtOAc was added and filtered. The filtrate was washed with brine and dried over Na2SO4. Then it was filtered and purified via flash chromatography and gave the product (0.94 g, 80%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.47 (m, 2H), 7.08-6.88 (m, 6H), 6.70 (tt, 1H); 13C NMR (CDCl3, 75 MHz) δ 163.52 (dd), 162.98 (d), 140.82 (t), 132.77, 130.26, 128.58 (d), 126.53, 116.03 (d), 109.20 (q), 102.98 (t); 19F NMR (CDCl3, 282 MHz) δ-31207.2 (q, 2F), −31965.6 (q, 1F); HRMS (EI+) found 234.0645 M+, calcd 234.0656 for C14H9F3.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:11][CH2:12][CH2:13][OH:14])=[C:4](O)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]2[C:3]=1[CH2:11][CH2:12][CH2:13][O:14]2
Reactant: COc1ccc(F)c(CCCO)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(F)c2c1OCCC2
Temperature: -74 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
After dissolving 4.78 g of 3-fluoro-2-(3-hydroxypropyl)-6-methoxyphenol and 9.4 g of triphenylphosphine in 70 ml of THF under a nitrogen atmosphere, the solution was cooled to −74° C. Next, 7 ml of DIAD was added to the reaction mixture, and the temperature was raised to room temperature prior to stirring overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (3.6 g) as an oil.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[Cl-].[NH4+].C(CNC(C1C=C2C(=CC=1)N=CC=C2)=O)#N.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[N:37]1[NH:38][N:39]=[N:40][C:41]=1[CH2:42][NH:43][C:44]([C:46]1[CH:47]=[C:48]2[C:53](=[CH:54][CH:55]=1)[N:52]=[CH:51][CH:50]=[CH:49]2)=[O:45]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:23]([N:38]1[N:39]=[N:40][C:41]([CH2:42][NH:43][C:44]([C:46]2[CH:47]=[C:48]3[C:53](=[CH:54][CH:55]=2)[N:52]=[CH:51][CH:50]=[CH:49]3)=[O:45])=[N:37]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NCc1nn[nH]n1)c1ccc2ncccc2c1
Reactant: BrCc1ccccc1
Agent: N#CCNC(=O)c1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1nnn(Cc2ccccc2)n1)c1ccc2ncccc2c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
Sodium azide (260 mg, 4.0 mmol) and ammonium chloride (210 mg, 4.0 mmol) were suspended in a solution of quinoline-6-carboxylic acid cyanomethyl-amide described in Preparation Example E-1 (420 mg, 2.0 mmol) in N,N-dimethylformamide (15 mL), and the solution was stirred at 100° C. for 12 hours. Benzyl bromide (0.12 mL, 1.0 mmol) and potassium carbonate (400 mg, 3.0 mmol) were added to a solution having half the amount of the solution containing quinoline-6-carboxylic acid (2H-tetrazol-5-ylmethyl)amide obtained, which was then stirred for 20 minutes at 50° C. Water and ethyl acetate were added to the reaction solution, which was then partitioned, NH silica gel was added to the organic layer, and the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography, and the title compound (20 mg, 0.058 mmol) was obtained as a white solid.
Reaction SMILES: C[O:2][CH:3](OC)[C:4](=O)[CH3:5].[CH2:9]([C:16]1[C:17]([NH2:28])=[N:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C:16]1[NH:21][C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][N:18]2[C:3](=[O:2])[C:4]([CH3:5])=[N:28][C:17]=12)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(OC)C(C)=O
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Product: Cc1nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn-2c1=O

Procedure:
Synthesized using method B with 1,1-dimethoxypropan-2-one and 3-benzyl-5-phenylpyrazin-2-amine as starting materials. Exact mass calculated for C20H18N3O+ m/z+316.14, found m/z+316.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[C:12]([O:32][CH3:33])[CH:11]=1)=[O:8])=O.C1(C)C(C)=CC=CC=1.C>C(Cl)(Cl)Cl>[C:3]1(=[O:2])[N:9]([C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)=[C:12]([O:32][CH3:33])[CH:11]=2)[C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: COC(=O)CCC(=O)Nc1ccc(OCCCN2CCN(c3ccccc3)CC2)c(OC)c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: COc1cc(N2C(=O)CCC2=O)ccc1OCCCN1CCN(c2ccccc2)CC1
Temperature: 150 °C
Reaction time: 20 h
Yield: 4.9 %

Procedure:
A mixture of 20 g of 1-{3-[4-(3-methoxycarbonyl-propionamido)-2-methoxyphenoxy]-n-propyl}-4-phenyl-piperazine and 2 ml of xylene is stirred at 150° C. for 20 hours. Then, chloroform is added to the reaction mixture, and said mixture is treated with activated charcoal and then evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography (Solvent: 1% methanol/chloroform), and then recrystallized from ethyl acetate. 910 mg of 1-[3-(4-succinimido-2-methoxyphenoxy)-n-propyl]-4-phenyl-piperazine are obtained as colorless needles. Yield: 54%
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[O:10][C:9](=[O:25])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].[Cl-]>CCN(CC)CC.CO.CS(C)=O>[C:9]([C:13]1[CH:12]=[C:11]2[C:16]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9](=[O:25])[O:10]2)=[CH:15][CH:14]=1)([O:10][CH3:11])=[O:25]
Reactant: O=c1cc(-c2ccccc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(-c3ccccc3)cc(=O)oc2c1

Procedure:
A solution of 4-phenyl-7-trifluoromethanesulfonyloxycoumarin (1.75 g) and tetrakis (triphenylphosphine)palladium (0) (600 mg) in Et3N (1.3 mL), MeOH (15 mL) and DMSO (25 mL) was stirred under an atmosphere of carbon monoxide for 1 hr. at 70° C. The mixture was then poured onto sat. NH4Cl solution, extracted with EtOAc, dried and evaporated. Chromatography on silica gel (30% EtOAc/hexane) yielded the title compound as a solid, m.p. 133°-135° C.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:9][C:10]([C:12]1[N:13]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:14][CH2:15][NH:16][CH:17]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[CH:24](O)=[O:25]>>[C:5]([NH:9][C:10]([C:12]1[N:13]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:14][CH2:15][N:16]([CH:24]=[O:25])[CH:17]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)NC(=O)C1=CNCCN1C(=O)C(F)(F)F
Reactant: O=CO
Solvent: O=S(Cl)Cl
Product: CC(C)(C)NC(=O)C1=CN(C=O)CCN1C(=O)C(F)(F)F

Procedure:
49.60 g (416.9 mmol) of thionyl chloride was added over 40 min at 20° C. to a solution of 96.94 g (347.1 mmol) of 1-trifluoroacetyl-1,4,5,6-tetrahydropyrazine-2-carboxylic acid tert-butylamide in 465.9 g (10.1 mol) of formic acid. After a reaction time of 2 hours at 20° C., the mixture was concentrated on a rotary evaporator at 60° C. and 80 mbar and the brownish-black residue was taken up with 400 ml of ethyl acetate and 400 ml of water. The aqueous phase was washed again with twice 250 ml of ethyl acetate and the combined organic extracts were dried over 50.1 g of sodium sulfate. After filtration, the solution was concentrated on a rotary evaporator and the viscous residue was stirred with 250 ml of diisopropyl ether. The precipitated solid was filtered off, washed with twice 100 ml of diisopropyl ether and dried. The yield was 96.76 g (91 %) of colorless crystals. The melting point of the title compound was: 158.4° to 160.3° C. Other data concerning the title compound was: