Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:15]([F:18])([F:17])[F:16])([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9][CH2:8]2)[OH:4].[C:21](OCC)(=[O:26])[CH2:22][C:23]([CH3:25])=[O:24]>C1(C)C(C)=CC=CC=1>[F:17][C:15]([F:18])([F:16])[C:3]([C:2]([F:1])([F:19])[F:20])([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:21](=[O:26])[CH2:22][C:23](=[O:24])[CH3:25])[CH2:10][CH2:9][CH2:8]2)[OH:4]
Reactant: CCOC(=O)CC(C)=O
Reactant: OC(c1ccc2c(c1)CCCN2)(C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)N1CCCc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Yield: 20.9 %

Procedure:
A stirred mixture of 6.0 g (0.02 mole) of α,α-bis(trifluoromethyl)-1,2,3,4-tetrahydro-6-quinolinemethanol, 2.6 g (0.02 mole) of ethyl acetoacetate, and 100 ml of xylene is refluxed for 16 hours. The mixture is allowed to cool and is evaporated. The residue is triturated with a mixture of toluene, ethyl acetate, and hexane (60:10:30). The insoluble portion is filtered off, washed with water, and dried to give 1.6 g (23%) of α,α-bis(trifluoromethyl)-1-(1,3-dioxobutyl)-1,2,3,4-tetrahydro-6-quinolinemethanol. C. A solution of 10.5 g (0.027 mole) of α,α-bis(trifluoromethyl)-1-(1,3-dioxobutyl)-1,2,3,4-tetrahydro-6-quinolinemethanol in 30 ml of concentrated sulfuric acid is heated on a steam bath for 30-45 minutes, cooled to approximately 60° C., and poured into ice. When the ice is melted, the precipitate is filtered off, washed with water, and dried. The solid is recrystallized from 2-ethoxyethanol to give 7.2 g (74% ) of 2,3-dihydro-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7-methyl-1H,5H-benzo[ij]quinolizin-5-one, m.p. 295°-296°.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]C)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:13]=2)[N:6]=1
Reactant: CCCCCCCCC=CCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCCCCCC=CCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (g, mmol) was reacted with N-(2-azidoethyl)octadec-9-enamide (g, mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-heptadec-8-enamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), δ 6.81 (s, 1H), δ 6.42 (s, 2H), δ 5.88 (s, 1H), δ 5.27 (s, 2H), δ 4.38 (s, 2H), δ 3.65 (s, 2H), δ 2.60 (s, 2H), δ 2.09 (s, 2H), δ 1.53-1.01 (m, 35H), 0.79 (t, J=6.3 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 174.2, 173.8, 148.3, 130.3, 130.1, 129.9, 129.8, 121.9, 85.1, 67.1, 49.5, 39.5, 39.1, 38.0, 37.7, 36.7, 36.6, 32.8, 32.3, 32.1, 31.7, 29.9, 29.8, 29.7, 29.5, 29.3, 29.2, 28.9, 28.7, 28.1, 28.0, 27.9, 27.4, 27.3, 27.3, 26.9, 25.9, 25.6, 25.3, 22.9, 22.8, 22.6, 14.3, 14.2 ppm; HRMS (ESI) calcd for C35H61N7O3(M+) 627.4836. found 627.4823, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)heptadec-8-enamide hydrochloride (0.128 g, 66% yield). 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), δ 6.96 (s, 1H), δ 6.45 (s, 1H), δ 6.09 (s, 1H), δ 4.58 (s, 2H), δ 3.58 (s, 2H), δ 2.75 (s, 2H), δ 2.10 (s, 2H), δ 1.96 (s, 4H), δ 1.69 (s, 2H), δ 1.41 (m, 4H), 1.23 (s, 24H), δ 0.84 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.5, 158.8, 155.7, 147.3, 129.7, 129.6, 127.6, 108.5, 94.6, 76.7, 51.3, 50.4, 48.6, 48.4, 48.2, 47.9, 47.8, 47.5, 47.3, 38.9, 37.5, 36.6, 45.9, 45.8, 33.9, 32.6, 31.9, 31.5, 29.8, 29.5, 29.4, 29.3, 29.2, 29.1, 28.2, 27.8, 27.0, 25.8, 24.9, 24.2, 23.8, 22.5, 13.5, 13.3 ppm; HRMS (ESI) calcd for C30H53N7O (M+) 527.4312. found 527.4298.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[S:19]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:21])=[O:20])(OCC)=O)C.[H-].[Na+].[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([O-:32])=[O:31]>O1CCCC1.C(OCC)(=O)C>[CH3:27][C:24]([CH3:25])([CH3:26])[CH2:23][O:22][S:19]([C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[CH:9]=[CH:37][C:36]1[CH:39]=[CH:40][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=1)(=[O:20])=[O:21]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)OCC(C)(C)C)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)COS(=O)(=O)c1cc([N+](=O)[O-])ccc1C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
2-(Diethoxyphosphorylmethyl)-5-nitro-benzenesulfonic acid, 2,2-dimethylpropyl ester Example 55, 1.15 g, 2.72 mmol) was dissolved in 55 mL of anhydrous tetrahydrofuran. Sodium hydride (0.12 g, 2.99 mmol) was added in one portion and the reaction mixture was stirred for twenty minutes. The solution turned a deep red color. After attaching a reflux condenser, 4-nitrobenzaldehyde (0.821 g, 5.43 mmol) was added and the mixture was heated to reflux in an oil bath. After six hours the solution was cooled to room temperature, diluted with ethyl acetate (300 mL), washed with brine (2×), washed with conc. sodium bisulfite (2×), and the organic layer was dried (MgSO4). After concentration on a rotovap the crude material was purified by a gradient flash column using 30 to 60% ethyl acetate in hexanes as the eluant to afford 1.13 g of the title compound as a yellow solid (91%): 1HNMR (CDCl3) δ8.91 (d, J=2 Hz, 1H), 8.51 (dd, J=9 Hz, 2 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 8.09 (d, J=16 Hz, 1H), 8.06 (d, J=9Hz, 1H), 7.74 (d, J=9Hz, 2H), 7.31 (d, J=16 Hz, 1H), 3.75 (s, 2H), 0.88 (s, 9H); MS (ES-NEG): [M−H]− 419; Anal. Calc. for C19H20N2O7S: C, 54.28; H, 4.79; N, 6.66. Found: C, 54.13; H, 4.68; N, 6.54.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.[N:14]1([C:20]([C@@H:22]2[CH2:27][C@H:26]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:25][N:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:23]2)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[OH2:39]>C1COCC1.C(=O)(O)[O-].[Na+]>[NH:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[C:2]([N:28]([CH2:29][CH2:30][CH3:31])[C@H:26]1[CH2:27][C@@H:22]([C:20]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:21])[CH2:23][N:24]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:25]1)=[O:39]
Reactant: O
Reactant: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Reactant: CCCN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Trichloromethyl)-1H-benzimidazole (1.09 g) and tert-butyl (3R,5S)-3-(morpholin-4-ylcarbonyl)-5-(propylamino)piperidine-1-carboxylate (1.49 g) were dissolved in THF (120 ml), sodium hydrogen carbonate (3.52 g) and water (60 ml) were added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (2:8-10:0) was concentrated under reduced pressure to give the object product (1.97 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[Br:12].[CH2:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=[N:31][OH:32])=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:32]/[N:31]=[CH:30]/[C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:22]=2)=[CH:6][C:5]=1[Br:12]
Reactant: ON=Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)c1ccc(CBr)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CO/N=C/c2cn(Cc3ccccc3)c3ccccc23)cc1Br
Temperature: 25 °C
Yield: 33.6 %

Procedure:
To a solution of 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.50g, 1.62 mmol) and 1-benzyl-1H-indole-3-carbaldehyde oxime (0.43 g, 1.70 mmol) in acetone (50 mL) was added cesium carbonate (2.12 g, 6.49 mmol). The mixture was heated to reflux for 6 hours and allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and brine and the layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 20/80) to give an off-white solid. This solid was recrystallized one time from ethyl acetate/hexanes (1/6) to give 4-[({[(1E)-(1-benzyl-1H-indol-3-yl)methylidene]amino}oxy)methyl]-2-bromobenzoic acid methyl ester (0.26 g, 34%) as off-white crystals. 1H NMR (400 MHz, CDCl3); δ 8.12 (s, 1H), 7.76 (m, 4H), 7.68 (s, 1H), 7.35 (d, 1H), 7.28 (m, 3H), 7.23 (m, 2H), 7.11 (d, 2H), 5.33 (s, 2H), 5.27 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[CH:17]1([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[CH2:19][CH2:18]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]4)=[O:27])=[CH:29][CH:30]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1C
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccc(OCC4CC4)cc3)ccc2n1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.7 %

Procedure:
To a solution of ethyl 5-amino-1-methyl-1H-indole-2-carboxylate (2.293 g) and 4-(cyclopropylmethoxy)benzoic acid (1.897 g) in DMF (23 mL) were added 1-hydroxybenzotriazole monohydrate (1.965 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.460 g) and N,N-dimethylaminopyridine (1.326 g), and the mixture was stirred at room temperature for 17 hr. After dilution with ethyl acetate, water was added, and the organic layer was washed successively with 1N hydrochloric acid, 1N aqueous, sodium hydroxide solution and saturated brine, and concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (2.466 g, yield 64%) as a beige solid.
Reaction SMILES: CCOCC.[CH:6]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16])[CH2:8][CH2:7]1.[CH2:18]([OH:28])[C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>N1C=CC=CC=1>[CH:25]1([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([O:16][CH2:15][C:14]#[C:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:6][CH2:7][CH3:8])=[O:28])[CH2:27][CH2:26]1
Reactant: O=C(Cl)CCCCCCC1CC1
Reactant: CCCCCCCC#CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCC#CCOC(=O)CCCCCCC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 60 ml. anhydrous ether and 1.5 g. 7-cyclopropylheptanoyl chloride is added 1.2 g. 2-decyn-1-ol. The mixture is cooled to 0° and 0.8 ml. pyridine is added. The solution is stirred at room temperature for 1 day. The product is worked up using the procedure of Example 1C to yield 2-decynyl 7-cyclopropylheptanoate.
Reaction SMILES: C[O-].[Na+].[CH3:4][S:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N+:15]=[N-:16]>CO.O>[CH3:21][O:20][C:18](=[O:19])[C:17]([N:14]=[N+:15]=[N-:16])=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([S:5][CH3:4])=[CH:7][CH:8]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(=Cc1ccc(SC)cc1)N=[N+]=[N-]
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of sodium methoxide prepared from Na metal (8.65 g, 0.38 m) in methanol(200 mL) at 0°-5° C., was added a solution of 4-(methylthio)benzaldehyde (12.6 ml, 94.7 mmol) and methyl azidoacetate (44 g, 0.382 mol) in methanol (30 mL). After stirring at the same temperature for 3 hours, the suspension was diluted with H2O (300 mL). The solids were filtered, washed with water and dried under vacuum to provide 19.4 g (82.0%) of methyl-2-azido-3-(4-methylthiophenyl)propenoate as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[CH:21][N:20]=1
Reactant: Nc1nccc(C(=O)O)n1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (135 mg, a white solid) from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (210 mg, 0.72 mmol, Amine-5, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (100 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: CC(C)=O.Cl[C:6]1[N:11]=[C:10](Cl)[C:9]([N+:13]([O-])=O)=[CH:8][N:7]=1.O.O.[I-:18].[Na+].[IH:20]>[Fe].O>[I:18][C:6]1[N:11]=[C:10]([I:20])[C:9]([NH2:13])=[CH:8][N:7]=1
Reactant: I
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: [I-]
Agent: [Fe]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1cnc(I)nc1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 4-necked roundbottom flask was charged with acetone (9.8 L), 2,4-dichloro-5-nitropyrimidine (670 g, 3.45 mol), and sodium iodide dihydrate (1929.6 g, 10.38 mol). Hydrogen iodide (67 ml, 40%) was then added dropwise. The resulting solution was allowed to react, with stirring, for three hours while the temperature was maintained at 20-30° C. Iron (978.6 g, 17.48 mol) was then added followed by the dropwise addition of water (300 ml). The resulting solution was allowed to react, with stirring, for an additional two hours while the temperature was maintained at reflux. The resulting slurry was filtered and the filtrate was concentrated under reduced pressure. The resulting aqueous solution was extracted four times with five liters of ethyl acetate. The combined organic layers were concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with 1:1 ethyl acetate/petroleum ether to afford the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[C:8]([O:11][CH2:12][CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])(=[O:10])[CH3:9].C(OC(=O)C[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])C.Cl>C(O)C.O>[F:26][C:25]([F:28])([F:27])[C:24]([NH:15][C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][CH2:12][O:11][C:8](=[O:10])[CH3:9])=[O:29]
Reactant: CC(=O)OCC[C@H](N)C(=O)O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(=O)OCC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reaction time: 14 h
Yield: 45.1 %

Procedure:
7.6 g (55 mol) of potassium carbonate are added to a suspension of 9.9 g (50 mmol) of O-acetyl-L-homoserine hydrochloride and 7.8 g (55 mmol) of trifluoroacetylacetic acid ethyl ester in 200 ml of ethanol, and stirring is carried out for 14 hours. 10.8 g (110 mmol) of 37% hydrochloric acid and 200 ml of water are then added. The product obtained after removal of the ethanol by distillation is filtered off with suction, washed with water and dried. 5.8 g (45%) of N-trifluoroacetyl—O—acetyl-L-homoserine are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Li]CCCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([B:17]([OH:22])[OH:18])[S:8][C:7]=2[CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc2ccsc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(B(O)O)sc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 6-methoxybenzo[b]thiophene (Graham, S. L., et al. J. Med. Chem. 1989, 32, 2548-2554)(18.13 g, 0.111 mol) in 150 mL of anhydrous THF at −60° C. was added n-BuLi (76.2 mL, 0.122 mol, 1.6 M solution in hexanes), dropwise via syringe. After stirring for 30 min, triisopropyl borate (28.2 mL, 0.122 mol) was introduced via syringe. The resulting mixture was allowed to gradually warm to 0° C. and then partitioned between 1.0 N HCl and EtOAc (300 mL each). The layers were separated, and the organic phase was dried over Na2SO4. Concentration in vacuo produced a white solid that was triturated from Et2O/hexanes. Filtration provided 16.4 g (71%) of 6-methoxybenzo[b]thiophene-2-boronic acid as a white solid.
Reaction SMILES: [CH2:1]([Br:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:11]([NH2:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>CC(C)=O>[Br-:10].[C:11]([C:12]1[CH:13]=[N+:14]([CH2:1][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH:15]=[CH:16][CH:17]=1)(=[O:18])[NH2:19]
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=O)c1cccnc1
Solvent: CC(C)=O
Product: NC(=O)c1ccc[n+](CC(=O)c2ccccc2)c1
Product: [Br-]

Procedure:
17.5 g of phenacyl bromide was dissolved in 16 ml of acetone combined with a hot solution prepared by dissolving 10.73 g of nicotinamide in 24 ml of alcohol, and heated for 5 minutes on a steam bath. After cooling, crystals thus formed were collected by filtration and washed with alcohol and benzene to obtain 15.5 g of slightly yellow crystals (3-carbamoyl-1-phenacylpyridinium bromide).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][C:6]#[N:7].[Cl:8][C:9]1[C:13]([Cl:14])=[N:12][C:11](=[C:15](Cl)Cl)[N:10]=1.[O:18]1CCOCC1>>[C:6]([CH2:5][CH2:4][N:3]([CH3:2])[C:15]([C:11]1[NH:12][C:13]([Cl:14])=[C:9]([Cl:8])[N:10]=1)=[O:18])#[N:7]
Reactant: CNCCC#N
Reactant: C1COCCO1
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Agent: Cl
Product: CN(CCC#N)C(=O)c1nc(Cl)c(Cl)[nH]1
Yield: 67 %

Procedure:
24 g (0.2 mol) of 3-methylaminopropionitrile hydrochloride were added to a solution of 21.8 g (0.1 mol) of 4,5-dichloro-2-dichloromethylene-imidazole in 100 ml of dioxane and the mixture was heated to the reflux temperature for two hours, while stirring. After cooling, the product was precipitated with water, filtered off, washed with water and dried. In this way, 16.5 g (67% of theory) of 4,5-dichloroimidazole-2-carboxylic acid N-(2-cyanoethyl)-N-methylamide were obtained. Melting point: 184° C. (from acetonitrile).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3([CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[C:7](=[O:20])[C:6]=2[CH:21]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C(Cl)Cl.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.O>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]4([CH2:10][CH2:11][C:12]5[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=5[CH2:14][CH2:15]4)[C:7](=[O:20])[C:6]=3[CH:21]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: O=C1c2cc(Br)ccc2OC12CCc1ccccc1CC2
Reactant: OB(O)c1cc(F)cc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1c2cc(-c3cc(F)cc(Cl)c3)ccc2OC12CCc1ccccc1CC2
Temperature: 110 °C
Yield: 92.5 %

Procedure:
A 10 mL microwave tube was charged with 5′-bromo-5,6,8,9-tetrahydro-3′H-spiro[benzo[7]annulene-7,2′-benzofuran]-3′-one (0.0573 g, 0.167 mmol), 3-chloro-5-fluorophenylboronic acid (0.0930 g, 0.53 mmol), Cs2CO3 (0.2537 g, 0.78 mmol), 1,4-dioxane (4 mL), water (1 mL), and PdCl2(PPh3)2 (0.0118 g, 0.0168 mmol). The tube was heated in a CEM microwave reactor at 110° C. for 30 min. The reaction mixture was diluted with CH2Cl2 and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.0607 g (92%) of 5′-(3-chloro-5-fluorophenyl)-5,6,8,9-tetrahydro-3′H-spiro[benzo[7]annulene-7,2′-benzofuran]-3′-one. LC-MS tR=2.55 min in 3 min chromatography, m/z 393, 395 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29][NH2:30]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2c(OC)cccc2OC)n(C)c(=O)c1O
Reactant: Cc1ccc(CN)cc1Cl
Product: COc1cccc(OC)c1-c1nc(C(=O)NCc2ccc(C)c(Cl)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 3-chloro-4-methylbenzylamine (107 mg, 0.75 mmol). The title product was obtained as a pink solid (51.1 mg, 77% yield). 1HNMR (500 MHz, CDCl3) δ: 12.09 (1H, s), 7.92 (1H, t, J=5.50 Hz), 7.39 (1H, t, J=8.24 Hz), 7.28 (1H, d, J=1.22 Hz), 7.17 (1H, d, J=7.63 Hz), 7.10 (1H, dd, J=7.63, 1.53 Hz), 6.62 (2H, d, J=8.24 Hz), 4.49 (2H, d, J=6.40 Hz), 3.76 (6H, s), 3.28 (3H, s), 2.33 (3H, s). HRMS (ESI) calcd for C22H23ClN3O5 (M+H): 444.1326; found: 444.1327.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:20]([OH:22])=O)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:23]([C:27]1[O:31][N:30]=[C:29]([NH2:32])[CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1.CCOC(C)=O>[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:20](=[O:22])[NH:32][C:29]1[CH:28]=[C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:31][N:30]=1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CC(C)(C)OC(=O)N1CCCCCC1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCCC[C@H]1C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorus oxychloride (0.88 g, 5.73 mmol) is added drop wise at 0° C. to a solution of perhydro-azepine-1,2-dicarboxylic acid 1-tert-butyl ester (0.93 g, 3.82 mmol) and 5-tert-butyl-isoxazol-3-ylamine (0.54 g, 3.82 mol) in pyridine (10.0 mL). The reaction mixture is slowly warmed up to room temperature and stirred for three hours. The mixture is diluted with EtOAc and washed twice with saturated NH4Cl solution. The organic phase is washed with 1N HCl, and after drying over anhydrous Na2SO4 the solvent is removed under reduced pressure to afford the crude product that is used in the next step without further purification; m/z 366 [M+H+].
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCN3CCOCC3)cccc21
Solvent: CO
Product: NCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 3-morpholinylpropylphthalimide (219 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.