Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([CH3:47])[C:41]([CH2:45]Br)=[C:42]([CH3:44])[CH:43]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:45][C:41]1[C:42]([CH3:44])=[CH:43][C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:39][C:40]=1[CH3:47])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1CBr
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1c(C)cc(OCc2ccccc2)cc1C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Cool a solution of (R)-4-Benzyl-3-pent-4-enoyl-oxazolidin-2-one (4.8 g, 19 mmol) in THF (100 mL) to −78° C. Treat the solution dropwise with 10M LiHMDS in THF (20 mL, 20 mmol) and stir at −78° C. for 30 minutes. Treat the solution with 5-Benzyloxy-2-bromomethyl-1,3-dimethyl-benzene (6.8 g, 22 mmol) and allow to slowly warm to room temperature. The reaction stirs 3 hr at room temperature. Quench the reaction with 1N HCl (aqueous) and extract with Et2O. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 7.0 g (78%) of desired product. MS (m/e): 484 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1)=[S:40]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:40][C:39]([N:41]3[CH2:42][CH2:43][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:45][CH2:46]3)=[N:38][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[C:12]=2[F:29])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Yield: 38 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (2.00 g, 4.53 mmol), NBS (0.85 g, 4.75 mmol) and 1,1-dimethylethyl 4-(aminocarbonothioyl)-1-piperazinecarboxylate (2.22 g, 9.05 mmol) the title compound of Step A was obtained (1.16 g, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.30 (d, J=5.49 Hz, 1H), 7.62-7.76 (m, 1H), 7.46 (td, J=7.46, 1.28 Hz, 1H), 7.38 (t, J=6.09 Hz, 1H), 7.32 (t, J=7.78 Hz, 1H), 7.25 (t, J=9.11 Hz, 2H), 6.46 (d, J=5.40 Hz, 1H), 3.56 (br. s., 4H), 3.47 (br. s., 4H), 1.42 (s, 9H). m/z (ES+): 668 [M+H]+.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH:30][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:25]=[CH:26][CH:27]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: NCCc1cccc(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2cccc(Cl)c2)nc1
Yield: 60.3 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), 2-(3-chlorophenyl)ethylamine (560 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (738 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:52][OH:53])[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:54][Mg]Br>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH:52]([OH:53])[CH3:54])[CH2:50][OH:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@@](CO)(C(C)O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30 %

Procedure:
To a solution of (2R,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 8a (1.38 g, 1.88 mmol) in tetrahydrofuran (30 mL) was added dropwise methylmagnesium bromide (1.9 mL, 5.63 mL) at room temperature. The mixture was stirred at room temperature for 45 min under N2 and quenched with 10 mL of saturated aqueous ammonium chloride. Most of the solvent of the mixture was removed in vacuo. The resulting mixture was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (5 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=8/1 to give the title compound 8b as colourless oil (414 mg, 30.0%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.55 (m, 1H), 7.46 (d, 1H), 7.40 (d, 1H), 7.35-7.30 (m, 5H), 7.30-7.23 (m, 8H), 7.00 (m, 4H), 6.74 (d, 2H), 5.03 (t, 1H), 4.72 (m, 4H), 4.53 (d, 1H), 4.49 (d, 1H), 4.42 (d, 1H), 4.18 (m, 2H), 4.05 (d, 1H), 3.94 (m, 2H), 3.89 (d, 1H), 3.85-3.77 (m, 2H), 3.73 (m, 1H), 3.43 (d, 1H), 2.92 (s, 3H), 1.28 (t, 3H), 1.23 (d, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[C:37]([NH:44][CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:50][C:49]1[CH:51]=[CH:52][C:46]([CH2:45][NH:44][C:37](=[O:38])[O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[CH:47][CH:48]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)cc1
Temperature: 60 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (29.9 mg, 0.108 mmol) in dry dichloromethane (3 mL) was added triethylamine (0.038 mL, 0.271 mmol), 2-chloro-1-methylpyridinium iodide (41.0 mg, 0.160 mmol), and 4-(N—BOC-aminomethyl)aniline (30.6 mg, 0.138 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 60° C. for 2 hours. LC/MS showed no starting material remaining. The reaction mixture was concentrated and purified by HPLC on a Waters Sunfire column to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.CCCCCC.[C:23]1([Se:29]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([Se:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: Cl[Se]c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc2c(c1)CCCC2[Se]c1ccccc1
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A solution of 5,6,7,8-tetrahydro-3-methylquinoline (7.5 g, 51 mmol) in tetrahydrofuran (100 mI) was treated under an atmosphere of nitrogen with 1.5%-butyllithium in hexane (35 ml, 52 mmol) at 0°. The resulting red solution was added to a solution of phenylselenyl chloride (10 g, 52 mmol) in tetrahydrofuran (50 ml) at 0°. After 30 min, water (100 ml) was added and the mixture concentrated in vacuo. The aqueous residue was partitioned between saturated aqueous sodium chloride (100 ml) and ether (100 ml). The organic phase was dried (Na2SO4) and evaporated in vacuo to give the crude product (15.2 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Br
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C

Procedure:
A solution of 2-bromo-5-(trifluoromethyl)benzoic acid (10 g, 37.2 mmol) in thionyl chloride (44.2 g, 372 mmol) was heated at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then azeotroped with toluene to afford 2-bromo-5-(trifluoromethyl)benzoyl chloride, which was used directly in the next step.
Reaction SMILES: C([NH:8][C@H:9]1[C@@H:14]([CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:8][C@H:9]1[C@@H:14]([CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](NCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](N)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
The product of Example 42A (28.2 g, 0.088 mol) in ethanol (400 mL) was treated with 10% palladium on carbon (2 g) and the mixture was stirred under H2 at 50° C. for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to provide the title compound (18.0 g, 89%). MS (DCI/NH3) m/z 231 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].O>O1CCCC1>[NH:1]1[CH:5]=[N:4][C:3]([NH:6][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[N:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1nc[nH]n1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nc[nH]n1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a solution of 1H-1,2,4-triazole-3-amine (1.00 g, 11.9 mmol) and pyridine (1.16 ml, 14.3 mmol) in tetrahydrofuran (40 ml) was added 2,2,2-trichloroethyl chloroformate (1.97 ml, 14.3 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product (1.38 g, 44.5%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.ClCCl.[Cl:15][C:16]1[C:21]([CH:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[OH:23])=[CH:20][CH:19]=[CH:18][N:17]=1>CCOCC>[Cl:15][C:16]1[C:21]([C:22]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: OC(c1cccnc1Cl)C1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1cccnc1Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
Pyridinium chlorochromate (20.0 g, 93 mmol) was added to a dichloromethane (200 ml) solution of 2-chloro-α-cyclohexyl-3-pyridinemethanol (17.0 g, 75 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was mixed with pyridinium chlorochromate (10.0 g, 46 mmol) and stirred for 2 hours at room temperature, and then ether was added to the reaction solution to remove insoluble matter by filtration. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-chloroform) to give 2-chloro-3-cyclohexylcarbonylpyridine (14.9 g, 88%) as an oily material.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH2:24][O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O.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>[CH3:28][O:27][C:20]1[CH:21]=[C:22]([CH2:24][O:25][CH3:26])[CH:23]=[C:18]([O:17][CH3:16])[C:19]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COCc1cc(OC)c(OB(O)O)c(OC)c1
Reactant: CCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nn2c(-c3c(OC)cc(COC)cc3OC)cccc2c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (1.0 g) dissolved in a mixture of 1,2-dimethoxyethane (50 mL) and water (25 mL) was added 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (1.26 g), tetrakis(triphenylphosphine)palladium(0) (0.64 g) and barium hydroxide octahydrate (1.75 g), and the reaction mixture was heated and stirred for 2 hours at 80° C. To the resultant reaction mixture was added water and ethyl acetate, and remove insoluble residue was filtered out with celite. The filtrate was extracted with ethyl acetate, the organic extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and the title compound (0.77 g) was obtained as yellow crystals from the n-hexane:ethyl acetate (3:1) fraction.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]1[C:58]2[CH:59]=[CH:60][C:61]([C:63]3[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=3)=[CH:62][C:57]=2[O:56][CH2:55][CH2:54]1>CN(C=O)C>[O:53]1[C:58]2[CH:59]=[CH:60][C:61]([C:63]3[CH:64]=[C:65]([NH:69][C:24]([C:19]4[C:20](=[O:23])[O:21][C:22]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][C:13]=5[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:66]=[CH:67][CH:68]=3)=[CH:62][C:57]=2[O:56][CH2:55][CH2:54]1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2ccc3c(c2)OCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3c(c2)OCCO3)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 67.9 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.020 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-phenylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 67% yield: LCMS (ESI) m/z 484 (MH+).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([O:7][CH2:6][CH2:5][CH2:4][NH2:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: NCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCCOCc1ccccc1
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
A 60% sodium hydride dispersion in mineral oil (4 g, 0.1 mol) in a small portion at room temperature was added to a stirred solution of 3-amino-1-propanol (7.51 g, 0.1 mol) in THF (150 mL). The mixture was stirred for 30 min under nitrogen, and benzyl bromide (11.9 mL, 0.1 mol) was added. The mixture was stirred for 10 h at room temperature, and concentrated in vacuo. The residue was partitioned between 1 N aqueous HCl solution and CH2Cl2. The aqueous layer was adjusted to pH 10 with 10% aqueous NaOH solution, and extracted with CH2Cl2 (3×100 mL). The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2/MeOH (3:1 to 2:1, v/v) to give 3-(benzyloxy)propylamine (1.37 g, 8.3%) as a yellow oil. 1,3-Dicyclohexylcarbodiimide (14.4 mg, 0.07 mmol) in CH2Cl2 (2 mL) at 0° C. was added dropwise to a mixture of 5 (32 mg, 0.07 mmol) and 3-(benzyloxy)propylamine (11.6 mg, 0.07 mmol), and 1-hydroxybenzotriazole hydrate (9.5 mg, 0.07 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred for 18 h at room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2/MeOH (30:1, v/v) to afford 8 (36 mg, 85%) as a pale yellow liquid. 1H NMR (CDCl3) δ 8.05 (s, 1H, H4), 7.44 (d, 1H, H5, J=8.7 Hz), 7.19-7.28 (m, 11H, H6+2×OCH2Ph), 6.78-6.82 (m, 3H, H2′+H5′+H6′), 6.06 (AB, 2H, 3′,4′-OCH2O—, Δδ=6.9 Hz, J=1.5 Hz), 5.84 (AB, 2H, 7,8-OCH2O—, Δδ=4.2 Hz, J=1.5 Hz), 4.45 (s, 4H, 2×OCH2Pb), 4.38 (s, 2H, 2-CH2OBn), 3.55 (m, 4H, 3-CONHCH2CH2CH2OBn), 1.87 (quintet, 2H, 3-CONHCH2CH2CH2OBn. J=6.3 Hz); MS (FAB, positive) m/z 604 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25]Br)=[CH:19][CH:18]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:25][CH2:24][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: Fc1ccc(CCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCc2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.63 g) in dimethylformamide (20 mL) under argon was treated with 55% sodium hydride (0.394 g), stirred for 15 minutes and treated with 4-fluorophenylpropyl bromide (1.25 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified on HPLC (dichloromethane-hexane; 4:1) and crystallized from diethyl etherhexane to provide 0.67 g of 4-[[3-(4-fluorophenyl)propyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 42°-43° C.
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]=O>O1CCCC1>[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1/[CH:30]=[C:11](\[CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)P(=O)(OCC)OCC
Reactant: O=Cc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1ccco1)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% oil-based sodium hydride (6.50 g) in tetrahydrofuran (400 mL) was added dropwise a solution of 4-tert-butyl 1-ethyl 2-(diethoxyphosphoryl)succinate (55.0 g) in tetrahydrofuran (100 mL) under ice-cooling over 30 minutes, and then the mixture was stirred under the cooling for 1 hour. Then, thereto was added a solution of 2-furaldehyde (12.8 mL) in tetrahydrofuran (40 mL) under ice-cooling over 15 minutes, and the mixture was stirred at room temperature for 1 hour. Ice water was poured into the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure to give 4-tert-butyl 1-ethyl (2E)-2-(2-furylmethylene)succinate (47.0 g) as a brown oil crude. Then, the oil (47.0 g) was stirred in trifluoroacetic acid (100 mL) at room temperature for 1 hour, and then concentrated under reduced pressure. The resulting residue was treated azeotropically with toluene several times to give (3E)-3-(ethoxycarbonyl)-4-(2-furyl)-but-3-enoic acid (39.2 g) as a brown oil crude. Then, the oil (39.2 g) was dissolved in acetic anhydride (100 mL), and thereto was added potassium acetate (19.8 g), and then the mixture was heated to reflux for 45 minutes. The reaction mixture was let stand to be cooled, and then thereto was added water (100 mL), and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give ethyl 4-(acetyloxy)benzofuran-6-carboxylate (24.7 g) as a pale orange solid. APCI-MS m/z: 266 [M+NH4]+.
Reaction SMILES: C([O:8][C:9](=[O:29])[CH:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[NH:22])[NH2:21])=[CH:16][CH:15]=1)=[O:12])C1C=CC=CC=1.[OH-].[Na+:31]>C1COCC1>[Na+:31].[C:20]([C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11](=[O:12])[CH:10]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:9]([O-:29])=[O:8])=[CH:19][CH:18]=1)(=[NH:21])[NH2:22]
Reactant: N=C(N)c1ccc(NC(=O)C(C(=O)OCc2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N=C(N)c1ccc(NC(=O)C(C(=O)[O-])c2ccccc2)cc1

Procedure:
8.26 g (19.5 mmol) of the benzyl ester from example 1 were dissolved in 100 ml THF and stirred overnight with 20 ml 2 M aqueous NaOH. The solvent was removed after filtration, water was added, and the solution extracted with diethyl ether. The aqueous phase was freeze dried and sufficiently pure for further derivatization.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][CH:3]=1.Cl.[CH3:11][NH:12][CH2:13][CH2:14][NH2:15]>CO>[CH3:11][N:12]1[CH2:13][CH2:14][N:15]=[C:6]1[C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: CNCCN
Agent: Cl
Solvent: CO
Product: CN1CCN=C1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 4-aminobenzonitrile (5.1 g, 43 mmol) in dry methanol (60 mL) at 0 C, hydrogen chloride gas was bubbled through until saturation was reached. The mixture was then stirred at room temperature overnight. It was concentrated in vacuo. The residue was dissolved in dry methanol (60 mL). To the solution, N-methyl ethylenediamine (19 mL, 216 mmol) was added. The mixture was then heated to reflux for 3 h. After being cooled in fridge overnight, the precipitated product was collected by filtration, then was dried on vacuum to give white solids (3.7 g). MS 176.0 (M+H).