Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[CH:16][CH:17]=1)[C:6](O)=[O:7].[CH2:30]([NH2:33])[CH:31]=[CH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH2:30]([NH:33][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([C:12]2[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]3[CH2:20][C:21]([CH3:27])([CH3:28])[NH:22][C:23]([CH3:26])([CH3:25])[CH2:24]3)=[CH:16][CH:17]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:31]=[CH2:32]
Reactant: C=CCN
Reactant: COc1cc(C(=O)O)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCNC(=O)c1ccc(-c2ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
To a solution of crude 3-methoxy-4-(6-(methyl(2,2,6,6 tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzoic acid (0.354 mmol) in DMF (4 mL) and CH2Cl2 (4 mL) was added TEA (0.40 mL, 2.83 mmol), allyl amine (0.053 mL, 0.71 mmol), and HATU (202 mg, 0.53 mmol). The crude reaction was allowed to stir at RT overnight. The crude mixture was quenched with sat aq NaHCO3 and diluted with CH2Cl2. The organic layer is washed with water (6×), brine, dried over MgSO4, filtered, and concentrated. The crude product was purified via HPLC to give N-allyl-3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzamide (8.2 mg). LCMS Rt=1.08 min (condition B); MS (M+1)=438.1
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10]C(C)C)=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH:22]=[C:21]([CH3:32])[C:20]=1[CH3:33].[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH:22]=[C:21]([CH3:32])[C:20]=1[CH3:33]
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)O)c2C)c1C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
To a solution of isopropyl 2-[4-fluoro-3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2-methyl-phenoxy]acetate (80 mg, 0.17 mmol, 1.0 eq) in a mixture of THF (5 mL) and MeOH (5 mL) was added NaOH (2M aqueous solution, 5 mL, 10 mmol). The reaction was stirred for 3 h then the organic solvent was removed under reduced pressure. The remaining aqueous solution was adjusted to pH 5 with diluted HCl and the mixture extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 400:1 to 4:1) to give the title compound as a white solid (74 mg, 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[C:13]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:33].Cl.O1CCOCC1>CO>[ClH:33].[O:31]=[C:13]1[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][N:14]1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](NC(=O)OCc3ccccc3)C2=O)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(N[C@H]1CCCN(C2CCNCC2)C1=O)OCc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
A flask was charged with (S)-tert-butyl 3-(benzyloxycarbonylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (Example 39, Steps A-B; 5.0 g, 12 mmol), CH2Cl2 (50 mL), and methanol (5 mL), 4N HCl in dioxane (29 mL, 116 mmol) was added and the reaction stirred overnight. The reaction was concentrated to afford crude (S)-benzyl 2-oxo-1,4′-bipiperidin-3-ylcarbamate hydrochloride (4.3 g, 100%) which was taken forward without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>CCO.O>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[CH:27][C:28](/[CH:29]=[CH:13]/[C:12](=[O:14])/[CH:11]=[CH:10]/[C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:9][CH:8]=2)=[CH:31][CH:32]=1
Reactant: CC(=O)/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccc(OC(F)(F)F)cc1)/C=C/c1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 32.3 %

Procedure:
A solution of (E)-4-(4-(trifluoromethoxy)-phenyl)-but-3-en-2-one (623 mg, 2.7 mmol) in EtOH (10 mL) was stirred for 5 min at 0° C. A solution of K2CO3 (748 mg, 5.4 mmol) in H2O (4 mL) was added and the reaction mixture was stirred for further 1 h. After the dropwise addition of 4-(trifluoromethyl)-benzaldehyde (392 μl, 2.9 mmol), the mixture was continued to stir for 4 h at 0° C. and for 2 h at ambient temperature. The resulting yellow precipitate was filtered and dried in vacuo to obtain NW337 as a pale yellow solid (337 mg, 34%). mp: 97-99° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.76 (d, 3J=16.1 Hz, 1H, Hvin), 7.75 (d, 3J=15.7 Hz, 1H, Hvin), 7.74 (d, 3J=8.8 Hz, 2H, HAr), 7.69 (d, 3J=8.1 Hz, 2H, HAr), 7.67 (d, 3J=8.7 Hz, 2H, HAr), 7.29 (d, 3J=8.0 Hz, 2H, HAr), 7.15 (d, 3J=16.0 Hz, 1H, Hvin), 7.07 (d, 3J=16.0 Hz, 1H, Hvin). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.2 (C), 150.7 (C), 142.1 (CH), 141.6 (CH), 138.1 (q, 4J(C, F)=1.3 Hz, CH), 133.2 (C), 132.0 (q, 2J(C, F)=32.7 Hz, C), 129.9 (CH), 128.5 (CH), 127.3 (CH), 126.0 (q, 3J(C, F)=3.8 Hz, CH), 125.9 (CH), 122.1 (C), 122.0 (C), 121.2 (CH), 118.7 (C). MS (FAB) m/z: 387.1 (M+). Anal. calcd for C19H12F6O2.0.5H2O: C, 57.73; H, 3.31. Found: C, 57.75; H, 3.20%.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[C:14]([CH:15]=[CH2:16])=[CH:13][CH:12]=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([Si:5]([O:8][C:9]1[C:10]([F:17])=[CH:11][CH:12]=[CH:13][C:14]=1[CH2:15][CH3:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Reaction time: 4 h

Procedure:
To a stirred solution of tert-butyl(2-fluoro-6-vinylphenoxy)dimethylsilane (1.18 g, 4.67 mmol) in ethyl acetate (61 mL) under nitrogen, was added 497 mg of 10% palladium on carbon. The flask was then equipped with a hydrogen containing balloon and the reaction mixture stirred rapidly for 4 hours. The hydrogen balloon was removed, the reaction mixture sparged with nitrogen, and then filtered through a plug of Celite®, eluting with EtOAc. The filtrate was concentrated to dryness to afford the title compound that was used without further purification. 1H NMR (500 MHz, CDCl3) δ 6.94-6.85 (m, 2H), 6.85-6.77 (m, 1H), 2.65 (q, J=7.6, 2H), 1.19 (t, J=7.5, 3H), 1.02 (s, 9H), 0.21 (d, J=2.7, 6H).
Reaction SMILES: [C:1]([O:6][CH:7]([CH2:14][CH3:15])[C:8]([C:11]([OH:13])=[O:12])([F:10])[F:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1[CH2:20][O:19][CH2:18]C1.COCCl>O>[C:1]([O:6][CH:7]([CH2:14][CH3:15])[C:8]([C:11]([O:13][CH2:18][O:19][CH3:20])=[O:12])([F:10])[F:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Reactant: C1CCOC1
Agent: COCCl
Solvent: O
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OCOC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Under nitrogen, a 20 mL reactor was charged with 70 mg (0.25 mmol) of 1-hydroxycarbonyl-1,1-difluoro-2-butyl methacrylate (purity: 78%) and 3 mL of THF (dehydrated one), followed by cooling to 0° C. Then, 65 μL (0.47 mmol, 1.9 eq) was added, followed by stirring at 0° C. for 10 min. Then, 30 μL (0.40 mmol, 1.6 eq) of chloromethyl methyl ether was added, followed by stirring at 0° C. for 20 min. Then, 5 mL of water was added to the reaction solution, followed by extraction with diisopropyl ether two times and removal of water with magnesium sulfate. After conducting filtration, diisopropyl ether was distilled off, thereby obtaining 58 mg of the target 1-(methoxymethyl)oxycarbonyl-1,1-difluoro-2-butyl methacrylate. Upon this, purity was 96%, and yield was 83%.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:6]1[C:7]([Cl:13])=[N:8][CH:9]=[N:10][C:11]=1[CH3:12])[CH2:4][CH3:5]>CC(O)=O>[CH2:3]([C:6]1[C:7]([Cl:13])=[N:8][CH:9]=[N:10][C:11]=1[CH2:12][Br:1])[CH2:4][CH3:5]
Reactant: BrBr
Reactant: CCCc1c(C)ncnc1Cl
Solvent: CC(=O)O
Product: CCCc1c(Cl)ncnc1CBr
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Br2 (1.28 g, 8 mmol) is added dropwise to a stirred solution 101 in HOAc (20 ml) heated at 85° C. After addition, the mixture is stirred at 85° C. for 1 hour. The solvent is removed in vacuo and EtOAc (25 ml) and NaHCO3 (25 ml) are added to the residue. The layers are separated and the organic layer is washed with Na2S2O3 solution (sat. 15 ml) followed by brine (20 ml). The organic phase is dried (Na2SO4) and evaporated. The resulting yellow oil is purified by flash column (6:1 EtOAc, hexane) to afford the product (102) as a light yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[N:23]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]1=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:17]2[C:16]([F:15])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])[C:24]1=[O:31])=[O:29]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2c(F)cccc2F)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2c(F)cccc2F)C1=O
Yield: 18.6 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(2,6-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.107 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.033 g (20%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,6-difluorophenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)[CH:7]=1)[CH3:2].IC.[CH3:26][Si](C)(C)N[Si](C)(C)C.[Na]>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([B:14]2[O:15][C:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[O:18]2)[CH:7]=1)[CH3:26])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.100 g, 0.31 mmol) and iodomethane (0.04 mL, 0.63 mmol) in THF (5 mL) at −78° C. was added sodium hexamethyldisilazane (1M in THF; 0.63 mL, 0.63 mmol). The reaction was warmed to room temperature and stirred under N2 for 1 hour, and then quenched with H2O and partitioned between EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: Cl[N:2]1[N:29]=[C:5]2[C:6]([N+:26]([O-])=O)=[C:7]([NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]([CH3:11])=[C:9]([CH3:10])[N:4]2[NH:3]1.CC(O)C>C1(C)C=CC=CC=1>[NH2:26][C:6]1[C:5]2[N:4]([N:3]=[N:2][N:29]=2)[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24]
Reactant: CC1=C(C)N2NN(Cl)N=C2C([N+](=O)[O-])=C1NCCOCCNC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1c(NCCOCCNC(=O)OC(C)(C)C)c(N)c2nnnn2c1C
Yield: 99.2 %

Procedure:
Under a nitrogen purge, 5% platinum on carbon (2.5 g) was added to a Parr vessel containing a solution of tert-butyl 2-{2-[(2-chloro-5,6-dimethyl-8-nitrotetrazolo[1,5-a]pyridin-7-yl)amino]ethoxy}ethylcarbamate (25.0 g, 63.2 mmol) in toluene (500 mL). The vessel was placed under hydrogen pressure (30 psi, 2.0×105 Pa) for four hours, and then 2-propanol (50 mL) was added. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with 2-propanol (500 mL) and ethanol (500 mL). The filtrate was concentrated under reduced pressure to yield 22.9 g of tert-butyl 2-{2-[(8-amino-5,6-dimethyltetrazolo[1,5-a]pyridin-7-yl)amino]ethoxy}ethylcarbamate as a brown oil.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6]CC)=[O:5])=[N-].[O:9]1[CH2:13][CH:12]=[CH:11][CH2:10]1.[OH-].[Li+]>C(Cl)Cl.CO.[OH-].[Na+].O.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH:11]12[CH:3]([C:4]([OH:6])=[O:5])[CH:12]1[CH2:13][O:9][CH2:10]2
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C1=CCOC1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(O)C1C2COCC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl diazoacetate (0.5 mL, 5.0 mmol) was added dropwise to a solution of 2,5-dihydrofuran (1.3 g, 19 mmol) and rhodium(II) acetate dimer (100 mg, 0.24 mmol) in methylene chloride (15 mL)—caution: gas evolution. The reaction mixture was stirred for 16 hours at room temperature, and then diluted with methylene chloride (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was redissolved in methanol (20 mL) and treated with lithium hydroxide (170 mg, 7.1 mmol). The mixture was stirred at room temperature for 3 hours, and then diluted with methylene chloride (100 mL), 1.0N sodium hydroxide solution in water (15 mL) and water (10 mL). The aqueous layer was separated, acidified to pH 3 via addition of solid citric acid, and then extracted with methylene chloride (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a yellow solid that was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([O:10][C:11]([NH:13][C@@H:14]1[C@@H:19]([OH:20])[CH2:18][CH2:17][O:16][CH2:15]1)=[O:12])([CH3:9])[CH3:8].C(N(CC)CC)C>C(Cl)Cl>[CH3:9][C:7]([O:10][C:11]([NH:13][C@@H:14]1[C@@H:19]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][CH2:17][O:16][CH2:15]1)=[O:12])([CH3:6])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (30 ml) in DCM (100 ml) was added dropwise to a solution of 1,5-an hydro-2,4-dideoxy-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-L-threo-pentitol (75 g) and triethylamine (58 ml) in DCM (900 ml) at 0° C., maintaining the temperature below 3° C. during the addition. The mixture was stirred for 30 min, warmed to 25° C. and stirred for 2 h. The reaction mixture was washed with water (2×1.4 l), the organic phase dried and the solvent evaporated to give 1,5-anhydro-2,4-dideoxy-2-({[(1,1-dimethylethy)oxy]carbonyl}amino)-3-O-(methylsulfonyl)-L-threo-pentitol (103.1 g).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C:28]1[C:29]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:29]3[C:28]([CH3:27])=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Cc1cc2ccccc2nc1N1CCNCC1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cc1cc2ccccc2nc1N1CCN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 3-methyl-2-piperazin-1-yl-quinoline.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[OH:13][CH:8]([C:7]([O:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Reactant: Oc1ccccc1
Product: COC(=O)C(O)C(Oc1ccccc1)(c1ccccc1)c1ccccc1
Yield: 71.8 %

Procedure:
5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.6 g (60 mmol) of phenol were heated together at 100° C. for 6 h. Removal of the excess phenol by distillation under high vacuum and purification of the residue by chromatography on silica gel with hexane/ethyl acetate mixtures resulted in 4.9 g (77%) of a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1)[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cncc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cncc2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 4-bromoisoquinoline (2.0 g) in 70 mL of toluene was added allyl tributyl stannane (3.28 mL) and Pd(PPh3)4 (1.10 g). The resulting solution was heated at reflux for 12 hours and then cooled to room temperature. The solution was concentrated in vacuo, dissolved in ether and washed successively with an aqueous solution of trithiocyanuric acid trisodium salt, water and brine. The organic layer was then dried over magnesium sulfate, filtered, concentrated in vacuo, and purified using flash chromatography (silica, 0-30% EtOAc/hexanes) to provide 0.965 g of 4-(2-propenyl)-isoquinoline. Mass spectrum [NH3/CI], (M+H)+=170.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[S:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28])(=[O:15])=[O:14])=[O:5].[NH3:34]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[S:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH2:34])=[O:28])(=[O:15])=[O:14])=[O:5]
Reactant: O=C(Cl)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: N
Solvent: c1ccccc1
Product: NC(=O)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reaction time: 2 h

Procedure:
A solution of 2 g of 11-[2-(2-chlorobenzoyl)-4-chlorobenzenesulphonamido]undecanoic acid chloride in 15 ml of anhydrous benzene is saturated with ammonia at 10° C. After stirring for two hours, the reaction medium is evaporated to dryness under vacuum, the residue is taken up with water and then extracted with ethyl acetate. After evaporation, the organic phase gives crystals which are recrystallized in benzene (1.22 g).
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH:9]1[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:12]#[N:13]>>[C:1]([NH:5][NH:6][C:7]([C:12]#[N:13])([CH:9]1[CH2:10][CH2:11]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#N
Reactant: CC(=NNC(C)(C)C)C1CC1
Product: CC(C)(C)NNC(C)(C#N)C1CC1
Temperature: 0 °C

Procedure:
A solution of 8.7g methyl cyclopropyl ketone t-butylhydrazone in 20 ml liquid hydrocyanic acid was heated for 6 hours in a pressure bottle at 60°C. The solution was cooled, poured into ice water and the aqueous solution extracted twice with ether. The ether extracts were combined, washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and the ether evaporated off. The yield was 10.0g (99%) of a brown liquid. The infrared spectrum was consistent with the structure of the proposed product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>O.Cl>[ClH:1].[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: O=N[O-]
Reactant: Cc1ccc(N)c(Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NN)c(Cl)c1
Temperature: -5 °C

Procedure:
A suspension of 2-chloro-4-methyl aniline (10.1 mL, 11.63 g, 82.1 mmol) in 64 mL water and 60 mL 12 N HCl was cooled to −5° C. (internal temperature) and stirred with a mechanical stirrer. A solution of sodium nitrite (8.26 g, 119.7 mmol) in 56 mL water was added over 30 minutes. The solution became more clear but some solid remained. The mixture was stirred at −5° C. for 20 minutes and then cooled to −10° C. A solution of tin(II) chloride dihydrate (53.60 g, 237.6 mmol) in 36 mL 12 N HCl was added dropwise over 30 minutes while maintaining an internal temperature of −5 to −10° C. The resulting pinkish-brown mixture was stirred at −5 to −10° C. for 2 hours and then filtered cold through a pre-chilled fritted glass funnel. The collected solids were washed with cold 1% ethanol in ether (100 mL) followed by cold ether (500 mL) and air dried for 30 minutes. After drying in vacuo, the desired product was obtained as a very pale yellow crystalline solid (7.76 g, 49%). 1H NMR δ (300 MHz, CDCl3) δ 10.09 (bs, 2 H), 7.89 (s, 1 H), 7.25 (d, 1 H, Jm=1.2 Hz), 7.13 (dd, 1 H, Jo=8.4 Hz, Jm=1.2 Hz), 7.02 (d, 1 H, Jo=8.4 Hz), 2.24 (s, 3 H); MS (CI) m/z 157/159.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([S:8]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH:16]1OCCO1)(=O)=O)[CH3:7])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].C1CN2C(=NCCC2)C1>CC(C)=O.C(OCC)(=O)C.O>[CH3:7][N:6]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])=[CH:16][C:15]2[CH:14]=[CH:13][S:12][C:11]=2[S:8]1
Reactant: CCOC(=O)CN(C)S(=O)(=O)c1sccc1C1OCCO1
Agent: C1CN=C2CCCN2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1=Cc2ccsc2SN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of the product from Step A (8.80 g, 26.3 mmol) and 4-toluenesulfonic acid (1.0 g) in acetone (250 mL) was stirred overnight at ambient temperature. Water (0.5 mL) was added and this mixture was stirred for 4 h followed by addition of a saturated aqueous solution of sodium bicarbonate (50 mL) and evaporation of the acetone. The aqueous mixture was extracted with ethyl acetate (2×200 mL) and the combined extracts were dried (MgSO4) and evaporated to give crude aldehyde which was dissolved in ethyl acetate (150 mL). DBN (0.5 g) was added and the mixture heated at reflux temperature for 2 h, cooled and washed with a saturated aqueous solution of sodium bicarbonate (50 mL). The ethyl acetate solution was dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 30 to 50% ethyl acetate/hexane) to give the desired product as a white solid (5.05 g, 70%).