Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(#N)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:30][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol), K2CO3 (3.8 g, 27.5 mmol) and ethyl bromopropionate (5 g, 27.6 mmol, 1.2 eq) in acetonitrile (200 ml) was heated at reflux for 16 hours. The mixture was cooled and filtered. The solvent was removed, and the residue was purified on a flash chromatography column (60 g, SiO2, eluted with DCM). The material thus purified weighed 7.27 g (83%). The fumarate salt was prepared by treatment of the free base (2.17 g) with fumaric acid (820 mg, 1.0 eq) in ethanol. Recrystallization from ethanol yielded 2.49 g of white crystals, m.p.=135°-136° C.
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH3:5].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[Na+].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:10][CH2:9][CH2:8][CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH3:11])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCOC(C)CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCOC(C)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 35 %

Procedure:
5.0 g of 3-pentyloxybutanol, 3.98 g of p-toluenesulfonyl chloride, 1.65 g of pyridine, and 8 ml of benzene were charged in a 30 ml-reaction vessel and, under N2 stream, stirred for 23 hours at room temperature. Then, into the reaction mixture, 6.3 ml of hot conc. NaOH aqueous solution was added and stirred for 5 min. The mixture was poured in 280 ml of cold 10%-hydrochloric acid solution and extracted with hexane. The hexane layer was washed successively with cold 5%-hydrochloric acid solution, saturated NaCO3 aqueous solution and water and dried with anhydrous MgSO4, followed by distilling-off of the solvent to 6.0 g of a crude product, which was purified by alumina column chromatography (hexane) to obtain 2.3 g of 3-pentyloxybutyl p-toluenesulfonate.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:16])=O>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][CH:4]=1)[CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)c1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(C(=O)Cl)cc1
Reaction time: 0.25 h

Procedure:
In a round bottom flask fitted with a reflux condenser is placed 4 g of p-dimethylaminobenzoic acid and 8 ml of oxalylchloride. The evolution of gas starts immediately and the spontaneous reaction is run at room temperature for 15 minutes. 8 ml of toluene is added and and the mixture is heated to gentle reflux for one hour. The reaction mixture is then distilled to dryness under reduced pressure to produce a blue-green solid which is washed with ether and dried on a watch glass.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][CH2:5][N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:3]1.[O:27]1[C:36]2[CH:35]=[C:34]([NH:37]C(=O)OC(C)(C)C)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1.[H-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[O:27]1[C:36]2[CH:35]=[C:34]([NH:37][CH2:8][CH:7]3[CH2:6][CH2:5][N:4]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:3][CH:2]3[OH:1])[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(cn1)OCCO2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc3c(cn2)OCCO3)C(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
A mixture of rac-(3R*,4R*)-tert-butyl 3-hydroxy-4-((tosyloxy)methyl)piperidine-1-carboxylate (prepared as described in Tetrahedron (2008), 64, 2456-2464, 0.26 g, 0.67 mmol) and tert-butyl (2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)carbamate (prepared as described in WO 2009/104159, 0.17 g, 0.67 mmol, 1 eq.) was dissolved in DMF (2.5 mL). NaH (60% dispersion in oil, 0.04 g, 0.88 mmol, 1.3 eq.) was added and the mixture was vigorously stirred at rt for 2 h. More NaH (0.03 g, 0.67 mmol, 1 eq.) was added. After two more hours, sat. aq. NaHCO3 (5 mL) was added and the mixture was extracted with EA (3×10 mL). The combined org. phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by CC (DCM/MeOH 19:1) to afford the title compound as a white solid (0.15 g, 62% yield).
Reaction SMILES: [CH2:1]1[O:24][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[O:3][CH2:2]1.[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.O>[CH2:1]1[O:24][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][CH2:12][N:25]=[N+:26]=[N-:27])[O:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2C2OCCO2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCc1ccccc1C1OCCO1
Yield: 95.7 %

Procedure:
A solution of 2-(2-(4-methylphenylsulphonyloxy)ethyl)benzaldehyde ethylene acetal (1.43 g, 4.10 mmol) and sodium azide (0.53 g, 8.2 mmol) in DMSO (20 ml) was stirred for 16 h, diluted with water, extracted three times with ether, washed with brine, dried over sodium sulphate and evaporated to afford the product as a yellow oil (0.86 g), MS (+EI) 190 [(M-NH2)+], 1H NMR (d6 -DMSO) 7.53-7.25 (4H, m), 5.92 (1H, s), 4.19-3.95 (4H, m), 3.53 (2H, t, J7.2 Hz), 2.98 (2H, t, J7.2 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:29])[C:12]([N:14]3[CH2:19][CH2:18][C:17](=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:10][C:3]=12.[NH:30]1[CH:34]=[CH:33][N:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+]>CO.[Cu]>[O:29]=[C:11]([C:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([N:31]3[N:32]=[CH:33][CH:34]=[N:30]3)=[C:3]2[NH:10][CH:9]=1)[C:12]([N:14]1[CH2:19][CH2:18][C:17](=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]#[N:22])[CH2:16][CH2:15]1)=[O:13]
Reactant: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(Cl)ccnc23)CC1)c1ccccc1
Reactant: c1c[nH]nn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(-n4nccn4)ccnc23)CC1)c1ccccc1
Temperature: 160 °C
Yield: 31 %

Procedure:
A mixture of compound of example 101 (34 mg, 0.084 mmol), 1,2,3-triazole (0.40 mL, 6.9 mmol), copper metal (5.4 mg, 0.084 mmol), and K2CO3 (11.5 mg, 0.083 mmol) in a sealed tube was heated at 160° C. for 5 h. The reaction mixture was diluted with MeOH (2 mL), filtered through Celite and concentrated. The residue was purified by preparative HPLC to yield title compound (3.1 mg, 0.026 mmol, 39%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCOCC1
Yield: 12.8 %

Procedure:
Prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloro ethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.39 mmol) from Example 16C (200 mg, 0.39 mmol) and morpholine (0.102 mL, 1.17 mmol) according to the procedure described for Example 16D to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (28 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 9.60 (brs, 1H), 9.08 (brs, 1H), 8.56 (s, 1H), 7.58-7.65 (m, 2H), 7.38-7.43 (m, 2H), 7.25 (m, 1H), 6.97 (m, 1H), 6.48 (s, 1H), 4.30-4.32 (m, 2H), 4.00 (s, 3H), 3.60-3.62 (m, 4H), 2.80 (m, 2H), 2.49-2.52 (m, 4H), 1.27 (s, 9H); LC-MS (ESI) m/z 563 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[CH:6][C:5]1=[O:12])[CH:2]=[CH2:3].C1C(=O)N(Br)C(=O)C1.[Cl:21]C(Cl)C(O)=O>CC#N>[CH2:1]([N:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[C:6]([Cl:21])[C:5]1=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCn1c(C)cc(O)cc1=O
Reactant: O=C(O)C(Cl)Cl
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C=CCn1c(C)cc(O)c(Cl)c1=O
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a stirred solution of 1-allyl-4-hydroxy-6-methylpyridin-2(1H)-one (500 mg, 3.0 mmol) in CH3CN (10 ml), at rt, was added sequentially n-bromosuccinimide (440 mg, 3.3 mmol) and dichloroacetic acid (546 μl, 6.62 mmol). The resulting mixture was stirred for 2 h. The heterogeneous mixture was filtered and the solid was washed with additional CH3CN to give 350 mg (59%) of the desired product as a tan solid. 1H-NMR (DMSOd6/300 MHz) δ 11.16 (s, 1H), 5.98-5.86 (m, 2H), 5.12 (dd, J=10.5, 1.5 Hz, 1H), 4.89 (dd, J=17.1, 1.5 Hz, 1H), 4.63-4.61 (m, 2H), 2.29 (s, 3H). ES-HRMS m/z 200.050 (M+H calcd for C9H11ClNO2=200.0470)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:9]2)([O-:3])=[O:2].C(Cl)CCl.[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)[O:15][C:14](=[O:16])[CH2:13][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH:9]=[CH:10]1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)Cn1ccc2cccc([N+](=O)[O-])c21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cn1ccc2cccc([N+](=O)[O-])c21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.2 %

Procedure:
A mixture of 2-(7-nitro-1H-indol-1-yl)acetic acid (0.15 g, 0.681 mmol), EDC (0.131 g, 0.681 mmol), DMAP (0.128 g, 1.048 mmol) and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.220 g, 0.524 mmol) in dry DCM (15 ml) was stirred at room temperature for 16 hours. Aqueous 2N HCl was added, and the organic phase was separated and dried over sodium sulfate; the solvent was removed and the crude was triturated with MeOH. The precipitate was filtered, washed with MeOH and dried affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(7-nitro-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.066 g, 0.106 mmol, 20% yield). MS/ESI+ 622.1 [MH]+; [αD]=−112.6, c=0.22, MeOH; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 8.00 (dd, 1H), 7.82 (dd, 1H), 7.52 (d, 1H), 7.22 (t, 1H), 7.16 (d, 1H), 7.05 (d, 1H), 6.92 (dd, 1H), 7.06 (t, 1H), 6.76 (d, 1H), 5.95 (dd, 1H), 5.30 (d, 1H), 5.17 (d, 1H), 3.90 (d, 2H), 3.33-3.54 (m, 1H), 3.18 (dd, 1H), 0.99-1.39 (m, 1H), 0.48-0.72 (m, 2H), 0.36 (q, 2H).
Reaction SMILES: [CH:1]([N:4]([CH3:17])[C:5]1[NH:9][C:8]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:7]=2[N:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=1.O>CO.C(Cl)(Cl)Cl.[OH-].[Pd+2].[OH-].[C]>[CH:1]([N:4]([CH3:17])[C:5]1[NH:9][C:8]2[CH:10]=[C:11]([NH:14][C:35](=[O:36])[CH2:34][CH2:33][C:30]3[CH:29]=[CH:28][C:27]([C:26]([F:38])([F:39])[F:25])=[CH:32][CH:31]=3)[CH:12]=[CH:13][C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(C)c1nc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)N(C)c1nc2ccc(NC(=O)CCc3ccc(C(F)(F)F)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
To a solution of said N-{2-[isopropyl(methyl)amino]-6-nitro-1H-benzimidazole (1.00 g) as obtained in Example 1-(1) in methanol (30 ml), 20% palladium hydroxide-carbon (200 mg) was added and stirred at room temperature under atmospheric pressure for 5 hours. The reaction solution was filtered through Celite, and the filtrate was condensed under reduced pressure. Thus obtained 6-amino-N-{2-isopropyl(methyl)amino]-1H-benzimidazole was dissolved in chloroform (15 ml), followed by successive addition of triethylamine (1.8 ml) and 3-[4-(trifluoromethyl)phenyl]propionic acid (930 mg) and dropwise addition, under cooling with ice, of 2-chloro-1,3-dimethyl-2-imidazolinium chloride (2M chloroform solution, 2.6 ml). After 15 hours' stirring at room temperature, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was condensed under reduced pressure, the resultant residue was purified on silica gel column chromatography, (methanol/ethyl acetate=1/10) and washed with ether to provide the title compound (1.00 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]([F:48])([F:47])[C:35]1[C:36]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[N:37][CH:38]=[CH:39][CH:40]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[C:35]([C:34]([F:33])([F:47])[F:48])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH2:46][CH2:45]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 7.5 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (5.7 mg, 7.5%) as light yellow oil. MS m/e=560.4 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([O-:10])=[O:9])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[Na+].S(=O)(=O)(O)O>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@@H](CCC(=O)O)C(=O)O
Yield: 97.4 %

Procedure:
72 g Sodium glutamate were reacted as a 10% solution with sulfuric acid according to the invention as in Example 6 to produce 54 g of glutamic acid and the corresponding amount of sodium sulfate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:7])[N:6]=1.[CH2:19]([O:26][CH2:27]CC1NC(I)=C(C)N=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.IC1NC(C)=NC=1C>>[CH2:19]([O:26][CH2:27][CH2:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:7])[N:6]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nc(CCOCc2ccccc2)[nH]c1I
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(CCOCc3ccccc3)nc2C)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except 2-(2-(benzyloxy)ethyl)-5-iodo-4-methyl-1H-imidazole (compound 227.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[I:9][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=1.[CH3:18][NH:19][CH:20]=[O:21].[CH3:22][NH:23][CH2:24][CH2:25][NH:26][CH3:27].[C:28]1([CH3:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[Cu].[Cu]I.Cl[Cu].CC([O-])=O.CC([O-])=O.[Cu+2]>[I:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1.[CH3:18][NH:19][CH:20]=[O:21].[CH3:22][NH:23][CH2:24][CH2:25][NH:26][CH3:27].[CH3:14][CH2:15][CH2:10][CH2:11][CH2:12][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:28][CH3:34]
Reactant: Cc1ccccc1
Agent: Cl[Cu]
Agent: [Cu+2]
Agent: [Cu]
Solvent: CNC=O
Product: CCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 7 h

Procedure:
Nine 15 mL test tubes with screw threads were equipped with one 10×3 mm Teflon-coated stirring bar each and charged with K3PO4 (430 mg, 2.03 mmol) and one of the following copper sources: 1) copper powder, bronze (Aldrich, 99%; 3.2 mg, 0.050 mmol); 2) CuI (Strem, 98%; 9.6 mg, 0.050 mmol); 3) CuCl (Strem, 97+%; 5.0 mg, 0.050 mmol); 4) CuSCN (Aldrich, 98+%; 6.1 mg, 0.050 mmol); 5) Cu2O (Alfa Aesar, 99%; 3.6 mg, 0.025 mmol); 6) CuCl2 (Strem, 98%; 6.8 mg, 0.051 mmol); 7) CuSO4.5H2O (Aldrich, 98+%; 12.5 mg, 0.0501 mmol); 8) Cu(OAc)2 (Strem, 99%; 9.1 mg, 0.050 mmol); 9) Cu(II) acetylacetonate (Lancaster, 98%; 13.1 mg, 0.0500 mmol). Each test tube was closed with an open-top screw cap fitted with a Teflon-lined silicon rubber septum, evacuated through a 21-gauge needle, and then backfilled with argon. Meanwhile, a stock solution of 5-iodo-m-xylene (2.16 mL, 15.0 mmol), N-methylformamide (1.06 mL, 18.1 mmol), N,N′-dimethylethylenediamine (160 μL, 1.50 mmol) and dodecane (internal GC standard, 0.68 mL) in toluene (15 mL) was prepared in a 25 mL pear-shaped flask under argon. To each test tube was added 1.28 mL of the stock solution containing 1.0 mmol of 5-iodo-m-xylene, 1.2 mmol of N-methylformamide, 0.10 mmol of N,N′-dimethylethylenediamine using a syringe. The top of the septum was then covered with a dab of vacuum grease to seal the injection spot. The reaction mixtures in the test tubes were stirred in a 80±5° C. oil bath for 7 h. The test tubes were then allowed to reach room temperature, the screw caps were removed, and ethyl acetate (2 mL) was added. A 50–100 μL sample of the supernatant solution from each test tube was diluted with ethyl acetate (1 mL) and the resulting solutions were analyzed by GC. The results are reported in FIG. 21.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:25][N:26]([CH3:28])[NH2:27]>>[CH3:25][N:26]([CH3:28])[NH:27][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Reactant: CN(C)N
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN(C)C)[nH]n1
Yield: 23 %

Procedure:
As described for example 8b, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using N,N-dimethylhydrazine instead of 4-aminomorpholine, to the title compound (25 mg, 23%), which was obtained as a white solid after recrystallization from ethyl acetate. MS: m/e=360.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)/[C:13](=[C:20](/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)\[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])/[C:12]2=[O:32])[CH:5]=1.O.O[Li].O>C1COCC1>[CH3:24][CH:23]([CH3:25])[CH2:22][CH2:21]/[C:20](=[C:13]1/[C:12](=[O:32])[N:11]([CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:33])=[O:2])[C:19]2[C:14]/1=[CH:15][CH:16]=[CH:17][CH:18]=2)/[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1cccc(CN2C(=O)/C(=C(/CCC(C)C)c3ccccc3)c3ccccc32)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC/C(=C1/C(=O)N(Cc2cccc(C(=O)O)c2)c2ccccc21)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
3-{3-[4-Methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester (24 mg, 0.05 mmol) was dissolved in THF (1 ml) and water (1 ml) and LiOH.H2O (14 mg, 0.33 mmol) was added in one portion. The mixture was stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure and acidified to pH=3. Purification by preparative HPLC afforded 3-[3-(4-methyl-1-phenyl-pent-(Z)-ylidene)-2-oxo-2,3-dihydro-indol-1-ylmethyl]-benzoic acid 10 mg. 1H NMR (300 Hz, CDCl3): δ ppm 0.88 (d, 6H), 1.36-1.44 (m, 2H), 1.64-1.68 (m, 1H), 3.33-3.38 (m, 2H), 5.04 (s, 2H), 6.01 (d, 1H), 6.58-6.61 (m, 2H), 6.96-7.02 (t, 1H), 7.26-7.29 (m, 2H), 7.37 (t, 2H), 7.43-7.52 (m, 3H), 7.93 (d, 1H), 8.03 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1>[Pd].[OH-].[Pd+2].[OH-].C(O)C>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(Oc2ncncc2C2=CCOCC2)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(Oc2ncncc2C2CCOCC2)cc1
Temperature: 50 °C

Procedure:
To a pressure vessel was added palladium hydroxide, palladium on carbon (396 mg, 2.82 mmol), ethanol (18.800 ml), and 4-(5-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-4-yloxy)aniline (760 mg, 2.82 mmol). The vessel was purged of air and backfilled with hydrogen (45 psi) before heating to 50° C. for 60 h. It was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure to afford the product as a dark yellow oil. MS (ESI, pos. ion) m/z: 272.1 (M+1).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:39]=[CH:38][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:30])=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][CH:66]2[CH2:68][O:67]2)=[CH:60][CH:59]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:32]([NH:31][C:29](=[O:30])[NH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:68][C@H:66]([OH:67])[CH2:65][O:64][C:61]4[CH:62]=[CH:63][C:58]([OH:57])=[CH:59][CH:60]=4)=[CH:39][CH:38]=3)[CH2:13][CH2:14]2)=[O:19])=[CH:23][CH:24]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCNC(=O)Nc1ccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=CO
Product: CCCCCCNC(=O)Nc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 29.4 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-{[(hexylamino)carbonyl]amino}benzyl)-1-piperidinecarboxamide formate (0.29 g, 0.54 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.220 g, 0.54 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.143 g, 0.159 mmol).