Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:21]=[CH:20][C:15]3[B:16]([OH:19])[O:17][CH2:18][C:14]=3[CH:13]=2)=[CH:7][C:6]=1[O:22][CH3:23])C.[OH-].[Na+].Cl>CO.O>[OH:19][B:16]1[C:15]2[CH:20]=[CH:21][C:12]([O:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[C:6]([O:22][CH3:23])[CH:7]=3)=[CH:13][C:14]=2[CH2:18][O:17]1
Reactant: CCOC(=O)c1ccc(Oc2ccc3c(c2)COB3O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(Oc2ccc3c(c2)COB3O)ccc1C(=O)O
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a solution of compound (D35) (0.1 g, 0.31 mmol) in methanol (2 mL) was added 2N NaOH (1 mL). The resulting mixture was stirred at rt O/N. The solvent was removed under reduced pressure to give crude product, which was dissolved in H2O (1 mL) and acidified using 1N HCl. The solid obtained which was filtered and washed with ether (10 mL) to afford the title compound (D36) (78 mg, 86%) as a white solid. Mp 109.6-110.1° C. 1H NMR 400 MHz (DMSO-d6) δ: 9.20 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.18 (s, 1H), 7.15 (d, J=9.4 Hz, 1H), 6.80 (s, 1H), 6.60 (d, J=8.6 Hz, 1H), 4.98 (s, 2H), 3.81 (s, 3H); MS (ES) m/z: 301 (M+1)+; HPLC purity: 100% (220 nm), 99.79% (254 nm).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:31]5[C:26]([C:25]([F:36])([F:35])[F:24])=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: OB(O)c1cccnc1C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccnc3C(F)(F)F)cc1-2
Yield: 25 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-(trifluoromethyl)pyridin-3-ylboronic acid were reacted to give 265 (0.058 g, 25%). 1H NMR (400 MHz, DMSO) δ 9.30 (d, J=2.2, 1H), 8.28 (d, J=8.0, 1H), 8.19 (t, J=7.9, 1H), 8.12 (s, 1H), 8.04 (dd, J=8.5, 2.3, 1H), 7.82 (t, J=17.9, 1H), 7.23 (d, J=8.5, 1H), 5.93 (dt, J=13.2, 6.7, 1H), 4.45 (t, J=4.9, 2H), 3.50 (t, J=4.8, 2H), 1.57 (d, J=6.6, 6H). MS (ESI(+)): m/z 458.1 (M+H)
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:20]([NH2:22])=[O:21])=[CH:8][C:9]([C:16]([F:19])([F:18])[F:17])=[C:10]([CH:15]=1)[C:11]([O:13]C)=[O:12])([CH2:3][CH3:4])[CH3:2].[OH-].[Na+].ClCCl.Cl>CO>[NH2:22][C:20]([C:7]1[C:6]([NH:5][C@H:1]([CH3:2])[CH2:3][CH3:4])=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]([F:17])([F:18])[F:19])[CH:8]=1)=[O:21]
Reactant: CC[C@@H](C)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](C)Nc1cc(C(=O)O)c(C(F)(F)F)cc1C(N)=O
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
(R)-Methyl 5-(sec-butylamino)-4-cyano-2-(trifluoromethyl)benzoate (45 mg, 0.150 mmol) was dissolved in DMSO (1 mL) and was treated with 30% aqueous hydrogen peroxide (0.05 mL) and potassium carbonate (6 mg, 0.043 mmol) at ambient temperature for 2 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, then filtered and concentrated to afford a yellow oil which was purified by column chromatography (silica gel, 10-40% ethyl acetate in hexanes) to afford (R)-methyl 5-(sec-butylamino)-4-aminocarbonyl-2-(trifluoromethyl)benzoate (27 mg, 0.085 mmol, 57% yield). (R)-M ethyl 5-(sec-butylamino)-4-aminocarbonyl-2-(trifluoromethyl)benzoate (27 mg, 0.085 mmol) was suspended in methanol (1 mL) and was treated with 1 M sodium hydroxide (0.2 mL, 0.2 mmol) at 45° C. for 1 h. Dichloromethane (0.5 mL) and 1M sodium hydroxide (0.2 mL, 0.2 mmol) was added and the mixture was stirred at 45° C. for a further 1.5 h. Dichloromethane (0.5 mL) and 1M sodium hydroxide (0.2 mL, 0.2 mmol) were added, and the mixture was stirred at 45° C. for a further 1 h and then at ambient temperature for 15 h. The reaction mixture was concentrated to afford an aqueous residue that was cooled in an ice bath, was acidified with 1N hydrochloric acid to pH ˜2, then extracted with ethyl acetate (2×). The organic portion was dried over sodium sulfate, then filtered and concentrated to provide 4-(aminocarbonyl)-5-{[(1R)-1-methylpropyl]amino}-2-(trifluoromethyl)benzoic acid (23 mg, 0.076 mmol, 89% yield). MS (EI) for C13H15F3N2O3: 305 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:6][C:5]=1[CH2:28][NH:29][CH2:30][CH2:31][CH3:32])([O-])=O.S1C=CC=C1.O=[Si]=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH2:17][NH:18][S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])=[CH:6][C:5]=1[CH2:28][NH:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCNCc1cc(-c2ccccc2CCNS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[Si]=O
Solvent: CO
Solvent: c1ccsc1
Product: CCCNCc1cc(-c2ccccc2CCNS(=O)(=O)c2ccccc2)ccc1N

Procedure:
A mixture of N-[2-(4′-nitro-3′-propylaminomethyl-biphenyl-2-yl)-ethyl]-benzenesulfonamide (0.00031 mol) in methanol (50 mL) was hydrogenated with 10% Pd/C (0.100 g) as a catalyst in the presence of thiophene solution (0.5 mL). After uptake of H2 gas (3 equiv.), the reaction mixture was filtered over Dicalite and the filtrate was evaporated to yield the title compound as a residue. (The compound was used without further purification, immediately in the next reaction step.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:11][N:10]([CH3:23])[C:9]1=[O:24])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11][N:10]([CH3:23])[C:9]1=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN1C[C@H](O)CC[C@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 4 h
Yield: 96.9 %

Procedure:
To a solution of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-1-methyl-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (0.85 g, 2.27 mmol) in THF (40 mL) is added tetrabutylammonium fluoride (3 mL 1M THF, 3 mmol) at room temperature. The reaction solution is stirred for 4 h, then H2O (40 mL) is added and the solution concentrated under vacuum to ½ its volume and extracted 3× with CH2Cl2 (40 mL). The combined CH2Cl2 extracts are adsorbed on silica and chromatographed (5% CH3OH/CH2Cl2) to give 0.568 g (72%) of ((3S,6R)-6-hydroxy-1-methyl-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.7-2.05 (m, 4H), 3.1 (s, 3H), 3.37 (dd, 1H), 3.73 (d, 1H), 4.07 (m, 1H), 4.31 (m, 1H), 6.0 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH3:21][C:22]1(C)OC(=O)CC(=O)[O:23]1.OS([O-])(=O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[O:23]=[C:22]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14](=[O:16])[CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1CCCC1C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)CC(=O)C2CCCC21
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
To a stirred solution of 2-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (0.24 g, 1.06 mmol) in DCM (4.5 mL) was added EDC (0.31 g, 1.59 mmol), DMAP (0.19 g, 1.59 mmol) and Meldrum's acid (0.15 g, 1.06 mmol). After stirring for 18 h at r.t., the reaction mixture was poured into aqueous 1M NaHSO4 solution (5 mL) and extracted with DCM (3×20 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give a clear yellow oil which was dissolved in EtOAc (5 mL) and heated to 80° C. for 18 h. The reaction mixture was then cooled and concentrated in vacuo to give the title compound (0.25 g, 42%) as a yellow solid that was used without further purification. δH (CDCl3) 4.64-4.55 (1H, m), 2.98-2.92 (1H, m), 2.37-2.20 (2H, m), 1.99-1.60 (6H, m), 1.58 (9H, s). LCMS (ES+) 198.0 ((M−tBu)+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:16])=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl.O1CCOCC1.[Na]>O>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[CH2:15][CH:13]3[CH2:14][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)N1CC2CC(C1)c1cc(N)ccc12
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(C(C)C)C2)ncc1Cl
Temperature: 120 °C
Yield: 34.7 %

Procedure:
10-Isopropy-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (30 mg, 0.14 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (41 mg, 0.14 mmol) and 4N HCl in dioxane (28 μl, 0.15 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 8 g Isco basic alumina column using 0-2% methanol in methylene chloride as the eluent to yield 2-[5-chloro-2-(10-isopropyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (23.2 mg, 35%) as a red orange foam. 1H-NMR (CDCl3) δ 11.0 (s, 1H), 8.68 (d, J=8.3 Hz, 1H), 8.08 (s, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.3 Hz, 1H), 7.37 (s, 1H), 7.21 (s, 1H), 7.06 (dd, J=3.3, 6.8 Hz, 2H), 3.10-3.0 (m, 4H), 2.75 (m, 2H), 2.55 (m, 4H), 2.27 (m, 1H), 1.68 (d, J=10.1 Hz, 1H), 0.85 (d, J=6.6 Hz, 6H); LC/MS (ESI+): 477 (M+H).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[Na:16].C(=O)([O-])[O-].[Na+].[Na+]>O>[S:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][CH:10]=1)([OH:4])(=[O:3])=[O:2].[Na:16]
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CCC(=O)Nc1ccc(S(=O)(=O)O)cc1
Reaction time: 96 h

Procedure:
Solid sodium N-(4-sulfophenyl)acrylamide (250 mg; 1 mmol) and solid sodium carbonate (106 mg; 1 mmol) were added successively to a stirred solution of PAMAM 4.0 (EDA) (78 mg; 0.011 mmol) in water (4 ml). The resulting solution was stirred under nitrogen for four days and then freeze dried to give a fluffy white solid. The crude product was purified by gel filtration (Sephadex LH20; water to give PAMAM 4.0 (EDA) terminated with 64 sodium N-(4-sulfophenyl)propanamide groups (206 mg). 13C nmr showed a faint trace of what was taken to be mono alkylated terminal amino groups. 1H nmr (D2O): δ2.10; 2.48; 2.58; 2.79; 3.20; 7.42 (d, J=7 Hz); 7.65 (d, J=7 Hz). 13C nmr (D2O): δ36.5; 37.9; 41.1; 53.4; 55.6; 124.8; 130.9; 143.0; 144.2; 177.4; 178.5.
Reaction SMILES: C[Mg]Cl.O1CCC[CH2:5]1.[C:9]([N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:11])[CH3:10].[Cl-].[NH4+]>O1CCCC1>[C:9]([N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([OH:34])[CH3:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)N(Cc1ccccc1C=O)c1ccccc1Oc1ccccc1
Reactant: C1CCOC1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)N(Cc1ccccc1C(C)O)c1ccccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
To an ice-cooled solution of 5.25 ml of 1M methylmagnesium chloride/tetrahydrofuran diluted with 15 ml of tetrahydrofuran was added dropwise a solution of 1.20 g of N-acetyl-N-(2-formylbenzyl)-2-phenoxyaniline in 7 ml of tetrahydrofuran, followed by stirring at room temperature for an hour. The reaction solution was again cooled on ice, and after addition of a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:1) to give 1.19 g of N-acetyl-N-[2-(1-hydroxyethyl)benzyl]-2-phenoxyaniline as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCCCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Bromo-2-fluoro-1-nitrobenzene (5.38 g, 24.45 mmol) was dissolved in dry DMF (50 mL) under nitrogen and treated with 3-aminopropan-1-ol (5.51 g, 73.4 mmol) at RT. The mixture was stirred at room temperature for 3 h. TLC indicated no starting material remaining. The mixture was diluted with ethyl acetate and washed with water several times, then with brine once. It was dried (MgSO4), then filtered and evaporated to give a yellow oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:20]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH3:20])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cn1cc(Br)cc(NC(=O)OC(C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Br)cn(C)c1=O
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)carbamate (150.0 mg, impure) in DMF (10 mL) was added NaH (60.0 mg, 1.5 mol, 60% in oil) in portions at 0° C. It was stirred for 30 min. Then CH3I (231.0 mg, 1.5 mmol) was added dropwise at 0° C. The reaction mixture was stirred for 2 h at 30° C. The reaction was quenched with saturated aqueous NH4Cl (15 mL), extracted with EA (20 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the title compound (120.0 mg, crude) as a green solid, which was used directly in the next step without purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4].[Cl:14][CH2:15][C:16](Cl)=[O:17].Cl>[OH-].[Na+].CCOCC>[Cl:14][CH2:15][C:16]([NH:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4])=[O:17]
Reactant: O=C(Cl)CCl
Reactant: NCC(=O)NCC(=O)NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CNC(=O)CNC(=O)CNC(=O)CCl
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2.5 g (0.013 mol) of glycylglycylglycine in 75 ml of 1.0N NaOH in a 500 ml flask under nitrogen at 0° C., a solution of 13.0 g (0.115 mol) of chloroacetyl chloride in 100 ml of ether was added dropwise from one addition funnel while simultaneously 100 ml of 1.0N NaOH was added dropwise from another After additions were complete, the reaction mixture was stirred for 1.5 hr. at 0° C. The mixture was then acidified with concentrated HCl while cooling. After stirring for an additional 30 min. the mixture was concentrated to one-third volume under reduced pressure at 40° C. The residue precipitated upon cooling in an ice bath. Isolation of the solid gave 2.75 g (78.5%) after two washings.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=[N:3]1.O.NN>C1COCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][CH:4]=[N:3]1
Reactant: Cn1ncnc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncnc1C(=NOCc1cccc(N)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of 2-{6-[({[(1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (11.27 g, 25.70 mmol, 1 eq.) in 500 ml of THF was added hydrazine hydrate (6.43 g, 128.52 mmol, 5 eq.). The reaction was stirred overnight at room temperature. The solvent was evaporated and the residue dissolved in EtOAc. Water was added and the layers separated. The aqueous layer was extracted with EtOAc and the organics were combined, dried over MgSO4 and concentrated to give 6-[({[(1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (7.85 g, 99%) as a clear viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.Cl>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2n1Cc1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
To a mixture of the compound obtained in Example 22 (2) (1.2 g) and N,N-dimethylformamide (23 ml), 60% sodium hydride (204 mg) was added at 0° C. and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added 4-fluorobenzyl bromide (0.65 ml) at 0° C. and the mixture was stirred at 15 to 30° C. for 2 hours. 2N hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane) to obtain 1 g of the desired product in a white amorphous form.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])=[O:11].[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH3:19][C:13]1[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=1[CH:10]1[CH2:9][CH2:8][C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=2)[O:11]1
Reactant: Cc1ccc(C(=O)C=Cc2ccccc2O)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C2CCc3ccccc3O2)c(C)c1
Reaction time: 0.5 h

Procedure:
2-Hydroxy-2',4'-dimethylchalcone (8.20 g) was suspended in ethanol (150 ml) and sodium borohydride (2.50 g) was added in portions. The mixture was stirred for 30 min and the resulting solution allowed to stand overnight. The solvent was distilled off and the residue dissolved in chloroform and washed with water. Evaporation of the chloroform gave the crude intermediate carbinol which was boiled under reflux with acetic acid (100 ml) for 2 hr. Evaporation gave an oily residue which was chromatographed on alumina, eluting with toluene. The main fraction, on evaporation of the solvent, was distilled under vacuum to give 2',4'-dimethylflavan, 4.80 g, b.p. 135°-145°/0.8 mm. Hg=107 Pa.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Cl)=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48])[CH:36]=[CH2:37]>>[CH2:35]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]2)=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48])[CH:36]=[CH2:37]
Reactant: C=CCOc1ccc(CCl)cc1[N+](=O)[O-]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCOc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1[N+](=O)[O-]

Procedure:
Analogously to Method D, 2.0 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 1.06 g of 1-allyloxy-4-chloromethyl-2-nitrobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.31 (1:1 EtOAc-heptane); Rt=6.99.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:36])[F:38])[CH:29]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)n2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.83 min; [M+H]+=492.2.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[C:17]2[N:18]=[C:19](O)[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]=2[CH:15]=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(C)C>CN(C=O)C>[CH2:6]([N:13]1[C:17]2[N:18]=[C:19]([Cl:3])[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]=2[CH:15]=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(O)nc2c1cnn2Cc1ccccc1
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)nc2c1cnn2Cc1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
Phosphoryl trichloride (74 mL/0.81 mol) is added dropwise to a solution of ethyl 1-benzyl-6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylate [CAS 74439-45-5] (40.0 g/0.135 mol) in 450 mL of DMF at 0° C. under nitrogen. The reaction medium is stirred at 80° C. for 24 hours so as to give a dark brown solution. It is then run into a mixture of ice-cold water, and extracted with EtOAc. The organic phase is washed with water, dried with sodium sulphate, filtered and concentrated to dryness. The solid obtained is taken up with isopropanol, filtered, washed with diisopropyl ether and oven-dried to give 30.6 g of a yellow powder (yield: 72%).