Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]=[C:6]1[C:10]([CH2:14][C:15](O)=[O:16])([CH2:11][CH2:12][CH3:13])[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[O:7]1>C1C=CC=CC=1>[O:5]=[C:6]1[C:10]([CH2:14][C:15]([Cl:3])=[O:16])([CH2:11][CH2:12][CH3:13])[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[O:7]1
Reactant: CCCC1(CC(=O)O)C(=O)Oc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCC1(CC(=O)Cl)C(=O)Oc2ccccc21

Procedure:
23.7 g of double-distilled thionyl chloride are added dropwise to a solution, stirred and heated to 70° C., of 23.4 g of (2,3-dihydro-2-oxo-3-propyl-3-benzofuranyl)acetic acid in 250 ml of anhydrous benzene. When the addition is complete, the mixture is heated until the evolution of gas has completely ceased. The medium is concentrated under vacuum, the residue washed with 200 ml of anhydrous benzene and the solvent evaporated off. This operation is repeated twice, and a very thick oil which does not crystallize is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1sccc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 95.8 %

Procedure:
A solution of 4-(2-methoxycarbonylthiophen-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (2.5 g, 7.7 mmol, 1.0 eq.) and Pd(OH)2/C (0.5 g, 0.6 mmol) in MeOH (70 mL) was degassed and purged with hydrogen (3×). The mixture was hydrogenated (4 atm) at room temperature overnight, then the vessel was evacuated and purged with nitrogen, and the material was filtered and washed with MeOH (150 mL). The remaining material was concentrated then again was hydrogenated (4 atm) at room temperature overnight. Filtering again as above, and concentrating the filtrate provided 4-(2-methoxycarbonylthiophen-3-yl)piperidine-1-carboxylic acid t-butyl ester (2.4 g).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:16][O-:17].[Na+]>>[CH3:16][O:17][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C[O-]
Reactant: Cn1cnc2c(Cl)nc3ccccc3c21
Agent: [Na+]
Product: COc1nc2ccccc2c2c1ncn2C

Procedure:
Using the method of Example 157, 4-chloro-1-methyl-1H-imidazo[4,5-c]quinoline (from Example 114) was reacted with sodium methoxide to provide 4-methoxy-1-methyl-1H-imidazo[4,5-c]quinoline, melting point after recrystallization from ethyl acetate 160°-162° C. Analysis: Calculated for C12H11N3O: %C, 67.6; %H, 5.2; N, 19.7; Found: %C, 67.3; %H, 5.0; %N, 19.8.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(F)cccc1N1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Combine 2,6-difluorobenzaldehyde (5.00 g, 35.2 mmol), 1-benzylpiperazine (7.30 mL, 42.2 mmol) and potassium carbonate (5.83 g, 42.2 mmol) in dry N,N-dimethylformamide (10 mL) under an atmosphere of nitrogen. Heat the reaction to 80° C. for 4 hours. Cool the reaction to room temperature (20° C.) and stir overnight. Quench the reaction with water (100 mL) and extract with ethyl acetate (3×100 mL). Combine the organic extracts, wash with saturated ammonium chloride (4×100 mL), dry over anhydrous magnesium sulfate/sodium sulfate, filter and concentrate under vacuum to provide the crude product as a yellow oil. Purify the crude material by flash chromatography (ethyl acetate:hexane, 30:70, TLC Rf =0.40) followed by recrystallization from hot ethyl acetate (50 mL). Collect the crystals by suction filtration and rinse with hexane to yield 5.16 g. Concentrate the mother liquor and recrystallize the solid from ethyl acetate (15 mL). Isolate the crystals as above to yield 1.71 g. Repeat the above process to yield an additional 0.95 g. This provides the 2-fluoro-6-[4-benzylpiperazin-1-yl]-benzaldehyde (7.82 g) as yellow crystals, mp 94°-95° C.; 1H NMR (CDCl3) δ 10.26 (1H,-s), 7.44 (1H, td, J=8.1, 6.3 Hz). 7.34 (4H, m), 7.29 (1H, m), 6.84 (1H, d, J=8.3 Hz), 6.74 (1H, dd, J=8.3, 8.0 Hz), 3.59 (2H, s), 3.12 (4H, m), 2.66 (4H, m); 13C NMR (CDCl3) δ 187.63, 187.56, 165.73, 162.27, 155.82, 137.82, 135.62, 135.46, 129.20, 128.27, 127.18, 116.91, 116.82, 114.26, 114.22, 109.38, 109.09, 62.95, 53.51, 52.96; 19F NMR CDCl3) δ -115.94 (m); IR (KBr) 2825, 1690, 1607, 1462, 1005 cm-1 ; EI/MS (70eV) 298(80%), 91(100%).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:12][P:13]([NH:19][N:20]([CH3:22])[CH3:21])([NH:15][N:16]([CH3:18])[CH3:17])=[S:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O>C(O)C>[CH3:17][N:16]([CH3:18])[NH:15][P:13]([CH2:12][NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([NH:19][N:20]([CH3:21])[CH3:22])=[S:14]
Reactant: CCOC(=O)CN(CP(=S)(NN(C)C)NN(C)C)C(=O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)CNCP(=S)(NN(C)C)NN(C)C
Yield: 53.8 %

Procedure:
N-trifluoroacetyl-N-[bis(2,2-dimethylhydrazino)phosphinothioylmethyl]glycine, ethyl ester (2 g, 0.005 mole), was dissolved in ethanol. The solution was stirred and sodium tetrahydrido boron (193 mg, 0.005 mole) was added portionwise over a ten minute period. The resulting solution was stirred for 30 minutes. The solvent was removed by evaporation under vacuum and the residue was washed with water. The water was saturated with sodium chloride and the aqueous layer and insoluble residue were simultaneously extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo to yield N-[bis(2,2-dimethylhydrazino)phosphinothioylmethyl]glycine, ethyl ester (800 mg), as a white solid, m.p. 75.5°-85° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1>>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:21]=[N:20]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Cn1cc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cn1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give [1-(1-methyl-1H-pyrazol-4-yl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 291(MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)=[N:18][CH:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:32](B1OC(C)(C)C(C)(C)O1)([CH3:34])=[CH2:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[C:32]([C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)=[N:18][CH:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1)([CH3:34])=[CH2:33]
Reactant: CS(=O)(=O)c1ccc(OCc2ccc(C3CCN(c4ncc(Br)cn4)CC3)cn2)cc1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1cnc(N2CCC(c3ccc(COc4ccc(S(C)(=O)=O)cc4)nc3)CC2)nc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 5-bromo-2-[4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidin-1-yl]pyrimidine (Example 57) (31 mg, 0.062 mmol) and isopropenylboronic acid pinacol ester (23 μL, 0.124 mmol) in dry N,N-dimethylformamide (0.3 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (complex with dichloromethane) (1 mg, 0.012 mmol) and cesium carbonate (40 mg, 0.124 mmol). The mixture was stirred at 90° C. overnight under N2, allowed to cool to room temperature, diluted with water (1 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound as a white crystal (23 mg, yield 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].Cl.[CH3:15]O>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:15])=[O:6]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(Cl)c(N)cc1OC
Reaction time: 8 h

Procedure:
To a solution of 50 g of 2-methoxy-4-amino-5-chlorobenzoic acid in 500 ml of methanol is added HCl gas until all the material dissolves. Stirring is continued overnight, the solvent removed, ether added, filtered, dried over magnesium sulfate and evaporated to dryness to obtain methyl 2-methoxy-4-amino-5-chlorobenzoate which is used directly in the next step.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)#[CH:15].ClC1N=CC(C2N=NN(C3C=C(C=CC=3C)C(O)=O)C=2)=CC=1>>[CH3:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:1]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=[N:2]1
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Reactant: C#Cc1ccccn1
Agent: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Product: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccccn2)nn1

Procedure:
4-Methyl-3-(4-pyridin-2-yl-[1,2,3]triazol-1-yl)-benzoic acid was prepared from 3-azido-4-methyl benzoic acid and 2-ethynyl pyridine (Aldrich) in the same manner as 3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (Example 1).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:18])[C:6]([C:16]#[N:17])=[N:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:17][C:16]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[N:7][C:6]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:18]
Reactant: N#CC(=NNc1ccccc1Br)C(=O)NC1CC1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Temperature: 72.5 °C
Yield: 54.1 %

Procedure:
A 500 mL, 3-necked flask equipped with a mechanical stirrer, thermometer, nitrogen inlet, reflux condenser, and addition funnel was charged with N-cyclopropyl-2-cyano-2-[(2-bromophenyl)hydrazono]acetamide (1.7 g, 5.6 mmol) in anhydrous toluene (0.2 L). The reaction mixture was cooled with stirring in an ice bath. Aluminum chloride (1.6 g, 12.0 mmol) was added in three portions. Removed ice bath and heated at 70-75° C. for 60 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (200 mL), added saturated Rochelle's salt (100 mL), stirred vigorously for 1 hour (until purple color dissipated to orange/yellow). Decanted organic layer from thick white aqueous layer, washed with additional Rochelle's salt, brine, dried and concentrated to an orange residue. The residue was slurried in ether (20 mL) to give title compound (930 mg, 52% yield). MS APCI, m/z=307/309 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[O:19][C:18]([CH:20]=[CH:21][C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1>[Pd].CO.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[O:19][C:18]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(C=Cc4ccc(C#N)cc4)o3)n2)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccnc(Nc2cccc(-c3cnc(CCc4ccc(C#N)cc4)o3)n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.4 %

Procedure:
A mixture of the 4-(2-{5-[6-(4-methyl-pyridin-2-ylamino)-pyridin-2-yl]-oxazol-2-yl}-vinyl)-benzonitrile (72 mg, 0.189 mmol) and 10% palladium on activated carbon (27 mg) in MeOH and DCM (10 ml each) was stirred vigorously under an atmosphere of hydrogen at ambient temperature and pressure for 24 h. Further catalyst (27 mg) was added and the mixture stirred for a further 18 h. The mixture was filtered and evaporated under reduced pressure before trituration from DCM/pentane to afford the title compound as a pale yellow solid (32 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.10 (d, J=5.0 Hz, 1H), 7.89-7.39 (m, 8H), 7.17 (d, J=7.2 Hz, 1H), 6.73 (t, J=13.6 Hz, 1H), 3.22 (s, 4H), 2.31 (s, 3H). (ESI+) m/z 382 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)=[CH:4][CH:3]=1.Cl.[Cl:26][C:27]1[CH:34]=[C:33]([NH:35][NH2:36])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>>[Cl:26][C:27]1[CH:34]=[C:33]([N:35]2[CH:6]([C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:36]2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: CCOC(=O)c1ccc2c(c1)CCC(=Cc1ccc(F)cc1)C2=O
Reactant: N#Cc1ccc(NN)cc1Cl
Agent: Cl
Product: CCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1c1ccc(F)cc1
Yield: 83 %

Procedure:
The title compound was prepared from ethyl 6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (Preparation 16; 324 mg, 1.0 mmol) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride (Preparation 1; 306 mg, 1.5 mmol) according to Method B (yellow solid, 394 mg, 0.830 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 1H), 1.31 (t, J=7.12 Hz, 3H), 1.79 (m, 1H), 2.95 (m, 2H), 3.97 (ddd, J=13.49, 11.21, 4.83 Hz, 1H), 4.31 (q, J=6.98 Hz, 2H), 5.94 (d, J=11.28 Hz, 1H), 7.15 (m, 6H), 7.66 (d, J=8.86 Hz, 1H), 7.80 (s, 1H), 7.85 (dd, J=8.19, 1.75 Hz, 1H), 8.16 (d, J=8.06 Hz, 1H). ES-MS m/z 474 (M+H).
Reaction SMILES: [OH-].[Na+].[BH4-].[Na+].[ClH:5].[CH3:6][N:7]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9][CH2:8]1.Cl>O>[ClH:5].[CH3:6][N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9][CH2:8]1
Reactant: CN1CCCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CN1CCCC(O)CC1
Reaction time: 2 h
Yield: 90 %

Procedure:
100 ml of 1N sodium hydroxide solution is added to a solution of 18.9 g of sodium borohydride in 100 ml of water. A solution of 163.6 g of 1-methylperhydroazepin-4-one HCl in 100 ml of water is added dropwise at an internal temperature of 0° to 5° C. The mixture is stirred for 2 hours at 0° to 5° C. and then for 2 hours at room temperature. The pH is adjusted to 2 to 3 by addition of semi-concentrated hydrochloric acid. The mixture is evaporated to dryness in vacuo, the residue is taken up in 600 ml of isopropanol, the inorganic salts are separated off at 60° to 75° C. and the product is crystallised in an ice bath. The product is filtered and dried to constant weight in vacuo at elevated temperature. 149 g (90%) of 1-methylperhydroazepin-4-ol HCl is obtained.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)[C:5]=2[O:4][CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:5]=2[O:4][CH2:3]1
Reactant: C1=C(c2cccc3c2OCO3)CCNC1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: c1cc2c(c(C3CCNCC3)c1)OCO2
Temperature: 25 °C
Yield: 100 %

Procedure:
Pd/C 10% (169 mg, 159 μmol,) was added to a solution of 4-(benzo[1,3]dioxol-4-yl)-1,2,3,6-tetrahydropyridine hydrochloride (760 mg, 3.17 mmol) and ammonium formate (1.00 g, 15.9 mmol) in methanol (28.8 ml) under argon. After refluxing for 60 min the reaction mixture was cooled to room temperature, filtrated and concentrated under reduced pressure. Saturated sodium bicarbonate solution was added to the residue and the mixture was extracted with dichloromethane (3×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo to yield the title compound as a white solid (0.654 grs, 100%). MS (ISP) m/z=206.0[(M+H)+].
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([O:49][CH3:50])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1>C(O)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([O:49][CH3:50])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc(C)c1O
Solvent: O=CO
Product: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)cc(C)c1O

Procedure:
A solution of 220 mg (0.29 mmol) (R)-2-[4-(1-tert-butoxycarbonyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3-methoxy-5-methyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 10.4) in 3 mL formic acid was stirred for 4 h at RT and then concentrated by evaporation i. vac. at 40° C. The crude product was purified by preparative HPLC-MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH2:22](Br)[CH2:23][CH2:24][CH3:25].[OH-].[K+]>CO>[CH2:22]([N:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:18]=[C:19]([O:20][CH3:21])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11][CH2:10]1)[CH2:23][CH2:24][CH3:25]
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)CNCC2
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCc2cc(OC)c(OC)cc2C(c2ccccc2)C1

Procedure:
A mixture of 4.32 g. (0.0154 mole) of 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 0.02 mole of n-butyl bromide and 0.02 mole of potassium hydroxide is dissolved in 120 ml. of dry methanol and refluxed for 48 hours. The reaction mixture is evaporated to dryness, taken up in ethyl acetate and filtered to remove inorganic salts. The filtrate is washed with water, dried and evaporated to give 3-n-butyl-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine as an oil.
Reaction SMILES: [CH2:1](Br)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH3:12][NH:13][CH3:14]>C(O)C>[CH3:12][N:13]([CH3:14])[CH2:1][CH:2]=[C:3]([CH3:4])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9]
Reactant: CNC
Reactant: CC(C)=CCC/C(C)=C/CBr
Solvent: CCO
Product: CC(C)=CCCC(C)=CCN(C)C
Yield: 72 %

Procedure:
Geranylbromide (20 g) in ethanol (50 ml) was added to 33% dimethylamine in industrial methylated spirits (240 ml) and the mixture was heated at reflux for 8 hours. The reaction mixture was evaporated to dryness, mixed with 2N sodium hydroxide (50 ml) and then extracted with diethyl ether (2×100ml). The ether extracts were combined and washed with water (50 ml), then dried with anhydrous magnesium sulphate and evaporated to dryness. The resulting orange oil was purified by chromatography (with a gradient CH2Cl2 :MeOH system as eluent) to give 1-dimethylamino-3.7-dimethyl-2,6-octadiene as an oil (12.1 g, 72%).
Reaction SMILES: [CH3:1][N:2](C(CN)=O)[C@@H:3]1[C@@H:8]([O:9][CH3:10])[C@@H:7]([OH:11])[C@H:6]([NH2:12])[C@@H:5]([O:13][C@H:14]2[O:19][C@H:18]([CH2:20][NH2:21])[CH2:17][CH2:16][C@H:15]2[NH2:22])[C@@H:4]1[OH:23].[OH-].[Ba+2].[OH-].C(=O)=O>>[CH3:1][NH:2][C@@H:3]1[C@@H:8]([O:9][CH3:10])[C@@H:7]([OH:11])[C@H:6]([NH2:12])[C@@H:5]([O:13][C@H:14]2[O:19][C@H:18]([CH2:20][NH2:21])[CH2:17][CH2:16][C@H:15]2[NH2:22])[C@@H:4]1[OH:23]
Reactant: CO[C@H]1[C@@H](O)[C@H](N)[C@@H](O[C@H]2O[C@H](CN)CC[C@H]2N)[C@H](O)[C@@H]1N(C)C(=O)CN
Agent: O=C=O
Agent: [Ba+2]
Agent: [OH-]
Product: CN[C@H]1[C@@H](O)[C@H](O[C@H]2O[C@H](CN)CC[C@H]2N)[C@@H](N)[C@H](O)[C@@H]1OC
Temperature: 100 °C

Procedure:
In this example, 10 g of the free base of Fortimicin D is dissolved in 500 ml of aqueous solution of saturated barium hydroxide. The solution is heated at a temperature of 100° C. for 3 hours and thereafter is allowed to stand until it is cooled to room temperature. The solution is neutralized with dry ice to precipitate the barium carbonate out. Filtration is carried out to remove the precipitate and the precipitate is washed with a small amount of water. The filtrate and the washings are combined and concentrated to about 20 ml. The concentrate is passed through a column packed with 500 ml of a cation exchange resin, Amberlite CG-50 (ammonium form). After the resin is washed with water, elution is carried out with 0.2 N aqueous ammonia. The eluate is recovered in 20 ml fractions and each of the fractions is subjected to determination of activity by the paper disc method. First, a small amount of reaction by-products is eluted. Thereafter, Fortimicin KE is eluted. Active fractions are subjected to thin layer chromatography and the fractions containing Fortimicin KE are combined and concentrated under reduced pressure to 20 ml. The concentrate is freeze-dried to obtain 7.8 g of the purified preparate of the free base of Fortimicin KE, the activity of which is about 970 unit/mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:42][C:43]1[C:51]2[C:50]([N:52]3[CH2:57][CH2:56][CH:55]([NH2:58])[CH2:54][CH2:53]3)=[N:49][CH:48]=[N:47][C:46]=2[NH:45][CH:44]=1>CN(C)C=O>[CH3:42][C:43]1[C:51]2[C:50]([N:52]3[CH2:57][CH2:56][CH:55]([NH:58][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:9])[CH2:54][CH2:53]3)=[N:49][CH:48]=[N:47][C:46]=2[NH:45][CH:44]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ncnc(N3CCC(NC(=O)c4ccncc4)CC3)c12
Reaction time: 18 h

Procedure:
To a solution of 4-pyridinecarboxylic acid (59.8 mg, 0.486 mmol), EDC.HCl (115 mg, 0.598 mmol), HOBt (92 mg, 0.598 mmol) and N,N-diisopropylethylamine (0.163 mL, 0.934 mmol) in N,N-dimethylformamide (1 mL), stirred for 10 minutes, was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride (100 mg), DU, and the reaction stirred for 18 h. The solvent was removed in vacuo and the mixture purified by high pH MDAP to give the title compound E27 (45 mg). 1H NMR (d6-DMSO) δ 11.53 (1H, s), 8.72 (2H, d), 8.66 (1H, d), 8.22 (1H, s), 7.78 (2H, d), 7.07 (1H, s), 4.09 (1H, m), 4.02 (2H, d), 3.06 (2H, t), 2.37 (3H, s), 1.95 (2H, d), 1.74 (2H, ddd), MS(ES+) 337 [M+H]+.