Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([C:13](OC)=[O:14])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:31]([O:34][CH2:35][CH3:36])(=[O:33])[CH3:32]>C1(C)C=CC=CC=1>[O:14]=[C:13]([C:11]1[N:10]=[CH:9][N:8]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=1)[CH2:32][C:31]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
202.65 g (0.55 mol) methyl (1-triphenylmethyl-1H-imidazol-4-yl)carboxylate are dissolved in 0.8 l dry toluene at 85° C. 44 g (1.1 mol) sodium hydride (60% dispersion in mineral oil) are added. To the stirred mixture 96.92 g (1.1 mol) ethyl acetate are dropped over 2 hours. The mixture is allowed to react 16 hours at 70° C. Subsequently the toluene is removed under reduced pressure. The resulting mixture is introduced into the following step without purification. For analytical purposes a small amount of the brown oily residue is dissolved in methylene chloride, washing with aqueous ammonium chloride solution and water, drying by means of sodium sulphate and evaporation lead to an oil. Crystallization with diethyl ether and recrystallization from ethanol/diethyl ether afford the title compound as white crystals, melting point 136°-139° C.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>C(O)C>[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[N:30][NH:29][C:16]2[CH:15]=[C:14]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=2)=[CH:34][CH:33]=1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (25.0 mg, 0.0464 mM), then 4-hydroxy-benzaldehyde (6.2 mg, 0.051 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (19.2 mg, yield: quantitative).
Reaction SMILES: [C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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>[C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([C:30]3[CH:31]=[CH:32][C:27]([C:19]4[S:18][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=4)=[CH:28][CH:29]=3)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Reactant: OB(O)c1ccc(-c2nc3ccccc3s2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)n1c2ccccc2c2cc(-c3ccc(-c4nc5ccccc5s4)cc3)ccc21
Yield: 79.5 %

Procedure:
A mixture of 5.8 g of 9-Acetyl-3-bromocarbazole and 5.7 g of (4-benzo[d]thiazol-2-yl) phenylboronic acid were stirred together in 30 ml of toluene. To this was added 0.03 g of tetrakis(triphenylphosphine)palladium, 4.2 g of potassium carbonate and 10 ml of aqueous ethanol were added and refluxed under nitrogen for 6 h. The reaction was quenched with water and the toluene layer was removed and passed through a celite column. The organic layers were combined and then evaporated in a rotary evaporator under vacuum to yield 6.7 g of 9-acetyl-3-[(4-benzo [d]thiazol-2-yl) phenyl]-9H-carbazole as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][C:10]2[N:9]=[CH:8][C:7]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:6]=3[C:5]=2[C:4](=O)[CH2:3]1.O.NN.[OH-].[K+]>C(O)CO>[CH3:1][C:2]1([CH3:20])[CH2:11][C:10]2[N:9]=[CH:8][C:7]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:6]=3[C:5]=2[CH2:4][CH2:3]1
Reactant: CC1(C)CC(=O)c2c(ncc3[nH]c4ccccc4c23)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC1(C)CCc2c(ncc3[nH]c4ccccc4c23)C1
Yield: 45.9 %

Procedure:
3,3-Dimethyl-2,3,4,7-tetrahydroindolo[2,3-c]quinolin-1-one of Example 1h (1.36 g, 5.14 mmol) was added to a mixture of ethylene glycol (8 mL) and hydrazine monohydrate (5 mL) at room temperature under stirring. The mixture was refluxed for 1 h, cooled, potassium hydroxide (1 g) was added, and the reaction mixture was refluxed for 2 h. The excess of hydrazine and water was slowly distilled off at 1 psi until the vapor temperature reached 190° C. The residue was cooled, diluted with water (60 mL), and the solid product was filtered off, washed with water and recrystallized from ethanol-water, 1:1. The product was isolated as colorless solid (0.59 g, 46%). Crystallization from toluene yielded the analytically pure sample; m.p. 275-277° C. 1H NMR (DMSO-d6) δ 1.03 (s, 6H), 1.72 (t, 2H), 2.76 (s, 2H), 3.30 (t, 2H), 7.20-7.23 (m, 1H), 7.49-7.60 (m, 2H), 8.17 (d, 1H), 8.66 (s, 1H), 11.45 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].Cl.[CH:28]1([CH:31]([NH2:34])[CH2:32][CH3:33])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:34][CH:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][CH3:33])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Reactant: CCC(N)C1CC1
Agent: Cl
Product: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 70.4 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.91 g, 2.20 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-propylamine HCl (0.56 g, 4.41 mmol) were treated substantially as described in Part C of Example 19a to produce 0.56 g (72%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (AP) m/z 361.8 [(M+H)+, 100].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[N+:22]([O-:40])[CH:23]=[C:24]([Cl:39])[C:25]=1[CH2:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)O.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:39][C:24]1[CH:23]=[N+:22]([O-:40])[CH:21]=[C:20]([Cl:19])[C:25]=1[CH2:26][C@H:27]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:10][C:11]=1[F:18])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(NC(=O)OC(C)(C)C)cc2F)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
To a stirred solution of 4-(tert-butoxycarbonylamino)-2-fluorobenzoic acid (0.200 g, 0.78 mmol) and (1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (0.270 g, 0.78 mmol) in dichloromethane (10.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.300 g, 1.57 mmol) and N,N-dimethylpyridin-4-amine (0.048 g, 0.39 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (25.0 mL) and extracted with dichloromethane (×2). The combined organic extracts were dried on magnesium sulphate, filtered, and the solvent removed in vacuo to afford a yellow oil. The crude material was purified by silica gel chromatography eluting sequentially with iso-hexane and 10% methanol in ethyl acetate to afford the title compound as a yellow solid (0.351 g, 77%).
Reaction SMILES: Cl.[S:2]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7]1)(=[O:5])(=[O:4])[NH2:3].[C:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21].CCN(CC)CC>>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:11]2[CH2:12][CH2:13][C:8]3([C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:6]([S:2](=[O:4])(=[O:5])[NH2:3])[CH2:7]3)[CH2:9][CH2:10]2)=[O:31])=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: NS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: CC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)N2CCC3(CC2)CN(S(N)(=O)=O)c2ccccc23)cc1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a suspension of 1-sulfamoylspiro[indoline-3,4′-piperidine]hydrochloride 3-1 (100 mg, 0.33 mmol) and phenyl 4-acetylphenylcarbamate 3-2 (92 mg, 0.36 mmol) in CHCL3 (3 mL) was added Et3N (0.23 mL, 1.65 mmol) at room temperature. The reaction mixture was heated to reflux for 1 h. The resulting suspension was cooled to room temperature. The resulting suspension was filtered and the filter cake was washed with CHCl3 to give 300 (47 mg, 33%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:12]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)O
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
A mixture of 3-bromo-phenyl acetic acid (5.00 g, 23.24 mmol), tert-butanol (1.89 g, 25.57 mmol), DMAP (3.12 g, 25.57 mmol), and DCC (5.27 g, 25.57 mmol) in CH2Cl2 (150 mL) was stirred for 24 h at room temperature. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the mixture was filtered. The organic solution was washed consecutively with 5.5% HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to provide the title compound (5.64 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)CCC>>[C:1]([O:5][C:6](=[O:22])[N:7]([C:8]1[N:9]=[C:10]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[CH:11]=[N:12][CH:13]=1)[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Product: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(-c2cnccn2)n1

Procedure:
Was prepared according to Example 6 from (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester and 2-tributylstannylpyrazine.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cnc1Oc1ccc(F)cc1

Procedure:
The title compound was prepared according to general procedure A using 2-bromo-5-chloro-3-nitro-pyridine (750 mg, 3.17 mmol), 4-fluorophenol (463 mmol, 4.13 mmol), K2CO3 (437 mg, 4.75 mmol) and DMF (5 mL). MS m/z: 269.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=O)[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[S:26])[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2ccc(Br)cc2C2CCCC12F
Solvent: C1CCOC1
Product: FC12CCCC1c1cc(Br)ccc1NC2=S

Procedure:
A solution of 0.74 g (2.6 mmol) of 8-bromo-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 100 ml of THF is refluxed with 2.16 g (5.34 mmol) of Lawesson's reagent for 1.5 hours. Then, the reaction mixture is concentrated by evaporation, and the residue is purified by column chromatography on silica gel with hexane-ethyl acetate: 0.59 g of product.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([NH2:26])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])C.O[Li].O>C1COCC1.O>[NH2:26][C:17]1[CH:16]=[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7]([NH:6][CH2:5][C:4]([OH:27])=[O:3])=[O:8])[CH2:10][CH2:11]2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]=1
Reactant: CCOC(=O)CNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(N2CCN(C(=O)NCC(=O)O)CC2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
As described example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine (1.5 g, 5.7 mmol), isocyanato-acetic acid-ethy ester (0.7 mL, 6.3 mmol) and diisopropylethyl amine (1.5 mL, 8.6 mmol) are reacted to give [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid-ethyl ester the product as a white solid (990 mg, 40%). A mixture of the ester (990 mg), LiOH.H2O (1 g) in THF-H2O (5:1, 45 mL) was stirred at rt for 3 h, then acidified with 1.0 N HC (aq.) to pH to 4–5. After the removal of THF in vacuo, crude product precipitated. 760 mg (76%) of the acid was obtained after drying under vacuum for 3 h. LC-MS: 363 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[C:9](O)(=O)C1C=CC=CC=1>>[N:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][CH:9]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccccc1N
Product: c1ccc2[nH]cnc2c1

Procedure:
A known method consists in condensing 1,2-diaminobenzene with benzoic acid in the presence of polyphosphoric acid to give benzimidazole, and sulphonating this with, for example, chlorosulphonic acid (Am. Chem. Soc. 79, 427 (1957)).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]([CH3:22])=O>CCCCCC.C(OCC)(=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:20]#[C:22][C:12]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCC#CC#CCOc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
In a flask were placed 3.78 g (0.024 mole) of 1-chloro-2,4-nonadiyne thus obtained, 3.32 g (0.02 mole) of ethyl 4-hydroxybenzoate, 5.5 g (0.04 mole) of potassium carbonate, and 50 ml of acetone and the mixture was refluxed by heating for 11 hours. After allowing to cool the reaction mixture to room temperature, the reaction mixture was poured in 250 ml of ice-water and the product was extracted with methylene chloride. After distilling off the solvent of the organic layer, the residue formed was purified by a silica gel column chromatography(developing solvent: hexane/ethyl acetate=3/1) to provide 4.0 g (yield 70%) of ethyl 4-(2,4-nonadiynyloxy)-benzoate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](SC(C)C)[N:14]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:10]=[CH:9]2)[CH2:4][CH2:3]1.OOS([O-])=O.[K+].[CH3:36][OH:37]>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:37][CH3:36])[N:14]=3)=[C:11]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[N:10]=[CH:9]2)[CH2:4][CH2:3]1
Reactant: CC(C)Sc1nccc(-c2c(-c3ccc(F)cc3)ncn2[C@H]2CC[C@H](O)CC2)n1
Reactant: CO
Agent: O=S([O-])OO
Agent: [K+]
Product: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2[C@H]2CC[C@H](O)CC2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The product of step (b) above, (10.8 g, 26.2 mmol) was dissolved in 43 mL of MeOH and Oxone™ (12.1 g, 19.6 mmol) was added and the resulting suspension was stirred at room temperature for 4-24 h. After HPLC confirmed that no starting material remained, the remaining Oxone™ salts were removed by filtration of the suspension through a Buchner funnel. A NaOMe/MeOH solution (25%, 16 mL) was added to the solution until the pH was about 12. After 20 min, HPLC confirmed that the reaction was complete and 100 mL of water was added to the reaction. The resulting solution was stirred at room temperature for 3 h, then filtered through a Buchner funnel and rinsed with 50 mL of water. The pale white solid was dried in the vacuum oven at 65° C. for 18 h to yield 6.0 h (62% yield) of title compound.
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 0.2N 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 to Fortimicin KE, the activity of which is about 970 unit/mg.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:5]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]([Cl:3])=[O:21])[CH2:15][CH2:14]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(C(=O)c2ccccc2)CC1
Product: O=C(Cl)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
Thionyl chloride (2.0 ml, 3.3 g, 27 mmol) was added to 1-benzoyl-4-piperidinecarboxylic acid (0.31 g, 1.33 mmol) at 25° C. After stirring for 48 hours, the solution was warmed to 30° C. and concentrated under a stream of nitrogen. The 1-benzoyl-4-piperidinecarbonyl chloride, sufficiently pure for subsequent reactions, was obtained as a colorless oil which crystallized during storage at 0° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CCO>[OH:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: OC1(c2ccccn2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: OC1(c2ccccn2)CCNCC1
Reaction time: 36 h
Yield: 93.9 %

Procedure:
A mixture of N-benzyl-4-hydroxy-4-(2-pyridyl)piperidine (1.2 g, 4.48 mmol), 20% Pd-C (0.2 g) and EtOH (100 mL) was stirred at H2 (150 psi ) for 36 h. The catalyst was removed by filtration and washed with more ethanol. Solvent was evaporated to give pure 4-hydroxy-4-(2-pyridyl)piperidine (0.75 g, 94%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>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.C1(C)C=CC=CC=1.CCO>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2ccnc(Cl)n2)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(c2ccnc(-c3ccccc3)n2)CC1
Temperature: 140 °C

Procedure:
To a microwave tube was added 2-chloro-4-(4-methyl-piperazin-1-yl)-pyrimidine (30 mg, 0.14 mmol), Pd(PPh3)4 (10 mg), phenylboronic acid (24 mg, 0.2 mmol), toluene/EtOH (4:1, 1 mL) and 2 M aqueous K2CO3 (0.2 mL). The resulting mixture was heated at 140° C. for 30 minutes using the microwave instrument. The resulting mixture was extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:31])[N:7]([CH3:30])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][C:13]=3[O:28]C)=[N:9]2)=[CH:4][CH:3]=1.B(F)(F)F.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:31])[N:7]([CH3:30])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][C:13]=3[OH:28])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc(OCCCN2CCCCC2)ccc1-c1nc2cc(Br)ccc2c(=O)n1C
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2O)nc2cc(Br)ccc2c1=O
Yield: 25.4 %

Procedure:
7-Bromo-2-[2-methoxy-4-(3-piperidin-1-ylpropoxy)phenyl]-3-methylquinazolin-4(3H)-one (38.5 mg, 0.0792 mmol) was dissolved in CH2Cl2 (0.5 mL), stirred with cooling with ice, and boron trifluoride (1.0 M in CH2Cl2, 160 μL) was added thereto. After stirred for 20 hours at room temperature, the reaction solution was diluted with ethyl acetate, and with cooling with ice, it was poured into aqueous 1 N sodium hydroxide solution, and extracted with ethyl acetate. This was washed with saturated saline water and dried with magnesium sulfate. The organic layer was concentrated under reduced pressure, and purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the intended compound (9.5 mg, 25%) as a pale yellow solid.