Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[CH3:30][NH2:31]>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([CH3:28])[C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([NH:31][CH3:30])[C:3]4=[O:29])=[CH:8][CH:9]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Product: CNC1CCN(c2ccc(N(C)C(=O)c3ccc(C4CCCCC4)cc3)cc2)C1=O

Procedure:
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with methylamine by method L. This resulted in the product with the molecular weight of 405.54 (C25H31N3O2); MS (ESI): 406 (M+H+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.[CH2:46]([NH:48][CH:49]([C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)[CH3:50])[CH3:47].C1C=CC2N(O)N=NC=2C=1>ClCCl.CO>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:48]([CH2:46][CH3:47])[CH:49]([C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)[CH3:50])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCNC(C)c1cccnc1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCN(C(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)C(C)c1cccnc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 145.3 %

Procedure:
In a 3-neck 50 mL round-bottomed flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was dissolved in dichloromethane (15 mL) at 0° C. under N2 atmosphere. To this reaction DIPEA (0.088 g, 1.2 eq.), EDC.HCl (0.131 g, 1.2 eq.) and N-ethyl-1-(pyridin-3-yl)ethanamine (0.102 g, 1.2 eq.) was added followed by HOBt (0.104 g, 1.2 eq.). Reaction mixture was stirred at 20° C. for 1 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% methanol: dichloromethane as mobile phase and visualization with UV, SM Rf=0.15 and Product Rf=0.40. Reaction was stirred for 3-4 h and yellow reaction mixture was evaporated on rotary evaporator under reduced pressure to afford 0.4 g of crude compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:11])[CH:7]=[CH:8][C:9]=1F)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a 100 mL round bottom flask was added 3-nitro-4-fluorotoluene (1.55 g, 10 mmol), 4-amino-1-N-Boc-piperidine (2.40 g, 12 mmol), powder K2CO3 (2.76 g, 20 mmol) and dry DMF (30 mL). The mixture was stirred at 85° C. overnight. Solvents were evaporated under reduced pressure. The residue was extracted with ethyl acetate and the combined organic layers were washed with brine. The organic layer was dried over Na2SO4 and filtered. Removal of solvents under reduced pressure gave an oil residue. 4-(4-methyl-2-nitrophenylamino)-piperidine-1-carboxylic acid tert-butyl ester was isolated as a solid (3.13 g, 94%) from Biotage flash column chromatography using hexanes and ethyl acetate (3/1 ratio).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([Cl:24])[C:7]2[N:8]([CH:21]=[N:22][CH:23]=2)[C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:20])[CH2:17][C:18]#[N:19])[CH2:12][CH2:11]1)[CH3:3].Br[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2C1CCCCO1.C(N(CC)C(C)C)(C)C.Cl.O1CCOCC1>C(O)C>[Cl:24][C:6]1[C:7]2[N:8]([CH:21]=[N:22][CH:23]=2)[C:9]([N:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:20])[CH2:17][C:18]#[N:19])[CH2:14][CH2:15]2)=[C:4]([CH:2]([NH:1][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][NH:30]3)[CH3:3])[CH:5]=1
Reactant: CC(N)c1cc(Cl)c2cncn2c1N1CCN(C(=O)CC#N)CC1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1COCCO1
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cncn2c1N1CCN(C(=O)CC#N)CC1
Temperature: 110 °C
Yield: 35.6 %

Procedure:
A mixture of 3-{4-[6-(1-aminoethyl)-8-chloroimidazo[1,5-a]pyridine-5-yl}piperazin-1-yl]-3-oxopropanenitrile (18 mg, 0.052 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (29 mg, 0.10 mmol) and N,N-diisopropylethylamine (27 μL, 0.16 mmol) in ethanol (1.0 mL) was heated at 110° C. overnight. The mixture was evaporated and a 4 M solution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) was added. The mixture was evaporated and a 4 M solution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) was added. The mixture was evaporated and purified by preparative LCMS (pH 10) to give the desired compound (8.6 mg, 36%). LCMS calculated for C21H22ClN10O (M+H)+: m/z=465.2. found: 464.9.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH:27]([CH3:29])[CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[NH:35][N:34]=[C:33]([CH2:36][C:37](O)=[O:38])[N:32]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH:27]([CH3:29])[CH3:28])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:37](=[O:38])[CH2:36][C:33]1[NH:32][C:31]([CH3:30])=[N:35][N:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Reactant: CC(C)c1nn(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: Cc1nnc(CC(=O)N2CCN(c3ccc4c(C(C)C)nn(C5CCC5)c4c3)C[C@@H]2Cc2ccccc2)[nH]1
Yield: 25 %

Procedure:
Prepared using the same procedure described in Example 189 from 6-((S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-isopropyl-1H-indazole and (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid to afford the title compound as colorless solid (35 mg, 25%). LC/MS (Method B) 3.62 min, [M+1]+ 512.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=3)[C:11]=2/[CH:12]=[CH:13]/[C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[O:6])[CH2:3][CH2:2]1.CI.[C:32](=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:24]=3)[C:11]=2/[CH:12]=[CH:13]/[C:14]2[N:18]([CH3:32])[CH:17]=[CH:16][N:15]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2ncc[nH]2)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2nccn2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.9 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[(E)-2-(1H-imidazol-2-yl)vinyl]-1H-1,2,3-triazole-4-carboxamide (150 mg) obtained in Example 322 was dissolved in acetone (3 ml) and DMF (3 ml), methyl iodide (72 μl) and potassium carbonate (300 mg) were added, and the mixture was stirred at room temperature for 3 days. After an insoluble material was removed by filtration, the reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in chloroform. The obtained chloroform solution was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-methanol (10:1) to give the title compound as a white powder (20 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.Br.[C:19](SCC1C=CC2C(=CC=CC=2)C=1)(=[NH:22])[CH2:20][CH3:21]>C(O)C>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:6][CH:7]=1)(=[NH:22])[CH2:20][CH3:21]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: CCC(=N)SCc1ccc2ccccc2c1
Agent: Br
Solvent: CCO
Product: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A mixture of tert-butyl 2-(4-aminophenyl)ethylcarbamate (709 mg, 3 mmol) and 2-naphthylmethyl propanimidothioate hydrobromide (930 mg, 3 mmol) in ethanol (10 mL) was stirred for overnight at ambient temperature. Then, the volatile components were removed by evaporation and the residue was partitioned between diethyl ether (10 mL) and water (10 mL). The aqueous phase was washed with diethyl ether (3×10 mL) and basified by NaOH to pH 10. The aqueous phase was extracted with chloroform (20×4) and the combined extract was dried (MgSO4). Concentration of the organic solvent afforded 831 mg (95%) of the title compound as a colorless powder. MS (ESI) m/z 292 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:19]C)(=[O:18])[CH:16]=[CH2:17].[OH-].[K+]>CO.O>[CH:4]1[C:5]2[CH:6]3[CH2:17][CH:16]([C:15]([OH:19])=[O:18])[CH:13]([C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: C=CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC2c3ccccc3C1c1ccccc12
Temperature: 162.5 °C
Reaction time: 72 h

Procedure:
Anthracene (40 gm) was combined with methyl acrylate (30 gm) in a Parr bomb and heated to 150-175° C. for 6 hours. The mixture was allowed to remain in the bomb at room temperature for 72 hours. The mixture was dissolved in methanol (225 ml), treated with a solution of potassium hydroxide (40 gm) in water (40 ml) and heated to reflux for 4 hours. The solution was cooled to room temperature and most of the solvent was removed on a rotary evaporator. The residue was dissolved in water (200 ml), filtered through charcoal and acidified with concentrated hydrochloric acid. The resulting mixture was allowed to stand overnight and the precipitate was filtered. The white solid was dried at 80° and recrystallized from benzene to provide the product (mp=188-189° C.).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(CBr)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of the product of Step A (4.44 g, 22.1 mmol) in CH2Cl2 were added N,N-diisopropylethylamine (1.2 sq.), 4-dimethylaminopyridine (0.1 eq), and tert-butyldimethylsilyl chloride (1.2 eq). The reaction mixture was stirred for 1.5 hours at room temperature, then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluted with 2.5% ethyl acetate/hexane to afford 5.0 g (71%) of the titled product.
Reaction SMILES: [NH2:1][C@:2]1([CH2:14][OH:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.N1C=CC=CC=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C1COCC1.CCOC(C)=O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:4]2[CH2:5][CH2:6][C@@:2]3([NH:1][C:22](=[O:23])[O:15][CH2:14]3)[CH2:3]2)=[CH:8][CH:9]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N[C@]1(CO)CC[C@@H](c2ccc(Br)cc2)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1N[C@@]2(CC[C@@H](c3ccc(Br)cc3)C2)CO1
Reaction time: 4 h
Yield: 71.5 %

Procedure:
((1R,3R)-1-Amino-3-(4-bromophenyl)cyclopentyl)methanol (I-4A, 3.19 g, 11.81 mmol) was dissolved in THF (59.0 ml). Pyridine (0.955 ml, 11.81 mmol) and 1,1′-carbonyldiimidazole (5.74 g, 35.4 mmol) were added portionwise. The reaction mixture was stirred for 4 h and was followed by LCMS. After completion, the mixture was diluted with EtOAc and washed with 1M HCl. The aqueous layer was back extracted twice with EtOAc. The organic layers were combined, washed with saturated NaCl, dried over MgSO4, filtered and concentrated to afford (5R,7R)-7-(4-bromophenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (2.5 g, 8.44 mmol) after flash chromatography (24 g silica gel column; eluent: hexane 2 CV followed by a gradient to 100% EtOAc over 15 CV). HPLC ret time=0.91 min; LC/MS M+1=298. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 5.72-5.81 (m, 1H), 4.35 (dd, J=13 Hz, 8 Hz, 2H), 3.19-3.24 (m, 1H), 2.38-2.44 (m, 1H), 2.15-2.26 (m, 1H), 2.11-2.14 (m, 1H), 1.99-2.05 (m, 1H), 1.79-1.85 (m, 1H), 1.65-1.72 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:39][CH2:38][CH2:37][C@H:31]1[C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:27])[NH:16][S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CN1CCOCC1.ON1C(=O)CCC1=O.CCN=C=NCCCN(C)C.[NH:66]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C@@H:67]([C:72](O)=[O:73])[CH2:68][CH:69]([CH3:71])[CH3:70]>CN(C=O)C.C1COCC1>[NH:66]([C:75]([O:77][C:78]([CH3:80])([CH3:79])[CH3:81])=[O:76])[C@@H:67]([C:72]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:39][CH2:38][CH2:37][C@H:31]1[C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:27])[NH:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=1)(=[O:18])=[O:19])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:73])[CH2:68][CH:69]([CH3:71])[CH3:70]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
H-Leu-Arg(Tos)-Pro-NHEt was dissolved in 80 mL of DMF and 200 mL of THF. With cooling the solution was neutralized with N-methylmorpholine. To the solution, a solution in which 8.86 g of Boc-D-Leu-OH and 23.02 g of HOSu were dissolved in 200 mL of THF, and 36.4 mL of WSC were added. Next the mixture was stirred at 0° C. for 5 minutes and at room temperature overnight. After confirmation with ninhidrin, the reaction mixture was concentrated under reduced pressure. To the residue, 500 mL of water was added, then the mixture was extracted 5 times with 200 mL of n-butanol and washed five times with water. The n-butanol layer was concentrated under reduced pressure, then the residue was solidified by treatment with ether. Thus 21.5 g of Boc-D-Leu-Leu-Arg(Tos)-Pro-NHEt (92.1% yield) was obtained.
Reaction SMILES: [NH2:1][C:2]1([C:26]#[N:27])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])OCC[O:13]2)[CH2:4][CH2:3]1.S(=O)(=O)(O)[OH:29]>O>[NH2:1][C:2]1([C:26]([NH2:27])=[O:29])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:13])[CH2:4][CH2:3]1
Reactant: COc1ccc(Cl)cc1C1(CCCCN2CCC(N)(C#N)CC2)OCCO1
Reactant: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)CCCCN1CCC(N)(C(N)=O)CC1
Temperature: 0 °C

Procedure:
A mixture of 4-amino-1-[5-(5-chloro-2-methoxyphenyl)-5,5-ethylenedioxypentyl]piperidine-4-carbonitrile (5.2 g, 13.1 mmol), prepared as in Example 20, water (1.6 mL) and sulfuric acid (41 mL) was warmed approximately 5 minutes on a steam bath and then cooled to 0° C. and diluted with water (150 mL). The mixture was washed with ethyl acetate (2×), cooled to 0° C. treated with potassium hydroxide, filtered, washed with chloroform and extracted with methylene chloride (4×). The combined extracts were dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate/hexane to give 4-amino-1-[5-(5-chloro-2-methoxyphenyl)-5-oxopentyl]piperidine-4-carboxamide (4.2 g, 11.4 mmol). Free base (135 mg, 0.367 mmol) was recrystallized from a solution of hydrogen chloride in ethanol to give 4-amino-1-[5-(5-chloro-2-methoxyphenyl)-5-oxo-pentyl]piperidine-4-carboxamide hydrochloride (65 mg, 0.16 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:32])[C:5]([C:7]1[S:19][C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([CH2:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10](=[O:29])[C:9]=2[C:8]=1[O:30][CH3:31])=[O:6].C(NC([OH:38])C)C.[CH:39]([N:42](C(C)C)[CH2:43][CH3:44])(C)[CH3:40].[I-].[Na+]>C(O)CCC.C(=O)([O-])O.[Na+]>[CH2:39]([N:42]([CH2:43][CH2:44][OH:38])[CH2:2][CH2:3][N:4]([CH3:32])[C:5]([C:7]1[S:19][C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([CH2:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10](=[O:29])[C:9]=2[C:8]=1[O:30][CH3:31])=[O:6])[CH3:40]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCNC(C)O
Reactant: COc1c(C(=O)N(C)CCCl)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Product: CCN(CCO)CCN(C)C(=O)c1sc2c(c1OC)c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 35.7 %

Procedure:
A solution of the obtained N-(2-chloroethyl)-3-methoxy-N-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]quinoline-2-carboxamide (200 mg, 0.43 mmol), N-ethylaminoethanol (228 mg, 2.55 mmol), diisopropylethylamine (330 mg, 2.55 mmol) and sodium iodide (64 mg, 0.43 mmol) in 1-butanol (5 mL) was stirred at 110° C. for 18 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate to ethyl acetate/methanol=20/1) to give N-{2-[ethyl(2-hydroxyethyl)amino]ethyl}-3-methoxy-N-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]quinoline-2-carboxamide (0.08 g) as a white non-crystalline solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH3:20])[CH:16]=2)[CH:11]=[CH:10][CH:9]=1)(C)(C)C.Cl.C(OC(C)C)(C)C>O1CCOCC1>[CH2:19]([O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][CH:9]=[C:8]2[NH2:7])=[CH:13][CH:14]=1)[CH3:20]
Reactant: CCOc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: CCOc1ccc2cccc(N)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
Next, to a (7-ethoxy-naphthalen-1-yl)-carbamic acid t-butyl ester (47.9 g, 167 mmol) in 100 mL anhydrous 1,4-dioxane was added 4N HCl in 1,4-dioxane (100 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. Diisopropyl ether was added to the reaction mixture and the precipitate was filtered. To the obtained solid was added saturated sodium bicarbonate and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 7-ethoxy-naphthalen-1-ylamine (27.0 g, 86.3% yield).
Reaction SMILES: [CH2:1]([C@@:4]1([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[O:27]S(C)(=O)=O)[CH:2]=[CH2:3]>C(O)C.O.[OH-].[Na+]>[CH2:1]([C@@:4]1([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@H:5]1[OH:27])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CC[C@]1(OCc2ccccc2)[C@H](O)[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1COCc1ccccc1

Procedure:
A solution of nucleoside 3 (3.59 g, 6.45 mmol) in ethanol (72 cm3), water (72 cm3) and 1 M aqueous sodium hydroxide (20.6 cm3) was stirred under reflux for 18 h. After neutralisation with dilute hydrochloric acid, the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (3×150 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×200 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give 4 as a white solid material (2.32 g, 74%). δH (CDCl3) 7.60 (1 H, d, J 1.2, 6-H), 7.50-7.23 (10 H, m, Bn), 6.22 (1 H, d, J 2.9, 1′-H), 5.80 (1H, m, 2″-H), 5.15-5.08 (2 H, m, 3″-Ha, 3″-Hb), 4.86-4.33 (6 H, m, 2×Bn, 2′-H, 4′-H), 3.82-3.71 (2 H, m, 5′-Ha, 5′-Hb), 2.72 (1 H, m, 1″-Ha), 2.52 (1 H, dd, J 7.6, 16.1, 1″-Hb), 1.70 (3 H, d, J 0.9, CH3). δC (CDCl3) 165.1 (C-4), 150.4 (C-2), 138.4, 136.8 (Bn), 137.7 (C-6), 132.3 (C-2″), 128.77 128.4, 128.3, 128.0, 127.9, 127.6 (Bn), 118.5, (C-3″), 107.8 (C-5), 88.0, 87.8, 83.7 (C-1′, C-3′, C-4′), 73.7, 72.9, 69.4 (Bn, C-2′), 64.7 (C-5′), 31.1 (C-1″), 12.4 (CH3) (Found: C, 67.5; H, 6.3; N, 5.3. C27H30N2O6,0.25H2O requires C, 67.1; H, 6.4; N, 5.8%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([CH3:15])=[CH:8][CH2:9][CH2:10][C:11](Cl)([CH3:13])[CH3:12])(=O)C.O1CCOCC1.[H][H]>O.[Pd]>[CH3:12][C:11](=[CH:10][CH2:9][CH2:8][CH:7]([CH2:6][CH2:5][OH:4])[CH3:15])[CH3:13]
Reactant: [H][H]
Reactant: CC(=O)OCCC(C)=CCCC(C)(C)Cl
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)=CCCC(C)CCO
Yield: 70 %

Procedure:
1 mole of 7-chloro-3,7-dimethyl-3-octenyl acetate was dissolved into 200 milliliters of dioxane and the solution was subjected to hydrogenation reaction in a reactor containing 20 grams of activated palladium black at about 25° C. under normal pressure until hydrogen was no more absorbed. Then, palladium black was filtered off, from the reaction mixture and dioxane was distilled off from the filtrate under reduced pressure. The residual liquid was added to the solution of 40 grams of sodium hydroxide in 200 milliliters of methanol, and heated under reflux for 72 hours. The resulting reaction mixture was diluted with 1200 milliliters of water, and the oil layer was separated from the aqueous layer. The oil layer thus separated was washed with 200 milliliters of water three times and then dried over 20 grams of Glauber's salt (sodium sulfate). By distillation of the oil layer under reduced pressure a fraction having a boiling point range of 110°-118° C./15mmHg was collected, whereby 0.7 mole of citronellol was obtained.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[N:8]=[CH:7][C:6]([Br:13])=[CH:5]2.[OH-:14].[Na+]>P(=O)(O)(O)O>[Br:13][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([OH:14])=[CH:11][C:10]=2[Br:12]
Reactant: Nc1cc(Br)c2ncc(Br)cc2c1
Reactant: [OH-]
Agent: O=P(O)(O)O
Agent: [Na+]
Product: Oc1cc(Br)c2ncc(Br)cc2c1
Temperature: 180 °C

Procedure:
6-Amino-3,8-dibromoquinoline (0.15 g) was suspended in phosphoric acid (75%, 11 ml) and heated in a sealed glass, tube at 180° C. for 72 hours. The mixture was allowed to cool to ambient temperature, diluted with ice (50 ml) and taken to pH 2 with aqueous sodium hydroxide (4M). The brown suspension that formed was extracted with ethyl acetate (twice), dried over magnesium sulphate then evaporated under reduced pressure to give 3,8-dibromo-6-hydroxyquinoline (M+−H 300, 2×Br) as a dark red solid that was used in the next stage without further purification, 1H NMR (d6 DMSO) δ: 7.14(1H, d); 7.60(1H, d); 8.52(1H, d); 8.71(1H, d). In a similar procedure to Step 3, 6-amino-3-bromoquinoline was converted to 3-bromo-6-hydroxyquinoline, brown solid, 1H NMR (d6 DMSO) δ: 7.19(1H, d); 7.40(1H, dd); 7.92(1H, d); 8.66(1H, s); 8.79(1H, s).