Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[CH:15][C:6]1=2.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:30]4[CH2:34][CH2:33][CH2:32][C@H:31]4[CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[O:21])=[CH:18][CH:17]=3)=[CH:15][C:6]1=2
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)C(=O)CN3)cc1
Product: O=C1CNc2ncc(-c3ccc(C(=O)N4CCC[C@H]4CN4CCCC4)cc3)cc2N1Cc1cc(F)ccc1F
Yield: 32 %

Procedure:
4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (35 mg) was reacted with (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine as in General Procedure 8 to give the title compound as a white solid (32% yield). M.p. 125° C., LCMS: m/z=532.10 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.22-1.26 (m, 2H), 1.68-1.82 (m, 4H), 1.89-2.15 (m, 4H), 2.56-2.70 (m, 3H), 2.80-2.90 (m, 1H), 3.42-3.52 (m, 1H), 4.33 (s, 2H), 4.43-4.50 (m, 1H), 5.02 (bs, 1H), 5.22 (s, 2H), 6.91-6.98 (m, 2H), 7.04-7.10 (m, 1H), 7.21 (d, J=1.5 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.54 (bd, J=7.6 Hz, 2H), 8.01 (d, J=1.5 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:10]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.O>CN(C)C=O>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]([CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=2)[N:10]=1
Reactant: CC(C)CCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN(CCC(C)C)c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of N-(3-methylbutyl)-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (1.20 g, 3.82 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.229 g, 5.73 mmol). The mixture was stirred for 30 min, and methyl 4-(bromomethyl)benzoate (1.05 g, 4.58 mmol) was added. The mixture was stirred at 60° C. for 1.5 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:97-40:60) to give the title compound (1.34 g, yield 76%) as a yellow oil.
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O>N1C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Yield: 78.2 %

Procedure:
A mixture of pyridine (15 ml), diphenyl phosphite (2.34 g), imidazole (0.68 g) and o-chlorophenyldiphenylmethanol (2.36 g) obtained in Example 1 (B) was refluxed for 3 hours. The reaction mixture was treated in the same manner as in Example 1 (C) to give 2.16 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 78.3%. M.P., 142°-143° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]#[N:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14](=[N:17][OH:18])[NH2:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1CN(Cc2ccccc2)CCO1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=NO)C1CN(Cc2ccccc2)CCO1

Procedure:
Reaction of 4-benzylmorpholine-2-carbonitrile with hydroxylamine hydrochloride and sodium hydroxide provided 4-benzyl-N′-hydroxymorpholine-2-carboximidamide, which was condensed with cyclopropanecarboxylic acid using 1,3-dicyclohexylcarbodiimide. Cyclization using tetrabutylammonium fluoride (see A. R. Gangloff et al., Tetrahedron Lett. 2001, 42, 1441-1443), followed by debenzylation, afforded 2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)morpholine.
Reaction SMILES: [CH:1]12[CH2:24][CH2:23][CH:4]([C:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]4=[CH:9][CH:8]=3)=[CH:6]1)[CH2:3][NH:2]2.[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1>[CH3:18][C:17]([CH3:19])([CH3:20])[CH2:16][N:15]1[C:10]2[C:11](=[N:12][C:7]([C:5]3[CH:4]4[CH2:23][CH2:24][CH:1]([CH:6]=3)[N:2]([C:30]([C:27]3[CH:28]=[CH:29][O:25][N:26]=3)=[O:31])[CH2:3]4)=[CH:8][CH:9]=2)[N:13]([CH3:22])[C:14]1=[O:21]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4)nc21
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4C(=O)c3ccon3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(2-Azabicyclo[2.2.2]oct-5-en-5-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2-5, 291 mg, 0.90 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 151 mg, 1.4 mmol, 1.5 equiv), DIPEA (0.47 mL, 2.7 mmol, 3.0 equiv) and HATU (510 mg, 1.4 mmol, 1.5 equiv) were added to anhydrous 1,4-dioxane (9 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 2-7 as a white solid. MS m/z (M+H): calculated=422.2187; observed=422.2189. 1H NMR δ (ppm)(CHCl3-d): 8.40 (1H, dd, J=27.77, 1.66 Hz), 7.22-7.17 (1H, m), 7.12 (1H, dd, J=8.11, 1.50 Hz), 6.97 (1H, m), 6.70 (1H, dd, J=11.92, 1.66 Hz), 5.55-5.52 (0.4H, m), 5.42-5.38 (0.6H, m), 3.95 (0.4H, m), 3.88 (1H, m), 3.62 (2.6H, m), 3.53 (0.4H, m), 3.47 (3H, d, J=3.86 Hz), 3.36 (0.6H, d, J=12.39 Hz), 2.21-2.11 (1H, m), 1.91-1.80 (1H, m), 1.61-1.52 (2H, m) 0.99 (9H, d, J=1.91 Hz). (Mixture of rotamers at RT).
Reaction SMILES: [Na].[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([O:19]CC)=[O:18]>C(O)C>[C:22]1([CH:16]([O:14][C:11]2[CH:10]=[CH:9][C:8]([N:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:13][CH:12]=2)[C:17]([OH:19])=[O:18])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: Oc1ccc(N2CCCCC2)cc1
Agent: [Na]
Solvent: CCO
Product: O=C(O)C(Oc1ccc(N2CCCCC2)cc1)c1ccccc1

Procedure:
2.3 g. of sodium is dissolved in 100 ml. of absolute ethanol; 17.7 g. of 4-piperidinophenol is introduced into the solution, and then 24.3 g. of ethyl α-bromophenylacetate is added dropwise thereto and the mixture refluxed for 10 hours. The reaction mixture is then evaporated, the residue mixed with water, and the aqueous solution extracted with ethyl acetate. The ethyl acetate solution is washed twice with dilute KOH and twice with water, then dried, and the solvent is evaporated, thus obtaining the ethyl ester of α-phenyl-α-4-piperidinophenoxy-acetic acid; hydrochloride, m.p. 149°-151°.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:40])[N:22]([C@@H:24]([C:32]1[O:33][C:34]([C:37](=[O:39])[NH2:38])=[N:35][N:36]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][N:22]([C:21](=[O:40])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C@@H:24]([C:32]1[O:33][C:34]([C:37]([NH2:38])=[O:39])=[N:35][N:36]=1)[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)c1nnc(C(N)=O)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)c1nnc(C(N)=O)o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
((1R)-1-(((1R)-1-(5-Carbamoyl-[1,3,4]oxadiazol-2-yl)-2-phenylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamic acid tert-butylester (300 mg, 0.55 mmol) was dissolved in dichloromethane (3 ml) and cooled to 0° C. Trifluoroacetic acid (3 ml) was added dropwise. The solution was stirred for 5 min at 0° C. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (5 ml), and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (5 ml), and the solvent was removed in vacuo. The residue was dissolved in 3M hydrogen chloride in ethyl acetate (5 ml), and the solvent was removed in vacuo. The residue was dissolved in 3M hydrogen chloride in ethyl acetate (5 ml), and the solvent was removed in vacuo to give 238 mg of crude 5-((1R)-1-(methyl((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-2-phenylethyl)-[1,3,4]oxadiazol-2-carboxylic acid amide, which was used for the further synthesis.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:15][NH:14][C:13](=O)[CH2:12][CH2:11]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:11][CH2:12][CH2:13][NH:14][CH2:15]1
Reactant: O=C1CCC(CCOC2CCCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(C2(CCOC3CCCCO3)CCCNC2)cc1Cl
Temperature: 60 °C
Yield: 90.6 %

Procedure:
3.9 g of the 5-(2-tetrahydropyranyloxyethyl)-5-(3,4-dichlorophenyl)piperidinone prepared above are dissolved in 50 ml of tetrahydrofuran and the solution is added to a suspension of 0.9 g of lithium aluminum hydride in 5 ml of THF heated to 60° C. The reaction mixture is heated for one hour at 60° C. and then cooled. 1 ml of water, 1 ml of 4N sodium hydroxide and 3 ml of water are added. The insoluble portion is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in ethyl ether, dried over MgSO4 and concentrated under vacuum to give 3.4 g of the expected product.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[S:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH3:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]=[N+:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH:19]([C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[CH3:16])[C:5]2[N:1]([C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[C:8]([NH2:10])=[S:9])[CH:2]=[CH:3][CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC(=S)c1ccccc1-n1cccc1
Reactant: Cc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: Cc1ccccc1C(c1cccn1-c1ccccc1C(N)=S)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-thiobenzamide and 1-(2-methyl-benzylidene)-piperidinium chloride.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.Br.Br[CH2:19][CH2:20][NH2:21].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[O:6][CH2:19][CH2:20][N:21]=1
Reactant: NCCBr
Reactant: O=C(O)c1ccccc1F
Agent: Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: Fc1ccccc1C1=NCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.5 %

Procedure:
A mixture of 2-fluorobenzoic acid (4.5 g, 32.14 mmol) and oxalyl chloride (4.1 mL, 48.2 mL) in 2 drops of DMF and 40 mL of methylene chloride was heated at reflux for 2 hours. The mixture was allowed to cool to room temperature and stirred for approximately 12 hours and then the solvents were removed by rotary evaporation. The residue was slowly added to a suspension of 2-bromoethylamine hydrobromide (5.7 g, 28 mmol) and triethylamine (21 mL, 160 mmol) in 200 mL of benzene. The mixture was heated at reflux for 12 hours, allowed to cool to room temperature and then stirred for an additional 12 hours. The mixture was quenched with water and the aqueous layer was separated and extracted with methylene chloride (2×50 mL). The combined extracts were dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (5:1) to give 2-fluoro-1-(4,5-dihydrooxazol-2-yl)benzene (1.96 g, 11.9 mmol).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:17]>CCOCC>[O:1]([C:8]1[N:13]=[C:12]([CH2:14][Br:17])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Oc2ccccc2)n1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1cccc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 8.45 mmol of (6-phenoxy-2-pyridyl)methanol in 75 ml ether is added, at -10°, 12.7 mmol of phosphorus tribromide. The solution is refluxed for 1 hour, after which approximately 1 ml of phosphorus tribromide is added and refluxing is continued for 2 hours. The reaction mixture is cooled to RT and resulting solid is filtered and washed with ether to yield the hydrogen bromide salt of (6-phenoxy-2-pyridyl)methyl bromide.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CC(C)=O>[CH2:19]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCBr
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCC1(C(=O)OCC)CCCC1=O
Yield: 89.52 %

Procedure:
Under mechanical agitation, 31.20 g (purity of 90%) of ethyl 2-oxocyclopentane carboxylate was added to 76.04 g (purity of 98%) of ground anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml of acetone. The reaction mixture was further stirred for about 15 minutes, then thereto was dropwise added 45.86 ml (purity of 98% of 1-bromo-n-pentane. Upon the completion of the addition, the reaction mixture was heated for reflux for 6 hours. The reaction mixture was filtered under the reduced pressure, and the filter cake was washed with diethyl ether until its color was purely white. Pale yellow filtrate was collected and dried over anhydrous magnesium sulfate, then the solvent was removed. The residue was distilled under reduced pressure, and 36.42 g of colorless liquid as a distillate cut of 156-162° C./22 mmHg was collected. Yield: 89.52%. MS: m/e 227(M+″+1), 226(M+″), 198, 181, 169, 156, 141, 127, 110, 95.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2]>[O-2].[O-2].[Mn+4]>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CNCC3
Agent: [Mn+4]
Agent: [O-2]
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3ccncc3c2c1-c1ccc(OC)c(OC)c1

Procedure:
In the same manner as in Example 7A, the compound obtained in Example 54A and activated manganese dioxide were reacted to yield ethyl 2-diethylaminomethyl-4-(3,4-dimethoxyphenyl)thieno[2,3-b:4,5-c']dipyridine-3-carboxylate, which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 141 to 142° C.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[F:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([N:27]=[C:28]=[S:29])=[O:26])=[CH:23][CH:22]=1>C1COCC1>[F:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([NH:27][C:28](=[S:29])[NH:1][C:2]2[S:12][C:5]3[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=3[C:3]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:26])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Reactant: O=C(N=C=S)c1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccc(F)cc2)sc2c1CC(C)(C)OC2
Temperature: 50 °C
Yield: 71.7 %

Procedure:
tert-Butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.28 g, 1.00 mmol) and 4-fluorobenzoyl isothiocyanate (0.18 g, 0.99 mmol) were dissolved in THF (5 mL) and heated at 50° C. for 22 hours. The solvent was removed and EtOH (10 mL) was added. The product was filtered and rinsed with EtOH (2×10 mL). tert-Butyl 2-(3-(4-fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.330 g, 0.71 mmol, 71% yield) was isolated as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 14.70 (s, 1H), 9.01 (s, 1H), 8.00-7.94 (m, 2H), 7.25-7.18 (m, 2H), 4.74 (apparent t, J=1.5 Hz, 2H), 2.76 (apparent t, J=1.5 Hz, 2H), 1.64 (s, 9H), 1.31 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Li].CO[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20](=[O:22])[CH3:21])[CH:14]=[CH:13]2>>[N:1]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20](=[O:22])[CH3:21])[CH:14]=[CH:13]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: COc1ccc2cc(C(C)=O)ccc2c1
Agent: [Li]
Product: CC(=O)c1ccc2cc(N3CCNCC3)ccc2c1
Reaction time: 65 h

Procedure:
Anhydrous piperazine (7 g, 81.3 mmol; dried in a vacuum desiccator over KOH-drierite mixture for 3 days) was dissolved in a mixture of dry, freshly distilled toluene and hexamethyl phosphoric amide (HMPA), 25 mL each. To the solution was added 556 mg (80.1 mmol) of lithium rod, cut in small pieces under argon atmosphere, and the mixture was stirred under argon for 24 hours, during which time all lithium has dissolved. Vacuum-dried 1-(6-methoxy-2-naphthyl)-1-ethanone (prepared as described in Arsenijevic et al., Org. Synth. Coll. 1988 6:34-36, the disclosure of which is incorporated herein by reference) (3.5 g, 17.5 mmol) was added, and stirring was continued for additional 65 hours. After quenching with 300 mL of water, extraction with dichloromethane (3×300 mL), drying with anhydrous magnesium sulfate, and evaporation, a mixture of white and yellow solids was obtained. Extraction with 300 mL of hot methanol gave raw product, 1-(6-piperazino-2-naphthyl)-1-ethanone, which was purified by column chromatography (70-230 mesh silica, 25×120 mm, 5% methanol in dichloromethane). The yield was 1.54 g (35%). After recrystallization from ethyl acetate, the sample melted at 170.5-172° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Na].Cl>C(O)CCCC>[C@@H:10]12[CH2:9][CH2:8][CH2:7][NH:6][C@H:5]1[CH2:4][CH2:3][CH2:2][NH:1]2
Reactant: c1cnc2cccnc2c1
Agent: Cl
Agent: [Na]
Solvent: CCCCCO
Product: C1CN[C@@H]2CCCN[C@H]2C1

Procedure:
1,5-Naphthyridine (5.0 g, 38.4 mmoles) in 450 ml of amyl alcohol was heated under reflux and sodium (21.3 g, 0.92 mole) was added in portions to the reaction mixture over a period of 30 minutes. 84 ml of concentrated hydrochloric acid were then added. The organic phase was separated off, washed twice using water and the combined aqueous extracts were extracted a further two times using ether. The ether phases were discarded, the aqueous phase was rendered basic using caustic soda while cooling with ice and the desired product was removed by repeated extraction using dichloromethane. The combined dichloromethane phases were dried and concentrated under reduced pressure. Quantitative yield (5.8 q) of crystals of m.p. 174°-176° C. (ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Cl:13][C:14]1[C:15]([N+:25]([O-:27])=[O:26])=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:19](=[O:20])[C:18]2[CH:22]=[C:14]([Cl:13])[C:15]([N+:25]([O-:27])=[O:26])=[CH:16][C:17]=2[O:23][CH3:24])[CH2:7]1
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-chloro-2-methoxy-4-nitrobenzoic acid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][Cl:21].Cl>C1COCC1.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][CH:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=1)[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: ClCCCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(CCCCl)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of p-tolylacetic acid (1 g) in THF (30 mL) was stirred at −78° C. for 30 minutes. n-Butyl lithium (2.66 M solution in hexane, 5.01 mL) was added to the solution, and the reaction solution was stirred at −78° C. for three hours. Thereafter, the reaction solution was stirred at 0° C. for 30 minutes, 1-bromo-3-chloropropane (0.725 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 24 hours. Thereafter, ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.53 g of the title compound. The property values corresponded to the reported values (CAS #2856-76-0).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][C:3]([CH3:24])([CH3:23])[CH2:2][NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CN
Reactant: CS(=O)(=O)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CNS(C)(=O)=O

Procedure:
Using the general method of Example 242, 1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.22 g, 0.672 mmol) was reacted with methanesulfonyl chloride (125 μL) to provide 270 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}methanesulfonamide as a cream colored powder, m.p. 204.0-206.0° C. Analysis: Calculated for C19H27N5O3S 0.50H2O: % C, 55.05; % H, 6.81; % N, 16.89; % S, 7.74; Found: % C, 55.10; % H, 6.58; % N, 17.23; % S, 7.51. % H2O calculated: 2.17; found: 2.28 (Karl Fisher).