Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].Cl[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1.O>CN(C)C=O>[Cl:22][C:21]1[C:16]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:7]=[N:8]2)=[N:17][CH:18]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:20]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(cnn2-c2ncc(C(F)(F)F)cc2Cl)c1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To a solution of 5-nitroindazole (1.63 g) in N,N-dimethylformamide (10 ml), 60% sodium hydride (0.5 g) was added, and the resultant mixture was stirred while cooling with ice. After 10 minutes, 2,3-dichloro-5-trifluoromethylpyridine (2.1 g) was added thereto, and the resultant mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-nitroindazole (1.8 g)
Reaction SMILES: Cl.[CH:2]1([O:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C([O:12][C@@H:13]1[C@H:17]([O:18]C(=O)C)[C@@H:16]([CH2:22][O:23]C(=O)C)[O:15][C@H:14]1[N:27]1[CH:35]=[N:34][C:33]2[C:28]1=[N:29][C:30]([CH3:37])=[N:31][C:32]=2Cl)(=O)C.C(N(CC)CC)C>O1CCOCC1>[CH:2]1([O:7][NH:8][C:32]2[C:33]3[N:34]=[CH:35][N:27]([C:28]=3[N:29]=[C:30]([CH3:37])[N:31]=2)[C@@H:14]2[O:15][C@H:16]([CH2:22][OH:23])[C@@H:17]([OH:18])[C@H:13]2[OH:12])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NOC1CCCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nc(NOC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 100 °C

Procedure:
O-Cyclopentylhydroxylamine hydrochloride (0.52 g, 3.75 mmol) was reacted with 9-(2,3,5-triO-acetyl-β-D-ribofuranosyl)-6-chloro-2-methyl-9H-purine (1.07 g, 2.5 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 3258-3260) by standard acylation and chlorination steps] in dioxan (40 ml) in the presence of triethylamine (0.63 g, 6.25 mmol). The reaction mixture was heated at 100° C. for 70 h, before being filtered and evaporated. The product (after purification by chromatography), followed by debenzoylation using methanolic ammonia to provide the title N-cyclopentoxy-2-methyladenosine (after column chromatography) as a foam 1H NMR (DMSO-d6)γ 1.47-1.93 (8H, m,--CH2CH2CH2CH2 --), 2.32 (3H, s,--CH3), 4.59 (1H, br m,--O--CH--), 5.88 (1H, d, H-1').
Reaction SMILES: C(O)CCC.[O:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[C:22](Cl)[N:21]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:20]([NH2:19])=[N:21][C:22]([N:16]3[CH2:15][CH2:14][N:13]([C:11]([CH:7]4[O:6][CH2:10][CH2:9][CH2:8]4)=[O:12])[CH2:18][CH2:17]3)=[N:23][C:24]2=[CH:25][C:26]=1[O:32][CH3:33]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCO1)N1CCNCC1
Solvent: O
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 111.7 %

Procedure:
To a solution of n-butanol (316 ml), water (24 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 9 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 10-12 hours. The crystals were collected by filtration, washed with n-BuOH and dried in vacuo at 40-50° C. to yield 40.1 g (94%) of Terazosin.HCl dihydrate. The product of this example was characterized by XRD and DSC melting point as shown in FIGS. 1 and 2 and in Table I as Trial H. This procedure was repeated in n-butanol using the water volumes indicated in Table I and yielding the results indicated for Trials G, I and J.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([CH:18]=1)[CH:16]=O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:16][C:15]1[CH:18]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=1[Cl:19]
Reactant: c1ccc2scnc2c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Clc1ccc(Br)cc1Cc1nc2ccccc2s1

Procedure:
Benzothiazole and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 100 to give the target compound. APCI-Mass m/Z 338/340 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[C:25]([CH3:26])=[CH:24][C:22]([NH2:23])=[C:21]([O:27][CH3:28])[CH:20]=1>>[Cl:18][C:19]1[C:25]([CH3:26])=[CH:24][C:22]([NH:23][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: COc1cc(Cl)c(C)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cc(Cl)c(C)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-chloro-2-methoxy-5-methylaniline (50 mg, 0.289 mmol) similar to Example 117 and isolated as a tan solid (26 mg, 34%). 1H NMR (CDCl3): 9.65–9.63 (m, 1H), 8.75–8.70 (m, 2H), 8.18 (s, 1H), 7.46–7.41 (m, 1H), 7.36 (s, 1H), 6.97 (s, 1H), 6.87 (s, 1H), 3.91 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=1[NH:25][NH2:26]>C(O)C.C1(C)C=CC=CC=1>[C:1]([C:3](=[CH:12][NH:26][NH:25][C:18]1[C:17]([Cl:16])=[CH:22][C:21]([Cl:23])=[CH:20][C:19]=1[Cl:24])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(=O)C(C#N)=CNNc1c(Cl)cc(Cl)cc1Cl

Procedure:
Four grams (18.9 mmol) of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide is dissolved in hot ethanol/toluene. To this is added, portionwise, 4 g of 2,4,6-trichlorophenylhydrazine. The mixture is heated to reflux for three days. Cooling of the mixture and evaporation of the solvent gives the crude product, which is recrystallized from ethanol (3X) to yield α-cyano-β-(2,4,6-trichlorophenylhydrazino)-N-ethoxycarbonylacrylamide, m.p.=161° (dec.).
Reaction SMILES: O=C1CCC(=O)N1OC(=O)C1C=CC(CN(CCC(OC(C)(C)C)=O)[C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=CC=1.C(#N)C.[OH2:55]>>[C:37]([O:36][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([OH:41])=[O:55])([CH3:38])([CH3:39])[CH3:40]
Reactant: O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)Cc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCC(=O)O

Procedure:
4-{[(2-tert-Butoxycarbonylethyl)-(16-tert-butoxycarbonylhexadecanoyl)-amino]methyl}benzoic acid 2,5-dioxopyrrolidin-1-yl ester was reacted with A1,B1-diBoc desB30 insulin as described in general procedure B. The work up was similar using a gradient 28-48% acetonitrile/water containing 0.1% TFA.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 7-(1-tert-butoxycarbonyl-4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (165 mg) in chloroform (1.5 ml) was added dropwise trifluoroacetic acid (0.5 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and aqueous sodium hydrogencarbonate solution was added to the obtained residue. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (135 mg).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:24]([O:26][C:27]1[C:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][NH:29][N:28]=1)[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27]1[C:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][N:29]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[O:20][CH:21]=[CH:22][CH:23]=4)[O:16][C:17]=3[CH3:18])=[CH:7][CH:6]=2)[N:28]=1)[CH3:25]
Reactant: CCOC(=O)Cc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Sodium hydride (60%, oily, 39.4 mg) was added to a solution of 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (300 mg), ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (195 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-1H-pyrazol-4-ylacetate (364 mg, yield 79%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].C[O-].[Na+].Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Yield: 87.2 %

Procedure:
In a flask similar to that of Example 6 were placed under argon atmosphere 1.74 g (5.98 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 0.80 mL (15.2 mmol) of acetonitrile, 8.0 mL of tetrahydrofuran (dielectric constant at 25° C.: 7.58), and 0.41 g (7.55 mmol) of sodium methoxide. The content was reacted at 52° C. for 4.5 hours. The resulting mixture was chilled in an ice bath. To the chilled mixture were slowly added under stirring 30 mL of toluene and 7.0 mL (7.00 mmol) of hydrochloric acid (1 mol/L), successively. The separated organic portion was taken out. After washing with two portions of saturated aqueous sodium chloride solution (10 mL), the organic portion was dried over anhydrous magnesium sulfate. The organic portion was then filtered and analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 1.64 g (yield: 88%) of 3-[2-cyclopropyl-4-(4-fluoro-phenyl)-3-quinolyl]prop-2-enenitrile was produced.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:12]1[CH:23]=[CH:22][C:15]([C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])=[CH:14][CH:13]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[CH2:19]([O:18][C:16]([CH:15]1[CH2:22][CH2:23][CH:12]([CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:10][OH:11])[CH2:13][CH2:14]1)=[O:17])[CH2:20][CH3:21]
Reactant: CCCOC(=O)c1ccc(C(CO)NC(=O)OC(C)(C)C)cc1
Solvent: CO
Product: CCCOC(=O)C1CCC(C(CO)NC(=O)OC(C)(C)C)CC1
Reaction time: 16 h
Yield: 89.9 %

Procedure:
Propyl 4-(1-tert-Butoxycarbonylamino-2-hydroxy-ethyl)-benzoate (3) (5.35 g, 16.5 mmol) was dissolved in MeOH (150 mL). Argon was bubbled for 20 minutes. 5% Rh/C (1 g) was charged to the solution and argon was bubbled for another 10 minutes. The reaction mixture was stirred at 60 psi hydrogen pressure for 16 hours then at 100 psi for 7 days. Another portion of 10% Rh/C 1% Pd/C (1.2 g) was added. The reaction mixture was stirred at 100 psi hydrogen pressure for another 7 days after which LC/MS analysis indicated complete hydrogenation of the aromatic ring. The reaction mixture was filtered through a celite bed and rinsed with MeOH. The filtrate was concentrated under vacuum to dryness. The residue was filtered through a silica gel bed and eluted with EtOAc/Hexanes (20˜ 40%) to give 4.9 g (89.9% yield) of the pure 1-4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[C:43](O)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[N:46][CH:45]=1>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:43]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: O=C(O)c1cccnc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)c2cccnc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and nicotinic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.01 minutes; C31H33ClN6O3 (573.10); mass spectrum: (M−H)−=572.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2C)=[O:9])[CH:3]=1.C(N(CC)CC)C.[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([N:27]([CH3:26])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[O:9])[CH:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CNC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cc(C(=O)Nc2ccc(O)cc2)ncn1)C1CCCCC1
Reaction time: 24 h

Procedure:
A solution of 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide, Intermediate 7 (75.0 mg; 0.30 mmol) in THF (4 mL) was treated with triethylamine (42 μl; 0.30 mmol) and N-methylcyclohexylamine (Aldrich, 43 μl; 0.33 mmol). The reaction mixture was stirred for 24 h. The solvents were removed in vacuo, then the crude product was purified by column chromatography (silica), eluting with cyclohexane containing an increasing amount of EtOAc. The title compound was obtained as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[O:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[C:1]([O:5][C:6](=[O:9])[CH2:7][CH:14]([CH:13]1[CH2:3][CH:1]2[CH2:4][CH:12]1[CH:11]=[CH:2]2)[OH:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CC(O)C1CC2C=CC1C2
Temperature: 70 °C

Procedure:
A couple of Zn—Cu (50 g) and tetrahydrofuran (90 ml) were placed in a four-necked round flask equipped with a stirrer and reflux condenser and then, a mixing solution of t-butylbromoacetate (53 ml) and 5-norbornene-2-carboxaadehyde (36 ml) dissolved in tetrahydrofuran 180 ml was slowly added to the flask. The resulting solution was refluxed at 70° C. for 2 hours and cooled into room temperature. After separating a couple of Zn—Cu from the solution, the remaining solution was extracted, washed with a solvent and distilled under reduced pressure to obtain 3-bicyclo[2,2,1]hept-5-ene-2-yl-3-hydroxyl-propionic acid t-butyl ester (hereinafter referred to as “BHP”, M-I) as a monomer (39 g).
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=O)=[CH:10][C:9]=1[O:18][CH3:19].[C:20]([CH2:22][C:23]([N-:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([OH:34])[CH:28]=1)=[O:24])#[N:21]>C(O)C>[OH:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[OH:33])[CH2:26][NH:25][C:23](/[C:22](=[CH:14]/[CH:13]=[CH:12]/[C:11]1[CH:16]=[CH:17][C:8]([OH:7])=[C:9]([O:18][CH3:19])[CH:10]=1)/[C:20]#[N:21])=[O:24]
Reactant: COc1cc(C=CC=O)ccc1O
Reactant: N#CCC(=O)[N-]Cc1ccc(O)c(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCc2ccc(O)c(O)c2)ccc1O

Procedure:
The compound was prepared as described in Example 37 by adding piperidine to a solution of 4-hydroxy-3-methoxycinnamaldehyde (35 mg, 0.2 mmol) and N-(cyanoacetyl)3,4-dihydroxybenzylamide (40 mg, 0.2 mmol) in ethanol. After recrystallization from ethanol-water a yellow solid was obtained (53 mg, 72%). The product gave the following analytical data:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OC(O)C)C>[OH:23][CH2:22][C:21]1[CH:20]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccc(CO)c1
Agent: CCOC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(CO)c3)c2cc1OC

Procedure:
A stirred mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile (7.46 g, 30 mmol), 3-aminobenzyl alcohol (7.39 g, 60 mmol), pyridine (2.43 ml, 30 mmol), and 90 ml of ethoxyethanol was refluxed for 5 h, cooled, and stirred with aqueous sodium bicarbonate. The resulting solid was filtered, washed with water, and dried. Recrystallization from methanol gave a brown solid, mp 250-255° C.
Reaction SMILES: [C:1]([O-:4])(=O)C.[Na+].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH2:9]>C(O)=O>[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH:9][CH:1]=[O:4]
Reactant: Cc1cccc(C)c1N
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Product: Cc1cccc(C)c1NC=O
Yield: 79 %

Procedure:
4.1 10.0 g of sodium acetate are dissolved in 120 ml of formic acid. 50.0 g of 2,6-dimethylaniline 11 are then introduced, and the mixture is stirred under reflux for 24 h. The mixture is subsequently subjected to conventional work-up, giving 48.9 g (79%) of N-(2,6-dimethylphenyl)formamide 12; MS-EI (M+)=149.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>C(#N)C.O>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][O:23][CH3:24])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 75.4 %

Procedure:
A solution of N-Boc-piperazine (1.00 g, 5.31 mmol) in acetonitrile (30 ml) was treated with K2CO3 (2.20 g, 15.9 mmol) and (2-bromoethyl)methyl ether (812 μl, 5.84 mmol) and heated to 80° C. for 18 h. The cooled mixture was diluted with water and extracted with DCM. The combined organcs were dried over MgSO4, filtered and evaporated and the residue purified by column chromatography on SiO2, eluting with 5% EtOH in DCM to afford 1-Boc-4-(2-methoxy-ethyl)-piperazine as a clear oil (978 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 3.41 (t, J=5.8 Hz, 2H), 3.29-3.25 (m, 4H), 3.21 (s, 3H), 2.45 (t, J=5.8 Hz, 2H), 2.33 (t, J=5.0 Hz, 4H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:10]([CH:11]=[O:12])=[C:9]([Cl:13])[N:8]=[CH:7][N:6]=1.O>O1CCCC1>[Cl:4][C:5]1[C:10]([CH:11]([OH:12])[CH3:1])=[C:9]([Cl:13])[N:8]=[CH:7][N:6]=1
Reactant: C[Mg]Br
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)ncnc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
Methylmagnesium bromide solution (1.4 M in toluene/tetrahydrofuran (75:25); 2.4 mL, 3.4 mmol) was added to a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 500 mg, 2.8 mmol) in tetrahydrofuran at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. Water was added and the mixture was extracted with ethyl acetate (3×25 mL). The organic layers were washed with water and brine, dried (sodium sulfate), filtered, and evaporated to give 1-(4,6-dichloro-pyrimidin-5-yl)-ethanol (540 mg, 100%) which was used directly in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 1.19 (d, 3H, J=6.3 Hz), 2.62 (br s, 1H), 5.48-5.54 (m, 1H), 8.68 (s, 1H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][OH:26]>C(N(CC)CC)C>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][O:26][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cccs1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
4-toluenesulfonyl chloride (162 g), toluene (363.3 g) and 2-(2-Thienyl)ethanol (104 g) are combined. Triethylamine (93 g) is added maintaining the temperature lower than 45° C. After 4 hrs, the mixture is washed with aqueous phosphoric acid, aqueous sodium hydroxide and then water. The organic phase is distilled off under vacuum. Isopropanol (314 g) and heptanes (365.9 g) are added. The batch is crystallized by cooling and isolated at −15° C. The crystals are filtered and washed with heptanes (175 mL). The crystals are then dried under vacuum at room temperature until a melting point of 30° C. is obtained.
Reaction SMILES: [CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][S:26]([CH3:25])(=[O:28])=[O:27])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCc1nc2cnc3ccccc3c2n1CCCCN
Product: CCCCCCc1nc2cnc3ccccc3c2n1CCCCNS(C)(=O)=O
Yield: 92.2 %

Procedure:
Using the general method of Example 232, 4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (1.00 g, 3.1 mmol) was reacted with methanesulfonyl choride (0.48 mL, 6.2 mmol) to provide 1.15 g of N-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a white solid.