Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1>C1C=CC=CC=1>[CH:11](=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: O=C1Nc2ccccc2C1=Cc1ccccc1
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of oxindole (49.5 g, 0.37 mole), benzaldehyde (50 ml, 0.5 mole) and piperidine (2 ml) in 500 ml of benzene is heated at reflux temperature, with removal of water, for one hour. Benzene is removed in vacuo and the residue is crystallized from ethanol to give 69.6 g of 3-benzylidene indolin-2-one (m.p. 177°-179°).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:32])[CH3:31])=[CH:4][C:5]2[N:9](COCC[Si](C)(C)C)[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:7][C:6]=2[CH:24]=1.[C:33]([C:35]1[CH:36]=[C:37](Br)[CH:38]=[CH:39][CH:40]=1)#[N:34]>>[C:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[C:3]1[C:2]([O:1][C:39]2[CH:40]=[C:35]([CH:36]=[CH:37][CH:38]=2)[C:33]#[N:34])=[CH:24][C:6]2[N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[NH:9][C:5]=2[CH:4]=1)(=[O:32])[CH3:31]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(=O)N1CCCC1c1cc2c(cc1O)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1cccc(C#N)c1

Procedure:
The entitled compound was obtained as an oily substance in the same method as in Example 121 (step 11), (step 12) or in accordance with the method or by combining it with an ordinary method but using 1-(2-(6-hydroxy-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 121 (step 10) and 3-cyanobromobenzene.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[C:17]([O:19]CC)=O.C(Cl)Cl.C([N:33]=[C:34]=[S:35])(=O)C1C=CC=CC=1>CO>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][N:11]1[C:12]2[CH:16]=[CH:15][NH:14][C:13]=2[C:17](=[O:19])[NH:33][C:34]1=[S:35]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1[nH]ccc1NCc1nc2ccccc2[nH]1
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2nc3ccccc3[nH]2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 168.2 %

Procedure:
Ethyl 3-[(1H-benzimidazol-2-ylmethyl)amino]-1H-pyrrole-2-carboxylate (0.33 g, 1.16 mmol) was added to CH2Cl2 (3 mL) and methanol was added until clear solution was obtained. The solution was stirred at r.t. for 1 h. Benzoyl isothiocyanate (0.73 mL, 0.46 mmol) was added and after stirring at r.t. for 30 minutes the mixture was concentrated. The residue was dissolved in ammonia (7N in methanol, 7 mL) and the mixture was heated at 80° C. in a sealed steel container for 2 h. After cooling to r.t. the precipitated product was filtrated and washed through with methanol, diethyl ether and ethyl acetate, obtaining 0.23 g (66%) of the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)=[O:6].C(O)(C)C.[Cl-].[NH4+]>[Fe].O>[OH:1][CH2:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccccc1CO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(NNC(=O)c2ccccc2CO)cc1

Procedure:
Thereafter, the nitro compound was added to 300 ml of isopropyl alcohol with the addition of 30 ml of water and 3 g of ammonium chloride followed by reflux for 2 hours with the addition of 30 g of reducing iron and then the reflux liquid was filtered and the solid precipitated upon cooling the filtrate was filtered to obtain 4.2 g of 1-(2'-hydroxymethylbenzoyl)-2-(p-aminophenyl)hydrazine.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29]([C:35](O)=[O:36])=[CH:28]2>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:29]2[N:30]([CH3:34])[C:31]3[C:27]([CH:28]=2)=[CH:26][C:25]([F:24])=[CH:33][CH:32]=3)=[O:36])=[O:10])[N:12]=1
Reactant: Cn1c(C(=O)O)cc2cc(F)ccc21
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc3cc(F)ccc3n2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-Fluoro-1-methyl-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.98 min; [M+H]+=503.4.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:8][C:7]2[C:9]([CH3:14])=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1.[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[Cl:13][C:11]1[CH:10]=[C:9]([CH3:14])[C:7]2[NH:8][C:4]([S:3][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[N:5][C:6]=2[CH:12]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Cc1cc(Cl)cc2nc(S)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc2nc(Sc3ccc(C=O)o3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
Aldehyde intermediate preparation: A mixture of sodium hydride (60% dispersion in mineral oil, 0.304 g, 7.61 mmol) and 2-mercapto-5-chloro-7-methyl-1H-benzimidazole (0.945 g, 4.76 mmol) in 15 ml of tetrahydrofuran is stirred at room temperature for 2 hours. 5-nitro-2-furaldehyde (0.671 g, 4.56 mmol) in 7 ml of tetrahydrofuran is then added dropwise over a 15 minute period and the mixture is stirred for 16 hours at room temperature. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in 100 ml of ethyl acetate and washed with water (2×30 ml). The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is triturated in diisopropylether and pentane and dried under vacuum to yield 911 mg of 5-(5-chloro-7-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde. Yield=65%. Analytical LC/MS (method B): retention time: 3.67 min., m/z=292.98 (1 Cl, positive ion mode).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[C:9]([NH:16][C@H:17]([C:19](O)=[O:20])[CH3:18])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(N=C=NC2CCCCC2)CCCCC1.CO>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:19](=[O:20])[C@H:17]([CH3:18])[NH:16][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COCCOCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: COCCOCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(2-Methoxyethoxy)ethanol (1.28 g, 10.5 mmol), 4-N,N′-(dimethyl)aminopyridine (128 mg, 1 mmol) and N-Boc-(L)-alanine (2 g, 10.5 mmol) were dissolved in freshly distilled CH2Cl2 (25 mL). The reaction mixture was cooled to 0° C. (ice bath) and dicyclohexylcarbodiimide (DCC, 2.39 g, 1.1 mmol) was added portionwise. The reaction mixture was stirred for 1 h at 0° C. and then warmed up to room temperature over 2 h. The dicyclohexyl urea was filtered off, washed with ethyl acetate (2×20 mL) and the solvents evaporated. Column chromatography (SiO2, 0.060-0.200 mm/1% MeOH in CH2Cl2) yielded compound 2a as a colorless to pale yellow oil (2.40 g, 8.3 mmol, 79%).
Reaction SMILES: [OH:1][C@@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[H-].[Na+].F[C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH:22]=[CH:21][C:20]=1[N+:32]([O-:34])=[O:33]>C1COCC1>[N+:32]([C:20]1[CH:21]=[CH:22][C:23]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)=[CH:24][C:19]=1[O:1][C@@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])([O-:34])=[O:33]
Reactant: Cc1ccccc1[C@H](O)CCC(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(OCc2ccsc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1[C@@H](CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 18.9 %

Procedure:
A stirred suspension of sodium (R)-4-hydroxy-4-(2-methylphenyl)butanoate (190 mg) in THF (15 mL) is treated with 60% sodium hydride (35 mg) and maintained at 25° for 0.5 hours. The mixture is treated with 2-fluoro-4-(thiophen-3-ylmethoxy)nitrobenzene (220 mg) and maintained at 50° C. for 3 hours. The solution is evaporated. The residue is dissolved in ethyl acetate, washed with water, dried and evaporated. The residue is purified by flash chromatography on silica, eluting with dichloromethane followed by ethyl acetate, followed by recrystallisation from ethyl acetate/pentane to give (R)-4-[2-nitro-5-(thiophen-3-ylmethoxy)phenoxy]-4-(2-methylphenyl)butyric acid (70 mg), a tan coloured solid, mp. 130-131° C. 1H NMR (CHCl3) 2.2-2.9 (4H,m), 2.4 (3H,s), 4.9 (2H, q), 5.5 (1H, q), 6.2 (1H,s), 6.5 (1H,d), 7.0-7.4 (7H,m), 7.9 (1H,d).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[C:7]=2[CH:8]=1)#[N:13]
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2ccccc2)[C@@H]1O
Yield: 58 %

Procedure:
A suspension of (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (prepared according to Evans et al., J. Med. Chem., 1983, 26, p. 1582 and J. Med. Chem., 1986, 29, p. 2194) (1.0 g, 4.6 mmol) in ethanol (4 ml) under argon was treated with phenylisocyanate (0.55 g, 4.6 mmol) and the reaction was heated at reflux temperature for 4 hours. The product precipitate out of the reaction. The reaction was then concentrated in vacuo and the residue was triturated with isopropylether to give the title compound as a colorless solid (0.9 g, 63%), m.p. 240°-241° C.: 1H NMR (CDCl3 /DMSO) δ8.3 (s, 1H), 7.7 (s, 1H), 7.4 (d, J=8.0 Hz, 3H), 7.26 (t, J=8.0 Hz, 2H), 7.0 (t, J=9.0 & 7.0 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 6.4 (d, J=8.0 Hz, 1H), 5.3 (d, J=5.0 Hz, 1H), 4.9 (t, J=9.0 & 8.0 Hz, 1H), 3.6 (dd, J=4.0 & 6.0 Hz, 1H), 1.5 (s, 3H), 1.3 (s, 3H); 13C NMR (CDCl3 /DMSO) 157.0, 156.5, 139.1, 132.2, 132.1, 128.4, 123.9, 121.8, 118.2, 117.8, 80.0, 74.3, 49.9, 26.1, 18.4; IR (KBr) 1132, 1267, 1491, 1550, 1612, 1645, 2226, 2932, 2978, 3433 cm-1.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[CH:24][CH:23]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[CH:26][CH:27]=2)\[CH3:21])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(OC)c3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(OC)c3)cc2)cc1)C(=O)O
Yield: 83.6 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 2-ethoxy-3-{4-[3-(3′-methoxy-biphenyl-4yl)-but-2-enyloxy]-phenyl}-propionate (example 113) (230 mg, 0.49 mmol) and sodium hydroxide (1M, 0.97 ml, 0.97 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-2-ethoxy-3-{4-[3-(3′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic acid (183 mg, 85%) as a colourless solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:40][CH2:39][C:18]2([N:22]=[C:21]([C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([O:33][CH2:34][CH2:35][CH:36]=[CH2:37])[CH:24]=3)[NH:20][C:19]2=[O:38])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:34]([O:33][C:25]1[CH:24]=[C:23]([C:21]2[NH:20][C:19](=[O:38])[C:18]3([CH2:39][CH2:40][NH:15][CH2:16][CH2:17]3)[N:22]=2)[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=1)[CH2:35][CH:36]=[CH2:37]
Reactant: C=CCCOc1cc(C2=NC3(CCN(C(=O)OC(C)(C)C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCOc1cc(C2=NC3(CCNCC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.1 %

Procedure:
Trifluoroacetic acid (27 ml) was added to a solution of 2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (2.39 g, 5.12 mmol) in methylene chloride (54 ml), and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure with azeotropic distillation with toluene, and the resulting residue (trifluoroacetate) was then dissolved in methanol (50 ml). A 4 N solution of hydrochloric acid in dioxane (16 ml) was added and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in a mixed solution of ethyl acetate (100 ml)-ethanol (5 ml), followed by washing with a 1 N aqueous K3PO4 solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (1.92 g). This compound was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:19]=[C:18]([C:20]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH:25]=3)[CH:17]=[CH:16][C:15]=2[F:33])[CH2:12][C:11]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[N:10]1.[ClH:41]>C(OCC)(=O)C>[ClH:41].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:19]=[C:18]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:17]=[CH:16][C:15]=2[F:33])[CH2:12][C:11]([C:34]([F:39])([F:40])[C:35]([F:37])([F:36])[F:38])=[N:10]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)c(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(C3=CCNCC3)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(2,4-Difluoro-phenyl)-5-[2-fluoro-5-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (360.0 mg, 0.70 mmol) prepared in Example 147 was added to a saturated solution of hydrochloric acid in ethyl acetate (5.0 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give 360.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9](=[O:12])[C:10](=[CH:15][N:16]([CH3:18])[CH3:17])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: COC(OC)N(C)C
Solvent: O
Product: CCOC(=O)N1CCC(=O)C(=CN(C)C)C1

Procedure:
To a round bottomed flask was loaded 8.56 grams of 4-oxo-piperidine-1-carboxylic acid ethyl ester, 10.3 ml of dimethylformamide dimethylacetal, and the mixture was refluxed at 90° C. for two hours. Then it was poured into 75 ml water and extracted with 2×250 ml dichloromethane. The combined organic layers was washed with 50 ml brine and dried over magnesium sulfate. Filter off the drying agent and concentrate gave 28 grams of 3-Dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid ethyl ester. This material (12.8 grams) was then loaded into a round bottomed flask along with 3.42 grams of (5-Amino-1H-[1,2,4]triazol-3-yl)-methanol and 100 ml 2-methoxyethanol. The mixture was refluxed for 18 hours. Then it was cooled down to 23° C. and concentrated to 5 ml. Then 50 ml ethyl ether was added and the precipitate was filtered and vaccum dried to yielded 1.5 grams of product. MS: 278.1 (M+H). H-NMR(CDCL3): δ 8.60(s, 1H), 4.98(s, 2H), 4.78(s, 2H, CH2), 4.22(q, 2H, J=4.8 Hz), 3.75 (t, 2H, CH2, J=4 Hz), 3.51 (t, 2H, J=4 Hz), 1.32 (m, 3H, CH3, J=4.8 Hz).
Reaction SMILES: [CH2:1]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].Cl.[CH2:16](O)[CH3:17]>>[CH2:16]([O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7])[CH3:17]
Reactant: CCO
Reactant: O=C(O)CCCCCCCCCCBr
Agent: Cl
Product: CCOC(=O)CCCCCCCCCCBr
Temperature: 25 °C

Procedure:
Compound 1, 11-Bromoundecanoic acid (41.38 g, 156 mmol), was placed in a 250 ml round-bottomed flask equipped with a reflux condenser. After absolute ethanol (60 ml) and concentrated HCl (1/2 ml) were added, the reaction mixture was refluxed overnight. The reaction mixture was allowed to cool to room temperature before the solvent was removed under reduced pressure The resulting yellow oil was dissolved in ether. The ether solution was extracted with saturated sodium carbonate (NaHCO3) and H2O, and dried over magnesium sulfate (MgSO4). The solvent was removed under reduced pressure. Purification of the crude product was obtained by vacuum distillation which yielded a colorless oil, ethyl-11-bromoundecanoate, compound 2 (37.32 g, 82.5% yield)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]=[O:15]>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:14][OH:15]
Reactant: C=O
Reactant: COc1cccc2c(O)ccnc12
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc2c(O)c(CO)cnc12

Procedure:
4-Hydroxy-8-methoxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide to give the novel compound 4-hydroxy-3-hydroxymethyl-8-methoxyquinoline, m.p. >350°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1nc(C)cc1C
Temperature: 0 °C
Yield: 42.2 %

Procedure:
A mixture of 3,5-dimethyl-1H-pyrazole (Aldrich, 10 g, 104 mmol), K2CO3 (43.1 g, 312 mmol), and ethyl 2-bromoacetate (12.69 mL, 114 mmol) in acetone (100 mL) was refluxed overnight. The salts were removed by filtration and the filtrate was evaporated under reduced pressure. The residue was dissolved in diethyl ether and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was dissolved in hot hexane and the insoluble material was filtered and discarded. The filtrate was cooled at 0° C. and the precipitate obtained was filtered and dried to give the title compound ethyl 2-(3,5-dimethyl-1H-pyrazol-1-yl)acetate (8 g, 43.9 mmol, 42.2% yield) as a gum. 1H NMR: (CDCl3-d6, 300 MHz) δ 5.82 (s, 1H), 4.72 (s, 2H), 4.18 (q, 2H), 2.18 (s, 3H), 2.17 (s, 3H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[CH:14][N:4]2[N:3]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>COCCO>[N:18]1([CH2:17][CH2:16][NH:15][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][N:13]=[CH:14][N:4]3[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Clc1nn2cnnc2c2c1CCCC2
Reactant: NCCN1CCCC1
Solvent: COCCO
Product: c1nnc2c3c(c(NCCN4CCCC4)nn12)CCCC3

Procedure:
A solution of 5.0 g of 6-chloro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine and 10.0 g of 1-(2-aminoethyl)pyrrolidine in 50 ml of 2-methoxyethanol was heated at reflux for 15 hours. The solution was then concentrated and the resulting residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated. The concentrate was triturated with ether and the solid which formed was separated by filtration to give 6-[2-(1-pyrrolidinyl)ethylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine melting at about 160°-162° C. after recrystallization from a mixture of toluene and hexane. This compound has the following structural formula ##STR3##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)[CH3:34])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(Oc3ccccn3)cc(C(=O)O)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Oc3ccccn3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyridin-2-yloxy)biphenyl-3-carboxylic acid (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (70 mg, 0.34 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150 mg, 0.39 mmol), and N,N-diisopropylethylamine (400 μL, 2.30 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[C:17]3[O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B:25](OC)([O:28]C)[O:26]C.[NH4+].[OH-]>C1COCC1>[C:6]1([C:12]2[C:17]3[O:18][C:19]4[C:24]([B:25]([OH:28])[OH:26])=[CH:23][CH:22]=[CH:21][C:20]=4[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1oc1c(-c3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
n-Butyllithium (13.51 mL, 33.8 mmol) was added dropwise to 4-phenyldibenzo[b,d]furan (3.3 g, 13.51 mmol) in 80 mL dry THF at −78° C. This reaction mixture was allowed to stir at room temperature for 5 hours and then cooled to −78° C. again. Trimethyl borate (4.52 mL, 40.5 mmol) was added slowly to the reaction. The reaction mixture was allowed to warm up to room temperature gradually over night with stirring. The mixture was poured into 50 mL of NH4OH solution with ice. The aqueous mixture was extracted with 3×80 mL ethyl acetate and dried over sodium sulfate, and the organic layer was evaporated to get yield 3.3 g (85%) product, which was used without purification and was confirmed by NMR.