Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[F:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=1.[BH4-].[Na+]>C(O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: NCCc1cccc(OCc2cccc(F)c2)c1
Reactant: O=Cc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Fc1cccc(COc2cccc(CCNCc3ccco3)c2)c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
1.44 g (15 mmol) of furan-2-carboxaldehyde and 7.5 g of molecular sieves 3 Å were added to a solution of 2.45 g (10 mmol) of 2-[3-(3-fluoro-benzyloxy)-phenyl]-ethylamine in 50 ml of dry ethanol. The reaction mixture was refluxed for 3 hours. The molecular sieves were filtered off and the solution was cooled to 5° C. 0.57 g (15 mmol) of NaBH4 was added under N2 and the reaction was stirred at room temperature overnight. Solvent was removed, a 5% NaHCO3 aqueous solution was added to the residue and the product was extracted with ethyl acetate. The crude product was purified by flash chromatography (dichloromethane/methanol/NH3 100:0:0→100:2:0.2, v:v:v). 2.2 g (68% yield) of an oil were obtained.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(N(CC)CC)C>ClCCl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: OB(O)c1ccncc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1ccncc1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.6 %

Procedure:
A mixture of 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.1 g, 0.21 mmol), 4-pyridylboronic acid (52 mg, 0.42 mmol), cupric acetate (58 mg, 0.32 mmol) and triethylamine (60 μL, 0.42 mmol) in dichloromethane (2 mL) was stirred for 2 d at room temperature. Chromatography on silica gel (ethyl acetate) yielded the desired product (26 mg, 21%), MS: m/e=549.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31].[Li+].[OH-]>O1CCCC1>[Cl:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:31])[C:24]=1[NH:23][C:6]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:10][C:5]=1[CH2:4][C:3]([OH:32])=[O:2]
Reactant: COC(=O)Cc1cc(OCCCCOc2ccccc2)ccc1Nc1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(OCCCCOc2ccccc2)ccc1Nc1c(Cl)cccc1Cl

Procedure:
A solution of the ester of Step A, above (2.0 g, 4.2 mmol) in tetrahydrofuran (100 mL) and 1N LiOH (12.7 mL) is stirred under nitrogen overnight. The solvent is removed and the residue slurried in water. The mixture is acidified using dilute HCl and extracted with ethyl acetate (2×500 mL). The combined organic phases are washed with brine and dried (MgSO4). Removal of the solvent affords a brown oil which crystallizes from acetonitrile (white solid, 0.620 g, approximately 90% pure by HPLC). This material is further purified by HPLC (Dynamax C18, 2"-column, acetonitrile-ammonium acetate buffer 3:2) to provide pure title compound (0.250 g, white solid, m.p. 128°-131° C., dec.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[CH3:11][N:12]([CH3:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>ClC(Cl)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[O:10][C:13](=[O:14])[N:12]([CH3:16])[CH3:11])#[N:7]
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1ccc(F)cc1O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cc(F)ccc1C#N
Yield: 67 %

Procedure:
Under N2, a stirred solution of intermediate 129, 4-fluoro-2-hydroxybenzonitrile (685 mg, 5.00 mmol), dimethylcarbamoyl chloride, and triethylamine (606 mg, 6 mmol) in dichloroethane (10 mL) was heated at reflux for 20 hrs. The cooled mixture was diluted with dichloroethane (10 mL) washed with water, and brine. The organic layer was separated, dried (Na2SO4), concentrated, and the residue purified by column chromatography (SiO2, 5% ethyl acetate-CH2Cl2) to provide 700 mg (Yield 67%) of the title compound as a white crystalline solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.03 (3H, s, NMe), 3.15 (3H, s, NMe), 6.99 (1H, dt, J=2.5 Hz, 8.5 Hz, Ar—H), 7.23 (1H, dd, J=2.5 Hz, 9.5 Hz, Ar—H), 7.61 (1H, dd, J=9 Hz, 6 Hz, Ar—H); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 36.76, 37.06, 102.84, 102.86, 111.59, 111.79, 113.24, 113.42, 114.99, 134.36, 134.45, 152.54, 155.06, 155.16, 164.26, 166.31. HRMS (ESI) calcd for C10H10N2O2F (M+H) 209.0726. found 209.0722.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][N:25]([CH2:30][C:31]([NH2:33])=[O:32])[CH2:24][CH2:23]2>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:19][C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([CH2:30][C:31]([NH2:33])=[O:32])[CH2:24][CH2:23]5)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3cnc(O)nn23)cn1
Reactant: NC(=O)CN1CCc2cc(N)ccc2C1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5c(c4)CCN(CC(N)=O)C5)nn23)cn1

Procedure:
7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (0.0609 g, 0.251 mmol) and 2-(6-Amino-3,4-dihydro-1H-isoquinolin-2-yl)-acetamide (0.064 g, 0.31) were reacted in an analogous manner to Example 908D at 50° C. for 16 h. The reaction mixture was concentrated and purified by Gilson RP-HPLC. HPLC rt=2.083 min, purity=91%. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.23 (bs, 1H), 9.63 (s, 1H), 9.10 (s, 1H), 9.01 (s, 1H), 8.44 (dd, J=8.9 Hz, 2.2 Hz, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.21 (d, J=4.4 Hz, 1H), 7.13 (d, J=8.9 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.98 (d, J=4.5 Hz, 1H), 4.50 (m, 1H), 4.33 (m, 1H), 4.05 (m, 2H), 3.95 (s, 3H), 3.70 (m, 1H), 3.43 (m, 1H), 3.23 (m, 1H), 3.08 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O>O1CCOCC1.O>[C:25]([O:24][C:22]([N:10]1[CH2:9][CH2:8][CH:7]([O:6][C:5]2[CH:13]=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1)=[O:21])([CH3:28])([CH3:27])[CH3:26]
Reactant: Brc1ccc(OC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Reaction time: 48 h
Yield: 86.4 %

Procedure:
To a solution of 4-(4-Bromo-phenoxy)-piperidine (1 g, 3.9 mmol) in dioxane (20 ml), water (20 ml) added Na2CO3 (1.6 g, 18.9 mmol) and (BOC)2O (1.3 g, 5.9 mmol). Reaction stirred at ambient for 48 hours, solvent was removed under reduced pressure and residue partitioned between EtOAc and water the layers were separated. The organic layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure to give (1.2 g) of product.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[N:6]=1)C.[ClH:21]>O>[OH2:3].[ClH:21].[CH3:10][N:9]1[C:5]([CH:4]=[O:3])=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[N:8]1
Reactant: CCOC(OCC)c1nc(-c2cccc(C)n2)nn1C
Agent: Cl
Solvent: O
Product: Cc1cccc(-c2nc(C=O)n(C)n2)n1
Temperature: 75 °C
Yield: 189.6 %

Procedure:
A mixture of 2-[5-(diethoxymethyl)-1-methyl-1H-1,2,4-triazol-3-yl]-6-methylpyridine (38 g, 0.1377 mol), water (92 mL) and concentrated HCl (23 mL, 0.276 mol) was heated at 70-80° C. for 2 h. The resulting solution was co-evaporated with water four times using a water aspirator vacuum, then dried in vacuo at 60° C. to give 33.5 g (94.5%) of the title product as a covalently-bound hydrate. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, D2O+TFA): δ 2.90 (s, 3H), 4.13 (s, 3H), 6.38 (s, 1H), 7.94 (d, J=8 Hz, 1H), 8.37 (d, J=8 Hz, 1H), 8.56 (t, J=8 Hz, 1H). LC-MS (API-ES) calcd for C10H10N4O: 202.09, found (M+H+): 203.1; (M+18+H+) 221.1 m/z.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Br:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][C:47](O)=[O:48])=[N:44][CH:45]=1>C1COCC1>[Br:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:48])=[N:44][CH:45]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)Cc1ccc(Br)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Br)cn1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
Under an inert atmosphere, 0.09 g (0.95 mmol) of 2-aminopyridine, 0.31 g (2.4 mmol) of diisopropylethylamine and 0.35 g (1.1 mmol) of TBTU are successively added to 0.26 g (0.95 mmol) of (5-bromo-2-pyridyl)acetic acid (a synthesis of which is described in Tetrahedron, 1997, 53(24) 8257-8268 Gurnos J. et al.) dissolved in anhydrous THF (4 ml). The reaction mixture is stirred for 3 hours at room temperature. The reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate (20 ml) and the organic phase thus obtained is then washed with saturated ammonium chloride solution (15 ml) and with saturated sodium hydrogen carbonate solution (15 ml), and then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate, 1% NH4OH), with a gradient of 0% to 20% ethyl acetate, 1% NH4OH. 0.125 g of compound is obtained in the form of a white powder. Yield: 45%. Melting point: 131° C. MH+: 292-294 (tr: 6.1 min., condition 1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH2:17]([O:24][N:25]1[C:29]([Sn](CCCC)(CCCC)CCCC)=[CH:28][CH:27]=[N:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:29]2[N:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:26]=[CH:27][CH:28]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2OCc2ccccc2)c(C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a solution of 2-amino-4-trifluoromethyl-5-iodo-benzoic acid methyl ester (750 mg, 2.17 mmol) in dioxane (15 mL) were added 1-benzyloxy-5-tributylstannanyl-1H-pyrazole (1.24 g, 2.60 mmol) and Pd(dppf)2Cl2 (177 mg, 0.217 mmol) and the resulting mixture was stirred at 100° C. for 16 h. An additional portion of catalyst (0.1 equiv) was added and the mixture was stirred at 100° C. for an additional 24 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:100 to 50:50)) to provide the title compound as an off-white solid (263 mg, 31%). ES-MS: m/z 392.3 [M+H]+, rt 6.48 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[C:19]([O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32]Br)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:20]1([C:19]([O:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[CH2:37][O:38][C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46])[CH2:32][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=3[CH3:18])=[CH:6][CH:7]=2)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)c(C)c1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2ccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)cc2)c(C)c1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 2.0 g (8.7 mmol) of methyl 4′-hydroxy-2-methylbiphenyl-4-carboxylate with 4.3 g (9.8 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 1.29 g (9.3 mmol) of potassium carbonate, the desired product is obtained in the form of a yellow oil (m=4.88 g; Y=91%).
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:10][C:11](=[O:13])[CH3:12])(=O)[CH3:8].[CH3:14][C@H:15]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:16]/[CH:17]=[CH:18]/C(O)C>>[C:11]([O:10][CH:7](/[CH:18]=[CH:17]/[CH2:16][C@H:15]([CH3:14])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:8])(=[O:13])[CH3:12]
Reactant: CC(C)=CCC[C@@H](C)C/C=C/C(C)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)/C=C/C[C@H](C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A flame-dried, 250 mL, three-necked flask containing a magnetic stirring bar was charged under argon with 7.9 g (8.1 mL, 0.10 mol) of dry pyridine. After cooling in an ice-bath, 10.2 g (9.4 mL, 0.10 mol) of acetic anhydride and then 10.0 g (0.051 mol) of (2RS,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol were added dropwise, and the reaction was stirred for 2 hours at 0° C. and then overnight at 20° C. The reaction mixture was poured onto 2N HCl/ice and extracted with 2×200 mL of ether. The combined extracts were washed with 2N HCl, sat. NaHCO3 solution, and brine, dried over Na2SO4, filtered and evaporated. Kugelrohr distillation at ca. 105°-130° C./0.1 mmHg afforded 12.05 g (99%) of (2RS,3E,6R)-6,10-dimethyl-3,9- undecadien-2-ol acetate as colorless liquid. Calcd. for C15H26O2 (238.4): C. 75.58; H. 10.99; Found: C, 75.47; H, 11.04%. [α]D25 =-2.16° (2.04% in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:20]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:33]3[CH2:34][CH2:35][N:30]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CCCCCCCCCCN1CCNCC1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CCCCCCCCCCN1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 65.6 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with 1-decylpiperazine (0.77 g, 3.4 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 1.08 g of the title product was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2].CCN(CC)CC.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:32](=[O:34])[CH3:33])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2]
Reactant: CCOc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCN(C(C)=O)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.3 %

Procedure:
To a stirred mixture of piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #1A) (0.25 g, 0.76 mmol) and NEt3 (0.01 mL, 0.76 mmol) in THF (10 ml) was added acetyl chloride (0.053 ml, 0.76 mmol) at 0° C. The mixture was stirred at room temperature for 20 min, then the solvent was distilled off; the residue was dissolved in water and extracted with ethyl acetate (3×10 ml). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was triturated with dry diethyl ether and the solid was filtered off to obtain 1-acetyl-piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #13A) (0.208 g, 73%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][OH:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][O:13][C:29](=[O:30])[NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CO
Product: O=C(Nc1ccc(Cl)cc1)ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
2 g of 7-chloro-2-hydroxyamino-5-phenyl-3H-1,4-benzodiazepine are reacted with 1 g of 4-chlorophenyl isocyanate, analogously to Experiment 1a. Melting point 200° to 203° C. (from methanol); yield 2.1 g.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].C(O)(=O)C(O)=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[O:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:13][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Yield: 99 %

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (5.00 g, 29.4 mmol) was dissolved in toluene (200 mL), and ethylene glycol (15 mL) and oxalic acid (500 mg) were added thereto, followed by stirring under heating and reflux for 5 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=8:2) to afford ethyl 1,4-dioxaspiro[4,5]decane-8-carboxylate (6.28 g, 99%).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[O:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([CH2:30][CH2:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:17])[CH2:16][NH:32][CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10][CH2:9]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CNCCc1ccccc1)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 34.9 %

Procedure:
3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 1.2 g (0.01 mol) of 2-phenylethylamine were refluxed with heating together with 200 ml of DMF for 24 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography by using solvent mixtures of ethyl acetate--methanol and methylene chloride--methanol respectively to obtain 1.5 g of the subject compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH:9]1[CH2:13][CH2:12][N:11]=[C:10]1S(O)(=O)=O.[OH-].[Na+]>CC#N>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]=[C:10]1[NH:11][CH2:12][CH2:13][NH:9]1
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: Cc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ccccc1N=C1NCCN1
Yield: 5.4 %

Procedure:
Ortho toluidine (536 mg, 531 μl, 5 mmol) and imidazoline-2-sulfonic acid (750 mg, 5 mmol, (Compound 7 obtained as described above)) and CH3CN (6ml) were heated in a thick-walled glass tube at 150° C. for 16 hours. The reaction mixture was then cooled to 0° and made basic to pH 14 by addition of 2.5 N NaOH solution. The mixture was extracted with methylene chloride, the combine extracts were died (K2CO3) and evaporated to dryness. Flash chromatography on silica gel yielded the title compound as a tan colored solid (47.0 mg, 5.37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.C(O)C.Cl>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)ccc1O)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1O)C2

Procedure:
To 7-(5-chloro-2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one were added aminoguanidine hydrochloride (0.53 g), ethanol (30 ml), concentrated hydrochloric acid (1.0 ml) and water (1.0 ml), and the mixture was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make the solution alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid (10 ml). The mixture was concentrated, and precipitated crystals were recrystallized from ethanol to give 7-(5-chloro-2-hydroxyphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 167) (1.1 g) as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]#[N:5])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([C:1]1([C:4]#[N:5])[CH2:3][CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#CC1CC1
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cyclopropyl cyanide (3.0 mL, 40 mmol) in 20 mL THF was dropwise added to a stirred, freshly prepared, mixture of lithium diisopropylamide (40 mmol) in THF (100 mL) at −78° C. After 30 min, a solution of benzyl bromide 7.8 mL, 60 mmol) in THF (20 mL) was dropwise added. The resulting mixture was warmed slowly over several hrs and stirred at rt 48 hr. The reaction was quenched (250 mL saturated NH4Cl), extracted with ether (3×100 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated to afford a yellow oil.