Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=C(C4C=CC(/C=C/C(O)=O)=CC=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1N(CC2CCCCC2)C(=O)N(CC2CCCCC2)C(=O)C=1N=O.C(C1C=C(C=CC=1)C(O)=O)=O>>[CH:30]1([CH2:29][N:10]2[C:11]([NH2:12])=[C:15]([NH2:14])[C:16](=[O:17])[N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:9]2=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Agent: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Agent: O=Cc1cccc(C(=O)O)c1
Product: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O

Procedure:
1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was prepared as in part (d) of Example 1 by reduction of 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (2.00 g) and immediately condensed with 3-formylbenzoic acid (Aldrich, 1.424 g) by the method of J. Perumattam (Synthetic Commun. 1989, 19: 3367-3370) to give title compound as an off-white solid (2.27 g, 85%), m.p. >250° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12]Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(CCCCl)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCS(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 3-chloropropyl 4-fluorophenyl sulfoxide and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.64 (m, 2H), 7.53 (s, 1H), 7.24 (m, 5H), 6.94 (d, 1H, J=7.7 Hz), 2.89 (m, 4H), 2.45 (m, 4H ), 1.99 (m, 3H), 1.77 (m, 5H), 1.24 (d, 6H, J=6.8 Hz); Anal. Calcd for C24H31FN2O2S+0.6EtOAc: C, 65.5; H, 7.45; N, 5.79. Found: C, 65.4; H, 7.30; N, 5.73; ESMS m/e: 431.1 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]2[N:18]=[CH:19][N:20]=[CH:21][C:9]=2[C:8]1=[O:22]>O1CCOCC1.N1C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:7]([CH3:6])[C:8](=[O:22])[C:9]2[CH:21]=[N:20][CH:19]=[N:18][C:10]1=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CN1C(=O)c2cncnc2Nc2ccccc21
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CN1C(=O)c2cncnc2N(C(=O)CCl)c2ccccc21

Procedure:
6.25 g (0.044 mol) of chloroacetyl chloride in 15 ml of absolute dioxan and 4.4 ml of dry pyridine in 15 ml of dioxan are added dropwise simultaneously (at 80° C. and in the course of 20 minutes) to a suspension of 4.6 g (0.020 mol) of 6-methyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 35 ml of absolute dioxan. The mixture is heated at the boil for a further 15 minutes and is then allowed to cool. The supernatant liquid is decanted off from the heavy dark phase, and the latter is washed with methylene chloride; the dioxan and methylene chloride phases are concentrated in vacuo. The oil which remains is dissolved in a little chloroform and filtered through neutral silica gel; the filtrate is evaporated and the residue is recrystallized from isopropanol, yield: 2.8 g, m.p. 176° to 178° C. (dec.).
Reaction SMILES: [CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:22]([NH:23]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:21](=[O:43])[N:12]2[C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:22]([NH2:23])[C:21](=[O:43])[N:12]2[C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(N)C(=O)N12
Reaction time: 18 h

Procedure:
t-Butyl 3-benzyl-7-triphenylmethylamino-3-cephem-4-carboxylate (929 mg) was dissolved in acetone (2 ml) and the solution cooled to -20°. p-Toluene sulphonic acid (330 mg) in acetone (2 ml) was added dropwise over 2 - 3 minutes and the solution left at 0° for 18 hours. The crystalline product was filtered, washed with a little cold acetone and dried (493 mg) m.p. 175°-177°. The mother liquors were taken up in ethyl acetate, washed with dilute aqueous sodium bicarbonate and brine, dried and evaporated. Chromatography on silica gave crystalline t-butyl 3-benzyl-7-amino-3-cephem-4-carboxylate (V). ##SPC12##
Reaction SMILES: [Si]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[Li]CCCC.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[OH:8][C:9]1[C:10](=[O:15])[N:11]([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc[nH]c1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cccc(O)c2=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
3-tert-Butyidimethylsilyloxy-1H-pyridin-2-one (1 eq.) (Posner et al. J. Org. Chem. 1992, 57, 4088.) is cooled down to −78° C., in THF (10 mL) and is treated with n-BuLi (1.6 M soln. in hexane, 1.1 eq.). The solution is stirred for 20 min at −78° C., followed by the addition of p-toluenesulfonyl chloride (1.1 eq.). The solution is allowed to warm up to room temperature over one hr, quenched with water (10 mL), extracted with EtOAc (3×), washed with brine (1×), dried (Na2SO4) and concentrated. The residue is taken up in ethanol (10 mL) and treated with conc. HCl (2 mL). The mixture is allowed to stir for 1 h, the solvent is removed to obtain the desired compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[OH:10].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@@H:4]2[CH3:3])[N:15]=[CH:14][N:13]=1
Reactant: C[C@H]1CCCC[C@H]1O
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Temperature: 0 °C
Yield: 26.3 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.12 g of sodium hydride (60% in oil), to which 1 ml of a tetrahydrofuran solution containing 0.28 g of cis-2-methylcyclohexanol was slowly added dropwise with stirring at 0° C. The mixture was stirred at 0° C. for 10 minutes, to which 1 ml of a tetrahydrofuran solution containing 0.3 g of 4,6-dichloropyrimidine was added at 0° C., followed by further stirring at room temperature for 3 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of 4-chloro-6-(cis-2-methylcyclohexyloxy)pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:8].C([O:20][CH2:21][CH:22]1[CH:27]([O:28]C(=O)C)[CH:26]([O:32]C(=O)C)[CH:25]([O:36]C(=O)C)[CH:24](Br)[O:23]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[O:1][CH:24]2[CH:25]([OH:36])[CH:26]([OH:32])[CH:27]([OH:28])[CH:22]([CH2:21][OH:20])[O:23]2)=[O:8])=[CH:10][CH:11]=1
Reactant: CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Reactant: COc1ccc(C(=O)c2sccc2O)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2sccc2OC2OC(CO)C(O)C(O)C2O)cc1
Reaction time: 20 h

Procedure:
2.8 g of (3-hydroxythiophen-2-yl)-(4-methoxy-phenyl)-methanone were dissolved in 350 ml of dichloromethane, and 12.64 g of 3,4,5-triacetoxy-6-bromo-tetrahydropyran-2-ylmethyl actate, 15.4 g of potassium carbonate, 3.6 g of benzyltributylamonium chloride and finally 3 ml of water were added. The mixture was vigorously stirred at room temp. for 20 h. After the reaction was complete, the residue after filtration and concentration was filtered through SiO2 with ethyl acetate/heptane'1:2. The solvent was removed and the residue was taken up in about 300 ml of methanol and, after addition of 35 ml of 1 N NaOCH3 solution in methanol, stirred at room temp. for 1 h. This was followed by neutralization with 7% methanolic hydrochloric acid (about 35 ml), addition of about 100 of dichloromethane/methanol/conc. ammonia=30:5:0.1 mobile phase mixture and stirring for 5 min. This was followed by concentration, taking up the residue with the same mobile phase mixture and removing insoluble salt from the solution. Chromatography on silica gel results in the product with the molecular weight of 396.42 (C18H20O8S), MS (ESI): 397 (M+H+), 235 (M+H+-gluc).
Reaction SMILES: [OH-].[Na+].C(O)C.[F:6][C:7]1[CH:28]=[CH:27][C:10]([NH:11][C:12]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:13]=2[C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=1.Cl>C(OCC)(=O)C>[F:6][C:7]1[CH:28]=[CH:27][C:10]([NH:11][C:12]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:13]=2[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(-c2cccs2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1ccc(-c2cccs2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of toluene 2.0 mL, ethanol 0.6 mL and water 0.4 mL of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added thiophene-2-boronic acid 42 mg, sodium carbonate 64 mg and tetrakis(triphenylphosphine)palladium(0) 13 mg at room temperature, and it was stirred under application of pressure at 160° C. for 5 minutes. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 0.5 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane] to give methyl 2-(4-fluoroanilino)-4-(thiophen-2-yl)benzoate. 2.0 mol/L Sodium hydroxide aqueous solution 1.0 mL was added to ethanol 7.0 mL solution of the obtained methyl 2-(4-fluoroanilino)-4-(thiophen-2-yl)benzoate, and it was stirred at room temperature for 1 hour and 30 minutes. 0.5 mol/L Hydrochloric acid and ethyl acetate were added to the reaction mixture, the organic layer was separated and collected, and the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(thiophen-2-yl)benzoic acid 3.5 mg of pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)=O.[CH3:12][NH:13][CH3:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:12][N:13]([CH2:1][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)[CH3:14]
Reactant: CNC
Reactant: O=Cc1cccc(C(=O)O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)Cc1cccc(C(=O)O)n1
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of 6-formyl-2-pyridinecarboxylic acid (available from Chemstep Product List, 250 mg, 1.65 mmol) in dichloromethane (4.6 ml) was added dimethylamine (2M solution in THF, 2.17 ml, 4.34 mmol) and acetic acid (0.083 ml). The mixture was stirred at room temperature for 15 mins when sodium triacetoxyborohydride (459 mg, 2.17 mmol) was added and the mixture stirred overnight. The reaction mixture was quenched by the addition of a few drops of methanol. The mixture was loaded onto an aminopropyl-SPE cartridge (5 g) pre-eluted with dichloromethane, which was eluted with dichloromethane followed by methanol. Fractions containing product were combined and dried under vacuum. The crude product was taken up in sodium hydroxide solution (2M, 25 ml) and washed with dichloromethane (2×25 ml). The aqueous layer was acidified to pH7 using hydrochloric acid (5M) and concentrated under vacuum to approximately 25 ml. The solution was loaded onto an Oasis cartridge (6 g), which had been pre-eluted with methanol (1 volume) followed by water (1 volume). The cartridge was eluted with water (1 volume) followed by methanol. Fractions containing product were combined and dried to give the title compound (85 mg).
Reaction SMILES: [N:1]([CH:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH2:5]1)=[N+]=[N-].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25](O)=[O:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>[Pd].C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:25](=[O:26])[NH:1][CH:4]1[CH2:5][C:6](=[O:12])[O:7][CH:8]1[O:9][CH2:10][CH3:11])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC1OC(=O)CC1N=[N+]=[N-]
Agent: [Pd]
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC1OC(=O)CC1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
A mixture of 4-azido-5-ethoxy-dihydrofuran-2-one (1.06 g, 6.2 mmol), (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.33 g, 6.2 mmol), and 10% palladium on carbon (0.50 g) in ethyl acetate previously degassed with N2 (50 mL) was stirred under 1 atm hydrogen at room temperature for 1 h. The mixture was diluted with dichloromethane, filtered (Celite) and evaporated. The crude mixture was dissolved in dichloromethane (100 mL), was treated with diisopropylethylamine (5.4 mL, 30.8 mmol), EDC (1.48 g, 7.71 mmol), and HOBT (1.04 g, 7.71 mmol) and was stirred at room temperature under nitrogen for 24 h. The reaction was diluted with ethyl acetate, was washed with 10% sodium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes provided (R)-2-(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.19 g, 56% yield) as a very viscous, pale yellow oil. 1H-NMR (500 MHz, CDCl3) δ 7.61 (br, 0.6H), 5.29 (s, 0.6H), 5.25 (br s, 0.4H), 4.29 (br, 1.2H), 4.20 (br s, 0.8H), 3.78 (m, 1H), 3.57 (m, 1H), 3.34 (br, 1.4H), 3.25 (br, 0.6H), 2.94 (br dd, J=14.9, 3.8 Hz, 1H), 2.31 (dd, J=18.0, 1.4 Hz, 1H), 2.1-2.3 (br 1H), 1.82 (br s, 1H), 1.39 (s, 9H), 1.17 (m, 3H) ppm. MS (ES+): m/e=343 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl.[C:14](=N)(OC)[CH3:15]>CO>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:12][C:14]([CH3:15])=[N:1][C:2]=2[CH:7]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Reactant: COC(C)=N
Agent: Cl
Solvent: CO
Product: Cc1nc2cc(C(C)(C)C)ccc2o1
Yield: 24 %

Procedure:
In a 100 ml round bottom flask was placed 7.25 g (0.044 mol) of 2-Amino-4-tert-butylphenol, (Aldrich Cat #193282) with 6.0 g (0.055 mol) of Methyl acetimidate hydrochloride (Aldrich Cat #254940) with 50 ml of MeOH. This was refluxed for 4 hours. Then the MeOH was removed under vacuum. This was separated between 50 ml of ether and 50 ml of water. The ether was separated, dried, and removed under vacuum. Then 50 ml of hexanes was added to the resulting solid. Remaining 2-Amino-4-tert-butylphenol was insoluble in hexanes and was removed by filtration. The remaining oil was chromatographed using 2% MeOH/CH2Cl2 to provide 5-tert-butyl-2-methylbenzoxazole (Yield=2 g, 24%).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[N:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:30]([O:18][C:15]1[CH:14]=[N:13][C:12]([CH:9]2[CH2:10][C:11]3[C:2]([F:1])=[N:3][C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:17][CH:16]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCOc1cc2c(c(F)n1)CC(c1ncc(O)cn1)CC2
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1cnc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxy-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1-fluoro-3-octyloxy-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21]([C:42]3[CH:47]=[C:46]([Cl:48])[C:45]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[CH:44][C:43]=3[O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[N:22][N:23]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:24]=2[C:25](OCC(C)C)=[O:26])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CO>C(OCC)C.[OH-].[Na+]>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:20]2[C:21]([C:42]3[CH:47]=[C:46]([Cl:48])[C:45]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[CH:44][C:43]=3[O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[N:22][N:23]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:33])=[O:34])[C:24]=2[CH2:25][OH:26])[CH2:18][CH2:19]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)n2nc(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C(=O)OCC(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2nc(-c3cc(Cl)c(OCc4ccccc4)cc3OCc3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2CO)cc1
Reaction time: 2 h
Yield: 69.4 %

Procedure:
A solution of lithium aluminium hydride (1M in ether, 0.3 ml, 0.3 mmol) was added dropwise to a stirred solution of 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-5-isobutoxycarbonyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.11 mmol) [prepared by use of the lithiation chemistry in the preceding example] in anhydrous diethyl ether (2 ml) at room temperature, under a nitrogen atmosphere. The suspension was stirred 2 h then sodium hydroxide solution (1M, 3 drops) was added, followed by methanol (0.5 ml). The mixture was partitioned between water (30 ml) and ethyl acetate (2×20 ml), and the combined organic phases were dried over magnesium sulphate, then concentrated in vacuo to give 4-[3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-5-hydroxymethyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (58 mg, 88%)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[CH:9][CH:8]=1.Cl>CN(C)C=O>[C:7]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([C:18]3[NH:19][N:3]=[N:2][N:1]=3)[CH:20]=[CH:21][CH:22]=2)=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(COc2ccc(-c3ccccc3)cc2)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(OCc3cccc(-c4nnn[nH]4)c3)cc2)cc1
Temperature: 125 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
To a mixture of sodium azide (2.96 g, 45.6 mmol) and ammonium chloride (2.44 g, 45.6 mmol) in dry N,N-dimethylformamide (100 mL) under an atmosphere of nitrogen, 3-(biphenyl-4-yloxymethyl)-benzonitrile (10.0 g, 35.0 mmol) was added and the reaction mixture was stirred at 125° C. for 18 hours. The cooled reaction mixture was poured on to a mixture of 1N hydrochloric acid (60 mL) and ice water (500 mL). The precipitate was filtered off and washed with water (3×100 mL), 50% ethanol (3×100 mL), ethanol (50 mL), diethyl ether (50 mL), ethanol (80 mL), and dried in vacuo at 50° C. for 18 hours affording 8.02 g (70%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][C@@H:6]([NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=1)[CH2:7]2.[O:34]=[C:35]([OH:46])[C@@H:36]([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][OH:45])[OH:43])[OH:41])[OH:39])[OH:37]>C(O)C>[O:34]=[C:35]([OH:46])[C@@H:36]([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][OH:45])[OH:43])[OH:41])[OH:39])[OH:37].[CH2:1]([C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][C@@H:6]([NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=1)[CH2:7]2)[CH3:35]
Reactant: Cc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](NC(=O)c1ccc(N3CCOCC3)cc1)C2
Agent: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: CCc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](NC(=O)c1ccc(N3CCOCC3)cc1)C2
Reaction time: 65 h
Yield: 120.2 %

Procedure:
(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide (100 mg, 0.22 mmmol) was dissolved in ethanol (3 mL) and a 50% aqueous D-gluconic acid solution (80 μL, 0.24 mmol) was added dropwise. The solvent was removed in vacuo to give a white viscous oil. The crude oil was recrystallized from a 5% H2O in acetone solution (3 mL) and a 10% H2O in acetone solution (3 mL), decanted, then allowed to stand at room temperature for 65 h. The solid was filtered and washed with a cold 3% H2O in acetone solution to give 95 mg (65% yield) of a white solid: nip 130-140° C. Anal. Calcd. for C27H36N4O2xC6H12O7xH2O: C, 59.8; H, 7.6; N, 8.5. Found: C, 60.0; H, 7.4; N, 8.3.