Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[CH3:11].[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24](I)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]>C1COCC1.[Zn]>[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24]([C:2]3[C:6]4[CH:7]=[N:8][CH:9]=[CH:10][C:5]=4[S:4][C:3]=3[CH3:11])=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1sc2ccncc2c1Br
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4ccncc34)c(C)nc12
Temperature: 100 °C
Yield: 6.1 %

Procedure:
225 mg of 3-Bromo-2-methyl-thieno[3,2-c]pyridine (0.98 mmol) is placed into the vial with 2.14 ml of Reiki Zn, suspension in THF (1.50 mmol) and capped and heated at 100° C. for 2 h. The excess Zinc is allowed to settle down and the solution is transferred to the vial containing 200 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.58 mmol) and 41 mg of PdCl2(pddf) (0.05 mmol) in 3 ml of dry THF. The vial is capped with a Teflon cap and heated at 80° C. for 2 days. The reaction mixture is quenched by sat. NH4Cl and extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:4:1) to give 12.8 mg of the title compound. Yield 4%. Mass spectrum (m/e): 365 (M+1); 1H-NMR (CDCl3): 8.54 (m, 1H), 8.46 (m, 1H), 7.80 (m, 1H), 6.74 (s, 1H), 3.41 (m, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 2.44 (s, 3H), 1.89 (m, 4H), 0.94 (m, 6H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][C:4]1[O:5][C:6]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17])=[CH:7][CH:8]=1.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>CCOCC>[CH3:21][N:2]([CH2:3][C:4]1[O:5][C:6]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:14]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:14]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:6]2[O:5][C:4]([CH2:3][N:2]([CH3:1])[CH3:21])=[CH:8][CH:7]=2)=[CH:15][N+:16]([O-:18])=[O:17])=[CH:15][N+:16]([O-:18])=[O:17])=[CH:7][CH:8]=1)[CH3:1]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reactant: NCCCCCCCCCCCCN
Solvent: CCOCC
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCCCCCCCCCCNC(=C[N+](=O)[O-])NCCSCc2ccc(CN(C)C)o2)o1
Yield: 77.1 %

Procedure:
A mixture of N,N-dimethyl-5-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine (2 g) and 1,12-diaminododecane (0.6 g) was heated at 100° for 3 hours. The oily residue was chromatographed (silica/methanol-0.88 ammonia, 79:1) to give an oil which solidified on trituration with ether giving the title compound (1.77 g) mp. 74°-76°.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13]([C:15]1([C:18]([O:20]CC)=[O:19])[CH2:17][CH2:16]1)=[O:14]>C(O)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13]([C:15]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]1)=[O:14]
Reactant: CCOC(=O)C1(C(=O)Nc2cc(Cl)c(Cl)cc2C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)c(Cl)cc1NC(=O)C1(C(=O)O)CC1
Temperature: 0 °C

Procedure:
A solution containing 0.34 gram (0.006 mole) of potassium hydroxide and 0.109 gram (0.006 mole) of water in 80 milliliters of ethanol was prepared in a 250 milliliter round bottom flask. With cooling to a temperature of 0° C. in an ice/NaCl bath and stirring, a solution of ethyl 1-(2-methyl-4,5-dichlorophenylaminocarbonyl)cyclopropanecarboxylate prepared in Example III in a small volume of ethanol was added and the mixture allowed to stir with warming to room temperature over a 72 hour period. The mixture was vacuum evaporated to give a white solid residue which was dissolved in water and extracted twice with ether. The ether extracts were discarded. The water solution was acidified to a pH of 2 with 25% Hcl solution causing separation of a solid which was taken up into ether, and the acidified aqueous phase was extracted four times. The combined ether extracts were dried over magnesium sulfate and vacuum evaporated to give a white solid. This white solid was water-washed and dried in a vacuum oven to give 1.85 grams (0.006 mole) of 1-(2-methyl-4,5-dichlorophenylaminocarbonyl)cyclopropanecarboxylic acid having a melting point of 248° C.-251° C.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:32])[C:10]2[N:11]=[CH:12][N:13]([C@@H:16]3[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C@H:18](O)[CH2:17]3)[C:14]=2[N:15]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.CS(Cl)(=O)=O.[N-:45]=[N+:46]=[N-:47].[Na+]>ClCCl.CN(C)C1C=CN=CC=1.CCOC(C)=O.O>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:32])[C:10]2[N:11]=[CH:12][N:13]([C@@H:16]3[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:31])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@H:18]([N:45]=[N+:46]=[N-:47])[CH2:17]3)[C:14]=2[N:15]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@@H](O)[C@@H](COC(=O)c3ccccc3)O2)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@@H](N=[N+]=[N-])[C@@H](COC(=O)c3ccccc3)O2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 66 %

Procedure:
To a mixture of 52 (290 mg 0.65 mmol) in dichloromethane (30 mL) were added 4-dimethylaminopyridine (12 mg, 0.065 mmol) and Et3N (0.45 mL), followed by methanesulfonylchloride dropwise (0.121 mL, 1.30 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 40 min under argon then hydrolyzed with water (20 mL). The organic layer was separated and evaporated. The residual oil was diluted in anhydrous DMF (20 mL). To the solution was added sodium azide (410 mg, 6.5 mmol) and the mixture was heated at 120° C. for 2 h under argon. The reaction was cooled to room temperature, diluted with AcOEt and washed with water. The organic layer was evaporated and the residue was then purified by column chromatography on silica gel column eluting with CH2Cl2-MeOH (9:1) to give 55 (200 mg, 65%) as a white solid. IR 2104 cm−1 (N3); 1H NMR (DMSO-d6) δ 1.08-1.12 (m, 6H, 2×CH3), 2.50-2.79 (m, 2H, H-2′, isobutyryl CH), 2.91-3.01 (m, 1H, H-2′), 4.18-4.23 (m, 1H, H-4′), 4.42-4.56 (m, 2H, H-5′, H-5″), 4.83-4.89 (m, 1H, H-3′), 6.21 (t, 1H, J=5.4 Hz, H-1′), 7.45-7.50 (m, 2H benzoyl), 7.62-7.66 (m, 1H benzoyl), 7.85-7.88 (m, 2H benzoyl), 8.20 (s, 1H, H-8), 11.53 (br s, NH), 11.91 (br s, NH).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[O:3]1.[NH4+:15].[OH-]>S(Cl)(Cl)=O.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:4]([CH2:11][C:12]([NH2:15])=[O:14])[O:3]1
Reactant: [NH4+]
Reactant: O=C(O)CC1OC(=O)c2ccccc21
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC(=O)CC1OC(=O)c2ccccc21

Procedure:
A solution of (3-oxo-1,3-dihydro-isobenzofuran-1-yl)-acetic acid (5.0 g, 26 mmol) in thionyl chloride (10 ml) was heated at 75° C. for 15 minutes. The excess thionyl chloride was removed under vacuum to give a red oil. The red oil was dissolved in CH2Cl2 (10 ml) and then the solution was slowly added to concentrated NH4OH (40 ml) at 0° C. The resultant solid was filtered and washed with water and hexane, followed by addition of toluene. Removal of the solvent led to 2-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)acetamide as a cream solid (4.2 g, 84%).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)([OH:8])[CH2:4][O:3]1>C(O)(C(F)(F)F)=O.CCO.[Pd]>[CH2:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:5]([OH:8])([CH2:6][OH:7])[CH2:4][OH:3])=[CH:12][CH:13]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCc1ccc(C#CC2(O)COC(C)(C)OC2)cc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCCCCCCCc1ccc(CCC(O)(CO)CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
A mixture of the product of Step B (0.03 g; 0.087 mmol) and 10% Pd/C (0.05 g) in 5% TFA in EtOH (10 ml) was stirred for 1 h under H2 (balloon) at room temperature, then filtered through a pad of Celite, washed with CH2Cl2 (2×10 ml). To combined filtrates were evaporated to dryness under reduced pressure and dried in vacuo for 1 h to give title compound (0.027 g; 99%) as a colourless solid. 1H-NMR (CDCl3) 7.05 (s, 4H); 3.66 (broad m, 7H); 2.61 (m, 2H); 2.51 (t, 2H, J=7.92 Hz); 1.73 (m 2H); 1.55 (t, 3H, J=6.93 Hz); 1.26 (m, 10H); 0.87 (t, 3H, J=6.93 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([N+:18]([O-])=O)[CH:17]=1)[O:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:14])[CH3:13])[CH2:7]1.FC1C=C(C=C(F)C=1)O[C@@H]1CCCN(C(=O)C)C1.C([O-])=O.[NH4+].CC(C)=O>CO.O>[NH2:18][C:16]1[CH:15]=[C:4]([CH:3]=[C:2]([F:1])[CH:17]=1)[O:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:14])[CH3:13])[CH2:7]1
Reactant: CC(=O)N1CCC[C@@H](Oc2cc(F)cc([N+](=O)[O-])c2)C1
Agent: CC(=O)N1CCC[C@@H](Oc2cc(F)cc(F)c2)C1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: CC(=O)N1CCC[C@@H](Oc2cc(N)cc(F)c2)C1
Yield: 75 %

Procedure:
Three 22 L 3-neck RBFs equipped with heating mantles, mechanical stirrers, thermowells, condensers, and nitrogen bubblers were purged under nitrogen for at least ten minutes. The flasks were charged with 0.454 kg (10 wt %) Pd/C, and 13.62 L (3 vol) methanol. A solution of 4.54 kg (˜16.1 mol) of a mixture of 1-[(R)-3-(3-fluoro-5-nitro-phenoxy) -piperidin-1-yl]-ethanone and 1-[(R)-3-(3,5-difluoro-phenoxy)-piperidin-1-yl]-ethanone in 4.54 L (1 vol) methanol was then charged to the flasks, and an additional 4.54 L (1 vol) methanol was added to the flasks. The solutions were warmed to a gentle reflux, and a solution of 5.07 kg (80.4 mol) ammonium formate in 3.63 L water was then added drop-wise for 10 hours. The reactions were deemed complete by TLC (1:1 hexanes:acetone/PMA stain) and HPLC, and were filtered through celite and concentrated. The concentrate was transferred to two 50 L extractors, and was partitioned between 47.2 L MTBE and 17.7 L 3N HCl. The layers were separated, and the organics were extracted with 6 L (2×) 3N HCl. The aqueous layers were neutralized with 3.54 kg NaOH to pH ˜7, then 9.6 L saturated sodium bicarbonate was added. The aqueous layers were then extracted with 6 L (3×) DCM. The combined organics were washed with 18 L brine, dried over sodium sulfate, filtered and concentrated to yield 3.06 kg of 1-[(R)-3-(3-amino-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone in 75% yield as a thick brown oil (theoretical yield=4.06 kg, purity=90.7% and 95.4% ee).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:12]([CH3:25])([CH3:24])[N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>O>[ClH:1].[ClH:1].[CH3:22][N:21]([CH3:23])[C:18]1[CH:17]=[CH:16][C:15]([C@H:13]2[CH2:14][C@@H:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=3)[NH:11][C:12]2([CH3:24])[CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(C2=NC(C)(C)C(c3ccc(N(C)C)cc3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc([C@@H]2C[C@H](c3ccc(N(C)C)cc3)C(C)(C)N2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 7 g. of 2-(p-methoxyphenyl)-5,5-dimethyl-4-(p-dimethylaminophenyl)-1-pyrroline hydrochloride in water is made alkaline with 3-N sodium hydroxide and extracted with methylene chloride. The organic phase is washed with water and dried over sodium sulfate. The oil which remains after removal of the solvent is taken up in 150 ml. of absolute ethanol and the solution treated with 5 g. of sodium borohydride. The mixture is then stirred at room temperature for 12 hours under nitrogen. Subsequently, the mixture is evaporated to dryness under reduced pressure and the residue suspended in water by intensive stirring. The non-dissolved constituent is filtered off, dried and recrystallized from n-pentane. The thus-purified base is taken up in ethanolic hydrochloric acid, again evaporated to dryness under reduced pressure and the residue recrystallized from ethanol/acetone. There is obtained cis-3-(p-dimethylaminophenyl)-2,2-dimethyl-5-(p-methoxyphenyl)-pyrrolidine dihydrochloride, having a melting point of 180° C.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].OS(O)(=O)=O.[C:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19])(=[O:14])[CH3:13].[C:24](O)([CH3:27])([CH3:26])[CH3:25].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([O:20][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:19])(=[O:14])[CH3:13]
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 114 h
Yield: 71.8 %

Procedure:
In a dry flask under nitrogen, MgSO4 (23.3 mmol) was suspended in CH2Cl2 (23 mL), the mixture was stirred vigorously as concentrated H2SO4 (5.85 mmol) was added dropwise. The resultant mixture was stirred for 20 min and 3-acetylbenzoic acid (5.84 mmol) was added in one portion followed by the dropwise addition of tert-butanol (29.3 mmol). This mixture was stoppered tightly and stirred at room temperature for 114 hours. Worked up by adding 100 mL saturated aqueous NaHCO3 and extracting 3× with 50 mL diethyl ether. The combined extracts were washed with brine, dried over MgSO4 and concentrated. Purified the residue by silica gel chromatography (90:10 hexanes:ethyl acetate) to yield 924 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.56 (m, 1H); 8.20 (m, 1H); 8.14 (m, 1H); 7.55 (t, J=7.6 Hz, 1H); 2.67 (s, 3H); 1.64 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]2([CH2:15][C:16]([OH:18])=O)[CH2:14][CH2:13][CH2:12]2)=[CH:5][C:4]=1[CH3:19].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:19])=[C:5]2[C:6](=[CH:7][C:8]=1[CH3:9])[NH:10][C:11]1([CH2:12][CH2:13][CH2:14]1)[CH2:15][C:16]2=[O:18]
Reactant: COc1c(C)cc(NC2(CC(=O)O)CCC2)cc1C
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(C)cc2c(c1C)C(=O)CC1(CCC1)N2
Yield: 165.1 %

Procedure:
To a solution of 2-(1-(4-methoxy-3,5-dimethylphenylamino)cyclobutyl)acetic acid (650 mg) in 10 mL toluene was added a large excess of polyphosphoric acid. The mixture was refluxed for 30 minutes, water was added, and the solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation, giving 6′-methoxy-5′,7′-dimethyl-1′H-spiro[cyclobutane-1,2′-quinolin]-4′(3′H)-one as a yellow solid (1 g). 1H-NMR (300 MHz, CDCl3) δ=6.25 (s, 1H), 2.78 (s, 2H), 2.55 (s, 3H), 2.125-2.38 (m, 5H), 1.95-2.06 (m, 2H), 1.73-1.83 (m, 2H) ppm. MS: m/z 246 (100, M+H)+
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[NH2:9]>O.Cl>[ClH:5].[Cl:5][C:6]1[CH:7]=[C:8]([NH:9][NH2:1])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: O=N[O-]
Reactant: COc1ccc(N)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)cc1Cl
Yield: 173.4 %

Procedure:
A solution of sodium nitrite (6 g) in water (50 ml) was added dropwise to a solution of 3-chloro-4-methoxyaniline (10 g) in concentrated hydrochloric acid (30 ml) at 0° C. with stirring. After the addition was completed, the reaction mixture was stirred at the same temperature for 1 hour. A solution of stannous chloride dihydrate (50 g) in concentrated hydrochloric acid (30 ml) was added dropwise at 0° C. The resulting mixture was stirred for 2 hours at the same temperature. The resulting precipitate was collected by filtration, washed with ice water and dried in vacuo at 50° C. to afford (3-chloro-4-methoxyphenyl)hydrazine hydrochloride (11.5 g) as a yellow brown solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)[CH3:18]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCNCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1
Product: CCN(CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)C(=O)C(c1ccccc1)c1ccccc1

Procedure:
Example 126 was prepared from diphenylacetyl chloride and N-(3-{1-[3-(ethylamino)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.33–7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s, 1H), 3.39 (m, 4H), 2.93 (d, 2H, J=10.9 Hz), 2.52–2.36 (m, 7H), 1.97 (t, 2H, J=10.9 Hz), 1.83–1.58 (m, 6H), 1.24 (d, 6H, J=7.6 Hz); ESMS m/e: 526.4 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl>O>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][N:2]([CH3:3])[CH3:1]
Reactant: ClCc1ccccc1Cl
Reactant: CNC
Solvent: O
Product: CN(C)Cc1ccccc1Cl

Procedure:
The dimethylamine and water streams were initially combined and preheated to 130° C. The stream of o-chlorobenzyl chloride was then introduced by way of a mixing chamber. The temperature in the reaction tube was set to approximately 140° C. After running through the reaction zone, the mixture was cooled and depressurized. The workup analogous to example 1 afforded the (2-chlorobenzyl)dimethylamine target product with a yield and purity as in example 3.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd]>[C:1]1([CH2:7][CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Agent: [Pd]
Product: c1ccc(CC2CCC3(CC2)OCCO3)cc1

Procedure:
For example, when n is the bridging group --CH2--, an appropriately substituted or unsubstituted phenylmethyl bromide, for example, 2-chlorophenylmethyl bromide, is reacted with triphenylphosphine in toluene, affording the corresponding phenylmethyltriphenylphosphonium bromide. The so-prepared phosphonium bromide is then treated with n-butyllithium, and reacted with 1,4-cyclohexanedione mono-ethylene ketal, yielding the appropriate 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane. The 8-phenylmethylene-1,4-dioxaspiro[4.5]decane is in turn reduced with hydrogen gas in the presence of 10% palladium on charcoal, giving the corresponding 8-phenylmethyl-1,4-dioxaspiro[4.5]-decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 2 provides a detailed description of how this reaction is conducted.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][N:12]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][OH:20])[CH:14]=[N:13]1.Cl>ClCCl.C(N(CC)CC)C>[CH3:11][N:12]1[CH:16]=[C:15]([CH2:17][CH2:18][CH:19]=[O:20])[CH:14]=[N:13]1
Reactant: Cn1cc(CCCO)cn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(CCC=O)cn1
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (0.361 ml) in dichloromethane (10 ml) cooled below -65° C. with a dry ice-acetone bath, a solution of dimethyl sulfoxide (0.381 ml) in dichloromethane (1 ml) was added with efficient stirring over 10 minutes. After 20 minutes below -65° C., a solution of 3-(1-methyl-1H-pyrazol-4-yl)-1-propanol in dichloromethane (2 ml) was added to the mixture over 10 minutes below -65° C. and the mixture was stirred at the same temperature for 20 minutes and then at -45~-40° C. for 30 minutes. After addition of triethylamine dropwise to the mixture over 10 minutes followed by stirring for 15 minutes, 1N hydrochloric acid solution was added to the mixture. The resulting mixture was extracted with a mixture of dichloromethane and methanol several times. The extract was concentrated under reduced pressure and the resulting residue was chromatographed on a silica gel using a mixture of dichloromethane and methanol as an eluent to give 3-(1-methyl-1H-pyrazol-4-yl)-1-propanal.
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[NH:3][C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl.C1(OC)C=CC=CC=1>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][NH:2][NH:3][C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5]
Reactant: COC(=O)COc1ccc(C(=O)NN(C)C(=O)OC(C)(C)C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNNC(=O)c1ccc(OCC(=O)OC)cc1
Reaction time: 2.5 h

Procedure:
To a stirred suspension of the product of step (a) (2.9 g) in a mixture of dichloromethane (20 ml) and anisole (2 ml) at 0-5° C. was added trifluoroacetic acid (27 ml). The resultant solution was stirred at low temperature for 20 minutes and then at ambient temperature for 2.5 hours. The reaction mixture was evaporated and the residue was triturated with dry ether. The solid was collected and washed with ether to give methyl 4-(3-methylcarbazoyl)-phenoxyacetate trifluoroacetate salt (2.9 g), as a white solid; m.p. 121-123° C.; NMR Spectrum (DMSO-d6) 2.80 (3H, s), 3.70 (3H, s), 4.93 (2H, s), 7.10 (2H, d), 7.85 (2H, d), 10.80-11.70 (1H, br s); Mass Spectrum m/Z 239 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19]C)=[O:18])[C:12]2=[CH:11][C:10]=1[Cl:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][C:10]=1[Cl:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCn2c1cc(Cl)c2C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(c1ccccc1)c1c(Cl)cc2n1CCC2C(=O)O

Procedure:
Methyl 5-benzoyl-6-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (1.10 g.) in 30 ml. of methanol containing 2 molar equivalents potassium carbonate in 10 ml. of water is heated at reflux temperature for three hours. The methanol is removed in vacuo and water is added to the residue. The solution is extracted with ethyl acetate, the aqueous phase is cooled to 0° and made acidic with 20% hydrochloric acid. The solid which precipitates is collected by filtration, washed with cold water and dried in vacuo. The residue is crystallized from methanol-water to give 5-benzoyl-6-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, m.p. 190° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[O:17][CH3:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[O:17][CH3:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCCCc1ccc(O)c(OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1ccc(OCc2ccccc2)c(OC)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 83.5 %

Procedure:
A mixture of ethyl 5-(4-hydroxy-3-methoxyphenyl)pentanoate (27.92 g), benzyl bromide (20.82 g), potassium carbonate (22.9 g) and N,N-dimethylformamide (DMF) (140 ml) was stirred for 15 hours at 90° C. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:6, v/v), was obtained ethyl 5-(4-benzyloxy-3-methoxyphenyl)pentanoate (31.64 g, 84%),