Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].C([S:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1)(=O)C.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17]>C(O)C>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][S:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1)[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: CC(=O)SC1C=CCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(CSC1C=CCCCC1)OCC
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A solution of fresh sodium ethoxide prepared from 7.6 g (washed well gram-atom metallic sodium) in 200 ml of absolute ethanol was treated dropwise with 56.18 g (0.330 mole) of 3-acetylmercaptocycloheptene in 10 ml of absolute ethanol. The reaction was heated under reflux for 15 minutes and then cooled to room temperature. A solution of 49.69 ml (0.330 mole) of bromoacetaldehyde diethylacetal in 30 ml of absolute ethanol was added dropwise. The reaction mixture was heated under reflux for 2.0 hours and cooled. The precipitated sodium bromide was filtered and washed with absolute ethanol. The filtrate was concentrated and the residue partitioned between ether/brine. The aqueous phase was further extracted with ether. The organic extracts were pooled, dried over magnesium sulfate, and evaporated to afford 80.1 g (0.328 mole, 99%) of pure 3-[(2,2-diethoxyethyl)thio]-1-cycloheptene, as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Br:11])[CH:5]=1)=[O:3].[Se](=O)=[O:13]>O1CCOCC1.O>[Br:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[O:13])[CH:9]=[CH:8][C:7]=1[F:10]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)c1ccc(F)c(Br)c1
Temperature: 25 °C

Procedure:
To 3-bromo-4-fluoroacetophenone (11.0 g) in 1,4-dioxane (160 ml) and water (15 ml) was added selenium dioxide (8.8 g). The mixture was heated at reflux for 10 h, cooled to room temperature, and the solvent then removed at reduced pressure. The residue was suspended in 50% diethyl ether in isohexane, and residual solid removed by filtration. The filtrate was dried over Na2SO4, and solvent then evaporated to give (3-bromo-4-fluorophenyl)oxoacetaldehyde as a yellow oil, which was used without further purification in the next step.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([N:7]([CH2:14][CH2:15][CH2:16][NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([N:7]([CH2:14][CH2:15][CH2:16][N:17]=[C:1]=[S:2])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:6]
Reactant: S=C(Cl)Cl
Reactant: CCN(CCCN)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCCN=C=S)c1ccccc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of thiophosgene (7.43 ml) in CH2Cl2 (300 ml) was added dropwise over 11/2 hours at 20° C. under a nitrogen atmosphere to a stirred solution of N-ethyl-N-(3-aminopropyl)aniline (17.8 g) and triethylamine (27.8 ml) in CH2Cl2 (500 ml). The mixture was stirred at 20° C. for a further 1/2 hours then heated under reflux for 11/2 hours. The mixture was allowed to cool, washed with water, dried over MgSO4, filtered and solvent removed from the filtrate in vacuo. The product was purified by chromatography on silica gel eluting with CH2Cl2 to give N-ethyl-N-(3-isothiocyanatopropyl)aniline (7.2 g) as a red oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH2:17]([O:24][C:7]1[C:2]([Br:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=[C:5]([NH2:11])[N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(OCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine, benzylalcohol and DBU in dioxane. ES-MS m/e (%): 348 (M{81Br}+H+, 96), 346 (M{79Br}+H+, 100).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:26][CH2:25][CH2:24][C:21]4[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=4)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NCCc1ccccc1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc(CCNC2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.1 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and 2-phenethylamine (61 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid. solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (30 mg) and a syn-form compound (24 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[CH:31][C:32]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[Pd](Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:30]=[CH:31][C:32]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:33][CH:34]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CC(=O)OC(C)(C)C)nc2)c1
Yield: 47.1 %

Procedure:
A mixture of N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (110 mg, 0.290 mmol), tert-butyl 2-(5-bromopyridin-2-yl)acetate (51.3 mg, 0.189 mmol), palladium(II) chloride (dppf) (28 mg, 0.038 mmol) and sodium carbonate (0.2 ml, 0.400 mmol, 2 M) in DMF (2 ml) was evacuated and purged with argon (3×), and then was irradiated in a microwave reactor for 10 minutes at 100° C. The mixture was filtered and purified on reversed phase HPLC to afford tert-butyl 2-(5-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)acetate (49.5 mg, 0.089 mmol). MS ESI calc'd. for C23H23F3N4O2 [M+H]+ 445. found 445.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16]1([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[C:22]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=[CH:24][C:25]([CH2:26][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:28][CH:29]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(Cn3c4ccccc4c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Carbazole (8.25 g, 49 mmol) was dissolved in N,N'-dimethylformamide (100 ml). Under a atmosphere of nitrogen was added sodium hydride (2.56 g, 64 mmol of a 60% suspension in mineral oil) in portion during 15 minutes. The mixture was then stirred at room temperature for 0.5 h. To the resulting mixture was added 4-phenylbenzylchloride (10 g, 49 mmol) in portions during 10 minutes. Then additional N,N'-dimethylformamide (100 ml) was added and the mixture was stirred at room temperature for 3.5 h. Water (125 ml) was added and the mixture was stirred vigorously at room temperature for 0.5 h, the solid formed was filtered off, washed with water (2×100 ml) and with hexane (2×100 ml). Drying in vacuo at 50° C. for 16 h afforded 15.9 g (97%) of 9-(biphenyl-4-ylmethyl)-9H-carbazole as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([OH:19])=O)=[C:4]2[CH2:3]1.[CH:20]1([C:23](=[N:25]O)[NH2:24])[CH2:22][CH2:21]1>CN(C)C=O>[CH:20]1([C:23]2[N:25]=[C:17]([C:16]3[N:15]=[CH:14][N:5]4[C:6]5[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=5[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=34)[O:19][N:24]=2)[CH2:22][CH2:21]1
Reactant: NC(=NO)C1CC1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nc(C4CC4)no3)ncn2-c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A mixture of 9.77 g (39 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 40 ml of N,N-dimethylformamide and 6.48 g (40 mmol) of N,N'-carbonyldiimidazole is stirred at 100° for 1 hour. 4.01 g (40 mmol) of cyclopropanecarboxamidoxime are subsequently added thereto and the mixture is stirred at 100° for a further 4 hours. The mixture is then evaporated and the residue is heated to 115° for 4 hours with 100 ml of acetic acid. The solution is evaporated to dryness and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. By recrystallization from methylene chloride and ethyl acetate there is obtained 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 202°-203°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:8]=[C:9](Br)[C:10]=1[OH:11])=[O:4].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([OH:11])=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(Br)c1O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccccc2)c1O
Temperature: 80 °C
Reaction time: 10 h
Yield: 70.5 %

Procedure:
To a solution of 5-Bromo-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methylester (0.3 g, 0.8 mmol) in toluene (5 mL) was added phenylboronic acid (0.19 g, 1.6 mmol), tetrakistriphenylphosphine (0.0.09 g, 0.08 mmol), Na2CO3(2.4 ml, 1N solution) and stirred the reaction mixture at 80° C. for 10 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and silicagel column chromatography (20:80 EtOAc:hexane) gave pure 4′-Hydroxy-4-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (0.21 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:26])[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19](=O)[CH2:18]1>[Zn].Cl[Ti](Cl)(Cl)Cl.C1COCC1>[C:10]1([C:8](=[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[CH2:22][C:17]([CH3:26])([CH3:16])[CH2:18]2)[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(O)cc2)CC(C)(C)C1
Yield: 94.2 %

Procedure:
The McMurry procedure described for 9 (example 5, step 1) was utilized using (4-hydroxyphenyl)(phenyl)methanone (2.97 g, 14.9 mmol), 3,3,5,5-tetramethylcyclohexanone (6.25 g, 44.9 mmol), Zn (9.69 g, 149 mmol), TiCl4.2THF complex (25 g, 7.5 mmol), and THF (200 mL). Standard work-up followed by purification gave 4.50 g (91%) of the title product 32 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.28-7.24 (m, 2H), 7.18-7.15 (m, 3H), 7.04 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H), 1.98 (s, 2H), 1.95 (s, 2H), 1.28 (s, 2H), 0.93 (s, 6H), 0.92 (s, 6H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)N>C(O)C>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[N:2]=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Solvent: CCO
Product: N#Cc1ccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-hydrazino-benzonitrile in ethanol as solvent according to the method described for example 43. MS: M=424.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][C:9]=2[S:18]([C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])(=[O:20])=[O:19])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[S:18]([C:21]([F:26])([F:25])[CH:22]([F:23])[F:24])(=[O:19])=[O:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(S(=O)(=O)C(F)(F)C(F)F)c(-c2ccc(Cl)cc2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(S(=O)(=O)C(F)(F)C(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 0 °C
Yield: 129.6 %

Procedure:
A solution of ethyl 5-(p-chlorophenyl)-4-[(1,1,2,2-tetrafluoroethyl)sulfonyl]pyrrole-2-carboxylate (0.54 g, 0.0012 mol) in ethanol is treated under nitrogen with a solution of sodium hydroxide (0.26 g, 0.0065 mol) in water. The reaction mixture is refluxed for three hours, poured into ice-water, treated with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a gum (0.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.[N:39]1([CH2:45][C:46]([N:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:47])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:42]3[CH2:41][CH2:40][N:39]([CH2:45][C:46](=[O:47])[N:48]4[CH2:49][CH2:50][CH2:51][CH2:52]4)[CH2:44][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:31])([CH3:32])[C:33]#[N:34])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 20% methanol in carbon dioxide). LR-MS: 729.4 [(M+H)+]
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:15].[C-:20]#[N:21].[Na+].Cl>CS(C)=O>[C:20]([CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])#[N:21]
Reactant: O=C1CCCC(=O)C1Cc1ccccc1CCCCl
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCc1ccccc1CC1C(=O)CCCC1=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A mixture of 22 g (0.079 mol) of 2-[2-(3-chloropropyl) benzyl ]- 1,3-cyclohexanedione 3 and 15.5 g (0.316 mol) of NaCN in 250 ml of dry dimethyl sulfoxide was stirred at 95 ° C for 3 hours. The reaction was filtered while hot to remove NaCl, and the dimethyl sulfoxide was distilled out under high vacuum. The residue was dissolved in 400 ml H2O, filtered through a diatomaceous earth filter aid (celite) to give a red solution and neutralized by the rapid addition of 40 ml concentrated HCl. The precipitate was recrystallized twice from ethyl acetate to give 16 g of the cyanodione, IIa, mp 143° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])(C)C)=[O:16])[CH2:3]1.CO.Cl>C(Cl)(Cl)Cl>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:21]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
The mixture of 6.0 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate, 120 ml of methanol, 40 ml of chloroform and 20 ml of 2M HCl is stirred at 60° C. over 20 hours. The reaction mixture is cooled and the organic solvent is evaporated off. The resulting aqueous solution is admixed with stirring with 80 ml of saturated sodium hydrogencarbonate solution and 80 ml of ethyl acetate. The biphasic mixture is cooled to 0° C. and admixed slowly with 3.30 ml of benzyl chloroformate and stirred over a further 2 hours. The reaction mixture is extracted with ethyl acetate-tetrahydrofuran. The organic phases are concentrated by evaporation and the title compound is obtained as a white solid from the residue by means of crystallization (ethyl acetate-heptane). Rt=5.72.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1cccc(CN=C=O)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(Cc3cccc(C)c3)c(=O)n(C3CCCC3)c12
Yield: 43.3 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(3-methyl-benzyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (18 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanatomethyl-3-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:17]([CH3:18])=[C:16]2[C:11]([CH2:12][CH2:13][C@@H:14]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]([Li])([CH2:31]C)[CH3:30].C(Br)C=C>O1CCCC1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:17]([CH2:18][CH2:31][CH:29]=[CH2:30])=[C:16]2[C:11]([CH2:12][CH2:13][C@@H:14]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:15]2)=[CH:10][CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Reactant: [Li]C(C)CC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCCc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of (2S)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-8-methyl-chroman-7-yl]-carbamic acid tert-butyl ester (0.41 g, 1.0 mmole) in anhydrous tetrahydrofuran (20 mL) containing 0.010 g of 1,10-phenanthroline at −40° C. was slowly added 2.4 equivalents of 1.3 M s-butyl lithium. After 1 equivalent of s-butyl lithium had been added, the deep red color of the indicator became apparent. The reaction was allowed to stand for 1.5 hours after which allyl bromide (0.24 g, 2.0 mmole) was added. After an additional 4 hours the reaction was quenched with water (4 mL). The reaction mixture was diluted with ether (250 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated and the solvent removed under vacuum. Column chromatography on silica gel (5% ethyl acetate/hexane) afforded 0.38 g (85%) of the title compound as an oil, [M+H]+: 448, [α]25D=+34.0° (c=1.03, THF).
Reaction SMILES: [C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])(OCC)=[O:2].O.[NH2:30][NH2:31].[OH:32][S:33]([OH:36])(=[O:35])=[O:34]>C(O)C>[S:33]([OH:36])([OH:35])(=[O:34])=[O:32].[NH:30]([C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])=[O:2])[NH2:31]
Reactant: NN
Reactant: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CN(C)CCC(=O)NN)[C@@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
Compound 13a (115 mg, 0.29 mmol) was dissolved in 10 mL of anhydrous ethanol and hydrazine monohydrate (73 mg, 0.07 mL, 1.46 mmol) was added to the solution. The reaction mixture was heated to reflux overnight. Hydrazine monohydrate (0.07 mL) was added again and heating was continued overnight. The resulting solution was evaporated to dryness. The crude product was purified by column chromatography (4:1:0.5 chloroform:methanol:NH4OH). The desired fractions were collected, concentrated, and dried in vacuo to yield a sticky solid. The product was dissolved in 8 mL of EtOH and 2N H2SO4 was added drop wise. The salt that was precipitated out was filtered and washed with EtOH. This salt, which was hygroscopic in nature, was dissolved in water (2 mL) and lyophilized to give a white solid: yield 71 mg (65%), MS: m/z 381 (M+H)+; 1HNMR (D2O) δ 8.44 (s, 1H, H-2), 6.09 (d, 1H, H-1′, J1′,2′=5.6 Hz), 5.10 (dd, 1H, H-2′, J2′,3′=4.5 Hz), 4.53-4.62 (bm, 2H, H-3′, H-4′), 3.86-3.94 (m, 1H, 5′-CH2), 3.52-3.66 (m, 3H, 5′-CH2, N(CH3)—CH2), 2.95 (s, 3H, N—CH3), 2.86 (t, 2H, NHCO—CH2), 2.70 (s, 3H, 8-CH3); UV λmax, nm, pH 1, 258.4 (∈ 15,000), pH 7, 259.3 (∈ 15,200), pH 13, 260.4 (∈ 15,700). Anal. (C15H24N8O4.2.0H2SO4.2.7H2O) C, H, N, S.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:6][CH:7]=1.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:18][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[N:6][CH:7]=1
Reactant: CC(C)CN
Reactant: CC(C)(C(=O)O)c1ccc(Br)cn1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cn1
Yield: 32 %

Procedure:
Prepared in a similar manner to example 27 from 2-(5-bromopyridin-2-yl)-2-methylpropanoic acid (example 46b) and isobutyl amine. Yield 32%. MS+H (301).