Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC[C:6]([C@:8]1([OH:30])[C@:24]2([CH3:25])[C@H:11]([C@H:12]3[C@:21]([F:27])([C@@H:22]([OH:26])[CH2:23]2)[C@:20]2([CH3:28])[C:15](=[CH:16][C:17](=[O:29])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)=[O:7])(=O)C.[OH-].[Na+].Cl.I(O)(O)(O)(O)(O)=[O:35]>CO.O>[F:27][C@@:21]12[C@:20]3([CH3:28])[C:15](=[CH:16][C:17](=[O:29])[CH2:18][CH2:19]3)[CH2:14][CH2:13][C@H:12]1[C@H:11]1[C@@:24]([CH3:25])([C@@:8]([OH:30])([C:6]([OH:35])=[O:7])[CH2:9][CH2:10]1)[CH2:23][C@@H:22]2[OH:26]
Reactant: [O-][I+](O)(O)(O)(O)O
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CC[C@](O)(C(=O)O)[C@@]3(C)C[C@H](O)[C@@]12F
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
In a 1000 mL round-bottomed flask was suspended 2-((8S,9R,10S,11S,13S,14S,17R)-9-fluoro-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate (Fludrocortisone-21-acetate, 22.8 g, 53.97 mmol) in MeOH (200 mL) and the suspension was degassed with nitrogen. 2M sodium hydroxide (40.5 mL, 80.95 mmol) was added to the solution and the mixture was stirred for 10 minutes. To the solution was added 4M HCl (20 ml, 80 mmol) and MeOH was removed in vacuo. The obtained residue was dissolved in THF (200 ml), a solution of orthoperiodic acid (15.99 g, 70.16 mmol) in water (40 ml) was added at room temperature and the obtained mixture was stirred for 1 hour. 100 ml of water was added and the organic solvent was removed in vacuo. An additional 100 ml of water was added to the aqueous residue and the obtained solid was collected by filtration, was washed with water (2×200 ml) and was air dried on the sinter, followed by drying in vacuo to yield 20 g of the desired compound as an off-white solid. APCI-MS m/z: 367 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([OH:8])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[C:24](=[O:26])=[O:25]>C1COCC1.O>[O:8]=[C:5]1[NH:6][CH:7]=[C:2]([C:24]([OH:26])=[O:25])[CH:3]=[C:4]1[C:9]([F:12])([F:11])[F:10]
Reactant: O=C=O
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1c[nH]c(=O)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (0.960 g, 3.97 mmol, Aldrich) in THF (20 mL) at −78° C. under N2 was slowly added n-butyllithium solution, 1.6 M in hexane (5.45 mL, 8.73 mmol). After addition, the mixture was stirred at −78° C. for 30 min. Then, dry ice was added and the mixture was stirred at −78° C. for 30 min and at rt for 30 min. Water (20 mL) was then added slowly, and the mixture was stirred at rt for 15 min. The aqueous phase was collected and acidified (pH=5-6) using concentrated HCl. The mixture was extracted with EtOAc (3×15 mL). The combined organic layers were dried (MgSO4), concentrated, and dried in vacuo to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 208 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:10][C:9](=[O:11])[CH2:8]2)[CH:2]=1.[H-].[Na+].[Cl-].[NH4+].O1CCC[CH2:17]1>>[CH3:17][N:10]1[CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:8][C:9]1=[O:11]
Reactant: C1CCOC1
Reactant: O=C1CC(c2cccnc2)N1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: CN1C(=O)CC1c1cccnc1
Temperature: 0 °C

Procedure:
To a solution of 0.105 g (0.71 mmole) 4-(pyridin-3-yl)azetidin-2-one in 5 ml of dry tetrahydrofuran at stirring under argon atmosphere 0.113 g (2.83 mmole) 60% dispersion of sodium hydride in mineral oil was added. After the sparkling ceased at stirring and ice cooling 0.066 ml (0.150 g, 1.06 mmole) iodomethane was added and stirred for 2 hours. Carefully 10 ml of saturated aqueous ammonium chloride solution was added and stirred for 10 minutes. The reaction mixture was filtered and the aqueous solution was extracted with 5×10 ml of chloroform and the combined solutions were dried over magnesium sulfate and evaporated on rotavapor at 35° C. The residue (0.112 g) was purified by column chromatography on 10 g of silica gel with benzene-diethylamine 8-2 furnishing 0.0674 g (59%) pure product.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:34]1([P:40]([CH2:47][SH:48])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.C(OCC)(=O)C>[C:34]1([P:40]([CH2:47][S:48][C:6](=[O:8])[CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: SCP(c1ccccc1)c1ccccc1
Reactant: CC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)SCP(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
N-Acetylglycine (1.90 g, 16.2 mmol) was dissolved in anhydrous DMF (75 mL). HOBt (2.48 g, 16.2 mmol) was added to the resulting solution followed by DCC (3.34 g, 16.2 mmol). Once precipitate (DCU) was observed, phosphinothiol 1b was added (3.77 g, 16.2 mmol). The reaction mixture was allowed to stir under Ar(g) for 3 h. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a white solid. This solid was dissolved in ethyl acetate and purified by flash chromatography (silica gel, ethyl acetate). Compound 51 was isolated in 96% yield. Spectral Data. As reported previously
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][C:20]=1[CH3:35].COC1C(S(C)CC2C=CC(C3C=CC(C(F)(F)F)=CC=3)=CC=2)=CC(C)=C(C=1)OCC(O)=O>>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[CH:21][C:20]=2[CH3:35])=[CH:8][C:7]([CH3:15])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:2])=[O:16]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Agent: COc1cc(OCC(=O)O)c(C)cc1[SH](C)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C

Procedure:
Preparation of (3-Methyl-4′-trifluoromethyl-biphenyl-4-yl)-methanol (compound 39A) The title compound was prepared in the manner analogous to Example 3A using (4-bromo-2-methyl-phenyl)-methanol and 4-(trifluoromethyl)benzeneboronic acid. MS m/z 249 (M-OH). Step 2. Preparation of 4chloromethyl-3-methyl-4′-trifluoromethyl-biphenyl (compound 39B) The title compound was prepared in the manner analogous to Example 3B using 39A. 400 MHz 1H NMR (DMSO-d6) δ 7.84 (d, 2H, J=8.3 Hz), 7.76 (d, 2H, J=8.3 Hz), 7.57 (s, 1H), 7.48 (m, 2H), 4.80 (s, 2H), 2.41 (s, 3H). Step 3. Preparation of [5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 39C) The title compound was prepared in the manner analogous to Example 1F using 1D and 39B. MS m/z 491 (M+1). Step 4. Preparation of [5-Methoxy-2-methyl-4-(methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid (compound 39) The title compound was prepared in the manner analogous to Example 1 using 39C. IR cm−1: 1740, 1322; 400 MHz 1H NMR (DMSO-d6) δ 7.81 (d, 2H, J=8.1 Hz), 7.73 (d, 2H, J=8.1 Hz), 7.51 (s, 1H), 7.39 (d, 1H, J=7.8 Hz), 7.16 (d, 1H, J=7.8 Hz), 7.04 (s, 1H), 6.53 (s, 1H), 4.71 (s, 2H), 4.00 (s, 2H), 3.73 (s, 3H), 2.39 (s, 3H), 2.02 (s, 3H); MS m/z 477 (M+1). Anal. Calc'd for C25H23F3O4S.0.1 H2O; C, 62.78; H, 4.89; found: C, 62.57; H, 4.82.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([NH:3][CH2:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:2]
Reactant: CCNCC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCNCC1CCNC1
Reaction time: 24 h
Yield: 74.6 %

Procedure:
A mixture of 151.6 g (0.69 mole) of N-ethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 5 g of 20% palladium on carbon, and 1100 ml of ethanol was shaken in an atmosphere of hydrogen at about 4.5×105Pa and at room temperature for 21.6 hours. Another 5 g of 20% palladium on carbon was added and the hydrogenation continued for 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure. The residue was distilled under vacuum (88-91° C., 11.5 mm Hg) to give 66.0 g N-ethyl-3-pyrrolidinemethanamine.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:29](=[O:32])[NH:30][CH3:31])[CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:33][CH3:34])=[O:10])(C)(C)C.[Cl:44]CCCl>Cl.O1CCOCC1>[ClH:44].[NH2:7][CH:8]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:29]([NH:30][CH3:31])=[O:32])[CH2:13][CH:12]1[CH2:33][CH3:34])=[O:10]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reactant: ClCCCl
Agent: Cl
Solvent: C1COCCO1
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(N)Cc1ccc(F)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
[2-[2-Ethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 40, is dissolved in 4M HCl in dioxane (20 mL). The reaction mixture is stirred for 1 hour, then 1,2-dichloroethane (20 mL) is added. Solvent is removed in vacuo to afford 1.1 g (99% yield) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=[CH:6][C:7]=1[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[S:21].O>CN(C)C=O>[OH:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([N:8]2[C:7]3[CH:6]=[CH:5][C:4]([C:16]([F:17])([F:18])[F:19])=[CH:3][C:2]=3[NH:1][C:20]2=[S:21])[CH2:10][CH2:11]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(C(F)(F)F)ccc1N[C@H]1CC[C@H](O)CC1
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H]1CC[C@H](n2c(=S)[nH]c3cc(C(F)(F)F)ccc32)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-amino-4-(trans-4-hydroxycyclohexylamino)benzotrifluoride (300 mg) in N,N-dimethylformamide (3 mL) was added 1,1′-thiocarbonyldiimidazole (234 mg), and the mixture was stirred at room temperature under nitrogen atmosphere for 15 hours. Water was added to the mixture, and the resulting precipitate was collected by filtration. The obtained solid was washed successively with water and diethyl ether to give 1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-2,3-dihydro-1H-benzimidazol-2-thione (242.8 mg) as a pale brown solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]=1[CH2:10][CH3:11])=[O:4].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([NH2:28])[CH:22]=1>CCO>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([NH:28][CH2:2][C:3]([C:5]2[CH:6]=[N:7][N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]=2[CH2:10][CH3:11])=[O:4])[CH:22]=1
Reactant: CCc1c(C(=O)CBr)cnn1-c1ccccc1
Reactant: COC(=O)c1ccc(C)c(N)c1
Solvent: CCO
Product: CCc1c(C(=O)CNc2cc(C(=O)OC)ccc2C)cnn1-c1ccccc1
Reaction time: 6 h
Yield: 40.4 %

Procedure:
A solution of 7.20 g (24.6 mmol) of 2-bromo-1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone and 8.52 g (51.6 mmol) of 3-amino-4-methyl benzoic acid methyl ester in EtOH (30 mL) was heated to 75° C. for 16 h. The solution was cooled and allowed to stand at rt for 6 h. The solids were filtered off and washed with cold EtOH to provide 3-[2-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethylamino]-4-methyl-benzoic acid methyl ester as a white powder (3.75 g). ESI MS m/z 378 [C22H23N3O3+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][S:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:8]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)N1CCCCC1)CN2
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)N1CCCCC1)CN2Cc1ccccc1

Procedure:
The title compound was prepared from 155A and benzaldehyde by procedures analogous to those described in Example 22A. HPLC: 99% at 7.2 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 411 [M+1]+. Chiral HPLC 100% e.e.; retention time 29.7 min; Conditions: AD (4.6×250 mm); Eluted with 25% isopropanol in hexane for 60 min at 11 mL/min.
Reaction SMILES: [CH2:1]([C:4]1([O:17][CH2:18][CH:19]=[CH2:20])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)C=C>ClCCl.C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[O:17]1[C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]2)[CH2:1][CH:20]=[CH:19][CH2:18]1
Reactant: C=CCOC1(CC=C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC=CCO2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Solutions of 1,1-dimethylethyl 4-(2-propenyl)-4-(2-propenyloxy)-1-piperidinecarboxylate (Description 130, 4.9 g, 17.4 mmol) in dichloromethane (1.2 L) and bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (717 mg, 0.87 mmol) in dichloromethane (1.2 L) were added dropwise simultaneously to dichloromethane (600 mL) over a period of 8 hours, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with 9:1 isohexane:ethyl acetate, to give the title compound (3.3 g, 75%). m/z (ES+) 254 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:13])[NH:7]2.[N-]=[N+]=[N-].[Na+].[C:18]([O-])(O)=O.[Na+]>CS(O)(=O)=O>[Br:1][C:2]1[C:3]2[CH2:18][CH2:4][CH2:5][C:6](=[O:13])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc2c(c1Br)CCC(=O)N2
Reactant: O=C([O-])O
Agent: CS(=O)(=O)O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccc2c(c1Br)CCCC(=O)N2

Procedure:
5-Bromo-6-methyl-3,4-dihydroquinolin-2(1H)-one (477.7 mg, 1.998 mmol) was treated with NaN3 (194.8 mg, 0.938 mmol, 1.5 equiv) in MeSO3H (3 g) at 0° C. to room temperature for 1 h. The mixture was neutralized with NaHCO3 and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure and the crude product was recrystallized from EtOAc (10 mL) to give 6-bromo-7-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:11])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>CS(C)=O>[CH3:18][O:11][C:2]([CH3:1])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(O)(C(=O)c1ccccc1)c1ccccc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(C)(C(=O)c1ccccc1)c1ccccc1
Yield: 80 %

Procedure:
5.7 g (2.5 . 10-2 mol) α-methyl-benzoin are reacted in 50 ml DMSO at room temperature with 5 g (2.8 . 10-2 mol) p-toluene-sulphonic acid methyl ester in the presence of 11 ml of a 10% by weight sodium hydroxide solution. The crude product is filtered through silica gel/petroleum ether and yields, besides 0.95 g (17% of theory) of educt, 4.8 g (80% of theory) α-methyl-benzoin methyl ether of m.p. 36° - 38°C (petroleum ether).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[N:10]=1.Br[C:32]1[CH:33]=[C:34](OC)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].BrCCCCCC>C(OCCO)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:34][CH2:33][CH2:32][CH2:37][CH2:36][CH3:35])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[N:10]=1
Reactant: COc1cccc(-c2nc(-c3cccc(OC)c3)nc(-c3ccc(O)cc3O)n2)c1
Reactant: COc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCCO
Solvent: CCCCCCBr
Product: CCCCCCOc1ccc(-c2nc(-c3cccc(OC)c3)nc(-c3cccc(OC)c3)n2)c(O)c1
Reaction time: 1 h

Procedure:
10 g (0.025 mol) of 2-(2,4-dihydroxyphenyl)-4,6-bis(3-methoxyphenyl)-1,3,5-triazine (prepared by the method of Example 8 starting from 3-bromoanisole), 3.8 g of potassium carbonate and 30 mg of potassium iodide are heated in 25 ml of 2-ethoxyethanol at 110 C. for one hour, followed by dropwise addition of 6.7 g (0.041 mol) of 1-bromohexane and stirring at 110 C. for a further 32 hours. After cooling, the mixture is filtered, the solid material is washed neutral with water and then washed with methanol and dried. The crude product is purified by column chromatography (250 g SiO2 35-70 μm; eluent toluene/petroleum ether 1:1). This gives the compound of formula ##STR24##
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])[CH2:4][C:3]1=[O:18].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([O:11][C@@H:46]2[CH:47]3[CH2:50][CH2:51][N:44]([CH2:49][CH2:48]3)[CH2:45]2)=[O:10])[CH2:4][C:3]1=[O:18]
Reactant: CN1CCN(C(C(=O)O)c2ccccc2)CC1=O
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1CCN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
2-(4-Methyl-3-oxopiperazin-1-yl)-2-phenylacetic acid (170 mg, 0.68 mmol) was suspended in dry THF (6 ml) and DCC (283 mg, 1.37 mmol), HOBT (185 mg, 1.37 mmol) and (R)-quinuclidin-3-ol (174 mg, 1.37 mmol) were sequentially added. The reaction was stirred at room temperature for two days and then the insoluble was filtered off. The solution was evaporated and the residue was purified by flash chromatography (DCM/MeOH/NH4OH=96/4/0.4) to obtain (R)-quinuclidin-3-yl 2-(4-methyl-3-oxopiperazin-1-yl)-2-phenylacetate (175 mg, 54.1% yield over 2 steps) as a off-white spongy solid
Reaction SMILES: IC1C=CC([C:8]23[O:15][CH2:14][C:11]([CH2:16][CH2:17][CH3:18])([CH2:12][O:13]2)[CH:10]([C:19]([F:22])([F:21])[F:20])[O:9]3)=CC=1.C(C12COC(C3C=CC(C#CCOC)=CC=3)(OC1)OC2)(C)(C)C>>[CH2:16]([C:11]12[CH2:14][O:15][CH:8]([O:13][CH2:12]1)[O:9][CH:10]2[C:19]([F:20])([F:21])[F:22])[CH2:17][CH3:18]
Reactant: CCCC12COC(c3ccc(I)cc3)(OC1)OC2C(F)(F)F
Agent: COCC#Cc1ccc(C23OCC(C(C)(C)C)(CO2)CO3)cc1
Product: CCCC12COC(OC1)OC2C(F)(F)F

Procedure:
1-[4-(3-Methoxyprop-1-ynl)phenyl[-4-n-propyl-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane was prepared from 1-(4-iodophenyl)-4-n-propyl-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane and methyl propargyl ether using the methodology described in Example 3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:51]3[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)=[O:26])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[N:19][CH:18]=3)=[O:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (11 mg, 0.030 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol), 1-hydroxybenzotriazole hydrate (4.7 mg, 0.030 mmol), and CH2Cl2 (2 mL) were added piperidine (3.9 mg, 0.046 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:26]Br>>[CH3:22][C:23]1[CH:30]=[C:29]([CH:28]=[C:25]([CH3:26])[CH:24]=1)[CH2:31][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1cc(C)cc(CBr)c1
Product: Cc1cc(C)cc(Cn2c(C(=O)c3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)c1
Yield: 79.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dimethylbenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (322 mg, yield: 79.5%).
Reaction SMILES: C([N:8]1[CH2:23][CH2:22][C:11]2([N:15]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][NH:13][C:12]2=[O:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:19][CH:18]([CH3:20])[CH2:17][CH2:16][N:15]1[C:11]2([CH2:22][CH2:23][NH:8][CH2:9][CH2:10]2)[C:12](=[O:21])[NH:13][CH2:14]1
Reactant: [H][H]
Reactant: CC(C)CCN1CNC(=O)C12CCN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Product: CC(C)CCN1CNC(=O)C12CCNCC2

Procedure:
A solution of 130 mg (0.412 mmol) 8-benzyl-1-(3-methyl-butyl)-1,3,8-triaza-spiro[4.5]decan-4-one in 2 ml methanol was debenzylated with hydrogen in presence of 30 mg 10% Pd/C at ambient temperature over night. Then the reaction mixture was filtered through a silica gel pad and the filtrate evaporated: 70 mg 1-(3-methyl-butyl)-1,3,8-triaza-spiro[4.5]decan-4-one as colorless solid: m.p. 103–105° C., MS (ISP): 226.3 MH+.
Reaction SMILES: S(O)(O)(=O)=O.CS[C:8](=[NH:10])[NH2:9].[OH-].[Na+].[N:13]1([CH2:20][C:21]2[S:22][C:23]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:25]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[C:8]([N:28]([C:26]([C:23]1[S:22][C:21]([CH2:20][N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:25][CH:24]=1)=[O:27])[NH2:29])(=[NH:9])[NH2:10]
Reactant: CSC(=N)N
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)N(N)C(=O)c1ccc(CN2CCCCCC2)s1
Temperature: 25 °C
Reaction time: 240 h
Yield: 114.2 %

Procedure:
6.07 g (21.7 mmol) of S-methylisothiourea sulfate and 43.5 ml (43.5 mmol) of 1 N NaOH were added to 11.0 g (43.4 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide, methanol was added to the reaction mixture until it became uniform solution (about 130 ml) and then the resulting solution was stirred at room temperature for 10 days. After removing insoluble matter by filtration, the solvent was evaporated and the resulting residue was directly subjected to a silica gel column chromatography, which was eluted with chloroform-methanol-aqueous ammonia (40:10:1) to give 7.32 g of the title compound.