Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([C:19]([CH2:21][C:22](OCC)=[O:23])=O)([F:18])([F:17])[F:16].CS(O)(=O)=O>>[CH2:1]([C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[O:14][C:22](=[O:23])[CH:21]=[C:19]2[C:15]([F:18])([F:17])[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: CS(=O)(=O)O
Product: O=c1cc(C(F)(F)F)c2cc(Cc3ccccc3)ccc2o1
Temperature: 65 °C
Yield: 44.3 %

Procedure:
A stirred suspension of 4-benzylphenol (4.67 g, 25.4 mmol), CF3COCH2CO2Et (7.00 g, 38.0 mmol), & MeSO3H (8.5 mL, 130.9 mmol) was heated at 65° C. for 9 h. On cooling, the mixture was partitioned between Et2O (200 mL) & H2O (50 mL), then the aqueous phase was basicified with 2 M NaOH. The organic layer was separated & washed with H2O & brine, before being dried (MgSO4). Filtration, solvent evaporation, & column chromatography (4:1 PE-Et2O) furnished 6-benzyl4-trifluoromethylchromen-2-one (3.42 g, 44%): δH (CDCl3)=4.10 (s, 2H), 6.85 (s, 1H), 7.20–7.40 (m, 5H), 7.45 (dd, 1H), 7.60 (d, 1H). This compound (2.00 g, 6.6 mmol) was dissolved in H2SO4 (20 mL), then the whole was stirred for 15 min. The mixture was carefully treated with crushed ice (80 g), then the resulting white precipitate was collected by filtration. The precipitate was air-dried, before being treated with hot THF (100 mL). After filtration, the filtrate was concentrated to yield 4-(2-oxo-4-trifluoromethyl-2H-chromen-6-ylmethyl)benzenesulfonic acid (2.20 g, 87%): δH ((CD3)2SO)=4.05 (s, 2H), 7.00 (s, 1H), 7.20 (d, 2H), 7.45 (d, 1H), 7.50–7.60 (m, 4H). This compound was reacted with (COCl)2, as described above in Preparation 1, to give a solid which was dissolved in EtOAc, before being filtered & concentrated to produce the title compound (2.30 g, 87%): Rf (2:1 PE-EtOAc)=0.60.
Reaction SMILES: [NH2:1][C:2]1([C:9]([OH:11])=O)[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2.N[C:13]1([CH2:20]O)[CH2:18]C2C[CH:14]1CC2.NO.C(Br)C(C)C>CN(C=O)C>[CH2:14]([NH:1][C:2]1([CH2:9][OH:11])[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2)[CH:13]([CH3:20])[CH3:18]
Reactant: NC1(CO)CC2CCC1C2
Reactant: NC1(C(=O)O)CC2CCC1C2
Agent: NO
Solvent: CN(C)C=O
Solvent: CC(C)CBr
Product: CC(C)CNC1(CO)CC2CCC1C2

Procedure:
2-Aminonorbornane-2-carboxylic acid was converted into 2-amino-2-(hydroxymethyl)norbornane as a diastereomeric mixture in a manner analogous to Method B1a. A solution of the amino alcohol (0.31 g, 2.16 mmol) and isobutyl bromide (0.23 ml, 2.16 ml) in DMF (3 mL) was heated at 90° C. for 92 h, then cooled to room temp. and partitioned between EtOAc (100 mL) and a saturated NaHCO3 solution (100 mL). The organic layer was washed with a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure to yield 2-(isobutylamino)-2-(hydroxymethyl)norbornane as a diastereomeric mixture (0.24 g, 55%): GC-MS m/z 197 (M+).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].N1(C2C=C3C(=CC=2)NC(=O)CC3)CCNCC1.[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46]>CN(C=O)C.O.C(N(CC)CC)C>[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:3][CH2:4]1)=[O:46]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(N3CCN(C(=O)c4cccc(Cl)c4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril monohydrobromide (1 g) was suspended in 15 ml of DMF. After adding 296 mg of sodium hydrogencarbonate, the suspension was stirred at room temperature for 30 minutes to convert the starting compound to 6-(1-piperazinyl)-3,4-dihydrocarbostyril. Then, to the mixture was added 0.62 ml of triethylamine and the mixture was stirred at room temperature while slowly adding dropwise 5 ml of DMF solution containing 532 mg of m-chlorobenzoyl chloride. After completion of addition the reaction mixture was stirred for at room temperature 1 hour. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 0.4 g of 6-[4-(3-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 197°-197.5° C., colorless scales.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH:8]([OH:11])([CH3:10])[CH3:9]>>[CH:8]([O:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[OH:7])([CH3:10])[CH3:9]
Reactant: C1CCC2OC2C1
Reactant: CC(C)O
Product: CC(C)OC1CCCCC1O
Yield: 84.1 %

Procedure:
Cyclohexene oxide (9.8 g, 0.1 mole) was added dropwise to a refluxing mixture of isopropanol (2 moles) in which was suspended acidified Fullers' earth (Fulcat 22B) (1% w/w) as catalyst. Immediately thereafter the catalyst was removed by filtration and the product was stripped of isopropanol by distillation. The residue was fractionated to yield 13.3 g of 2-isopropoxy cyclohexanol (yield 90% based upon cyclohexene oxide).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=[C:12]([C:34]3[CH2:39][CH2:38][CH:37]([O:40][Si](C(C)(C)C)(C)C)[CH2:36][CH:35]=3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[NH:14][CH:13]=[C:12]([CH:34]3[CH2:35][CH2:36][CH:37]([OH:40])[CH2:38][CH2:39]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[NH:14][CH:13]=[C:12]([CH:34]3[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ncc2c(n1)c(C1=CCC(O[Si](C)(C)C(C)(C)C)CC1)cn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCNc1ncc2[nH]cc(C3CCC(=O)CC3)c2n1
Product: CCCCNc1ncc2[nH]cc(C3CCC(O)CC3)c2n1
Reaction time: 4 h

Procedure:
A solution of N-Butyl-7-(4-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)-5-trityl-5H-pyrrolo[3,2-d]pyrim-idin-2-amine (992 mg, 1.54 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (5.0 mL). The reaction mixture was stirred for 4 hours and quenched by a saturated aq. solution of NaHCO3 and diluted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue was dissolved in MeOH (6.0 mL) and Pd/C (44 mg) was added. The reaction mixture was then stirred under the hydrogen atmosphere for 12 hours and then filtered. The filtrate was concentrated to afford a brown residue. A solution of the residue in CH2Cl2 (10 mL) was added a mixture of PCC (665 Mg, 3.084 mmol) and silica gel (668 mg). After 30 min, the reaction was quenched with water and extracted with EtOAc (3×). The combined organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product 4-(2-(butylamino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexanone (MS m/z 287.2 [M+H]+). A solution of 4-(2-(butylamino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexanone in MeOH (10 mL) was added NaBH4 (67 mg, 1.71 mmol) slowly at −40° C. The reaction was quenched with water after 1 h and extracted with EtOAc (3×). The combined organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product which was used without further purification. MS m/z 289.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17]CN3C(=O)N4C=CC=CC4=N3)[CH2:14][CH:15]=2)=[CH:2]1.[O:29]=[C:30]1[N:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]2=[N:32][N:31]1CCOS(C1C=CC(C)=CC=1)(=O)=O.N1CCC(C2C3C(=CC=CC=3)NC=2)CC1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:31]3[C:30](=[O:29])[N:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]4=[N:32]3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: O=c1n(CCCN2CC=C(c3c[nH]c4ccccc34)CC2)nc2ccccn12
Reactant: Cc1ccc(S(=O)(=O)OCCn2nc3ccccn3c2=O)cc1
Agent: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: O=c1n(CCN2CCC(c3c[nH]c4ccccc34)CC2)nc2ccccn12

Procedure:
2-{2-[4-(1H-Indol-3-yl)-piperidin-1-yl]-ethyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one was prepared in a similar fashion to of 2-{2-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (example 22) using of toluene-4-sulfonic acid 2-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2-yl)-ethyl ester and 3-Piperidin-4-yl-1H-indole. Yield: 70 mg of compound was obtained (39%). mp: 142° C.; M+: 362.1; H-NMR: 8.14 (b, 1H, NH), 7.74 (m, 1H), 7.62 (m, 1H), 7.35(m, 1H), 7.08 (m, 5H), 6.94 (m, 1H), 6.45 (m, 1H), 4.23 (m, CH2), 3.13 (d, CH2), 2.93 (m, CH2), 2.82 (m, 1H) 2.28 (t, CH2), 2.04(m, CH2), 1.86(m, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:40])[CH2:17][CH:16]([CH2:18]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:15][CH:14]2[CH:10]1[CH2:11][N:12]([C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])[CH2:13]2.[Br-:41].[Li+]>CC(C)=O>[Br:41][CH2:18][CH:16]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:29](=[O:39])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[CH2:13]2)[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])([OH:40])[CH2:17]1
Reactant: [Br-]
Reactant: COc1ccccc1CC(=O)N1CC2CC(CS(=O)(=O)c3ccc(C)cc3)CC(O)(c3ccccc3OC)C2C1
Agent: [Li+]
Solvent: CC(C)=O
Product: COc1ccccc1CC(=O)N1CC2CC(CBr)CC(O)(c3ccccc3OC)C2C1
Yield: 65.7 %

Procedure:
A solution of 1.16 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-6-tosylmethylperhydroisoindol-4-ol and 0.345 g of anhydrous lithium bromide in 60 cm3 of acetone is heated at reflux for 18 hours and then concentrated to reduced volume (10 cm3). Following the addition of 20 cm3 of water, the mixture is subjected to extraction with 40 cm3 of ethyl acetate, washed with 20 cm3 of water and then dried over magnesium sulphate. After concentration to dryness under reduced pressure (2.7 kPa), the residue is washed with 20 cm3 of ethyl ether, drained and dried under reduced pressure (2.7 kPa). 0.66 g of (3aRS,4RS,6SR,7aSR)-6-bromomethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol is obtained in the form of a white solid. M.p.K =191° C.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7](OC)=[C:5]([OH:6])[CH:4]=1.[C:12]([O-:15])([O-])=O.[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1COCC1>[CH:18]1([O:6][C:5]2[CH:4]=[C:3]([CH:11]=[C:10]([O:15][CH3:12])[CH:7]=2)[CH:2]=[O:1])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C([O-])[O-]
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(C=O)cc(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 1-L flask equipped with a mechanical stirrer, nitrogen inlet, thermometer, and condenser, were charged with isovanillin (91.2 g, 0.60 mol, 1.0 equivalent) and THF (250 mL), followed by addition of Bu4NBr (19.3 g, 0.06 mol, 10 mol%, 0.10 eq.) and anhydrous K2CO3 (124 g, 0.90 mol, 1.5 eq.). The reaction mixture was stirred vigorously and heated to reflux (about 65 to about 75° C.). Cyclopentyl bromide (89.4 g, 0.60 mol, 1.0 eq.) was added dropwise and the mixture was stirred at refluxed for 6 hours. A second portion of cyclopentyl bromide (44.7 g, 0.30 mol, 0.5 eq.) was added dropwise and stirring and heating was continued for 6 hours. The reaction solution was monitored by TLC for completion, thereby cooled to room temperature, and any remaining solids removed by filtration. The filter pad was washed with THF (2×90 mL) to remove remaining 3-cyclopentyloxy-5-methoxybenzaldehyde on the filter pad. 3-Cyclopentyloxy-5-methoxybenzaldehyde was thereby isolated in THF and its purity verified using HPLC.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C@@H:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8][C:7]=2[CH:20]=1)=[O:2].CC(C)([O-])C.[K+].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br.O>CN(C=O)C>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C@H:10]2[CH2:9][CH2:8][C:7]3[CH:20]=[C:3]([CH:1]=[O:2])[CH:4]=[CH:5][C:6]=3[O:11]2)=[CH:14][CH:15]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=Cc1ccc2c(c1)CC[C@H](Cc1ccc(O)cc1)O2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)CC[C@H](Cc1ccc(OCc3cccc(F)c3)cc1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3,4-dihydro-6-formyl-2-(4-hydroxybenzyl)-2H-benzopyran (1.8 g, 6.7 mmol) in DMF (10 ml) at 0° C. was added potassium tertbutoxide (0.83 g, 7.4 mmol). After 30 minutes m-fluorobenzyl bromide (0.91 ml, 7.4 mmol) was added and the resulting slurry was warmed to room temperature and stirred for 2 hours. Water was added and the precipitate was collected, washed with water and air dried (2.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Reaction time: 0.5 h
Yield: 107.3 %

Procedure:
To a mechanically stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H -pyran-4-yl)amino)benzoate (15.3 g, 46.6 mmol) and acetaldehyde (7.90 mL, 140 mmol) in 1,2-dichloroethane (DCE) (150 mL) under nitrogen was added acetic acid (16.01 mL, 280 mmol). After 30 min, sodium triacetoxyborohydride (29.6 g, 140 mmol) was added to the reaction mixture. The reaction was stirred overnight, at which time the nitrogen was removed and acetaldehyde (7.90 mL, 140 mmol) was added. After 2 h, the reaction mixture was diluted with water and Na2CO3 (sat′d) and extracted with EtOAc (3×). The ethyl acetate layers were dried over Na2SO4, filtered, and concentrated to obtain methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (17.8 g, 50.0 mmol, 107% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (d, J=2.02 Hz, 1 H), 7.54 (d, J=2.27 Hz, 1 H), 3.89-3.73 (m, 5 H), 3.26 (td, J=11.56, 1.89 Hz, 2 H), 3.15-2.86 (m, 3 H), 3.36 (s, 3 H). 1.66-1.55 (m, 2 H), 1.55-1.36 (m, 2 H), 0.79 (t, J=6.95 Hz, 3 H). MS(ES) [M+H]+ 358, 356.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[C:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=1)([OH:13])=[O:12].Cl.[CH2:23](O)[CH3:24]>>[CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][C:7]2[C:18]3[C:17](=[CH:16][CH:15]=[C:14]([C:11]([O:13][CH2:23][CH3:24])=[O:12])[CH:19]=3)[NH:20][C:6]=2[CH2:5][CH2:4]1
Reactant: CCO
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CN(C)C1CCC(=O)CC1
Agent: Cl
Product: CCOC(=O)c1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3

Procedure:
A solution of 15.5 g. of 4-dimethylaminocyclohexanone and 15.2 g. of 4-carboxyphenylhydrazine in 200 ml. of 5-N hydrogen chloride in ethyl alcohol was refluxed for twentyfour hours and the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in water, the aqueous solution was made alkaline with dilute sodium hydroxide and extracted with methylene dichloride and the extract was evaporated to dryness under reduced pressure to give, after recrystallization from isopropyl alcohol, 17.8 g. of 3-(dimethylamino)-6-ethoxycarbonyl-1,2,3,4-tetrahydrocarbazole, m.p. 188°-190° C.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([C@@H:24]([NH2:27])[CH2:25][CH3:26])=[CH:20][CH:19]=1>>[CH3:12][C:8]1([CH3:11])[CH2:7][O:6][C:5]2([CH2:13][CH2:14][C:2]([CH2:15][CH2:16][NH:27][C@H:24]([C:21]3[CH:20]=[CH:19][C:18]([CH3:28])=[CH:23][CH:22]=3)[CH2:25][CH3:26])([OH:1])[CH2:3][CH2:4]2)[O:10][CH2:9]1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: CC[C@H](N)c1ccc(C)cc1
Product: CC[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(C)cc1
Yield: 55 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-p-tolyl-propylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 55% of theory; LC (method 5): tR=1.10 min; Mass spectrum (ESI+): m/z=376 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:17][S:18][CH2:19][C@@H:20]([NH2:22])[CH3:21].CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:9]([C:10]#[CH:11])=[C:8]([NH:22][C@@H:20]([CH3:21])[CH2:19][S:18][CH3:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CSC[C@H](C)N
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C#Cc1c(N[C@@H](C)CSC)ccc(C#N)c1Cl

Procedure:
A mixture of 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.120 g, 0.477 mmol), (S)-1-(methylthio)propan-2-amine (0.075 g, 0.715 mmol) (prepared essentially as described in US2005182275A1) and DIEA (0.166 mL, 0.953 mmol) in DMSO (2 mL) was heated (sealed tube) at 100° C. for 45 min. Upon cooling, the reaction mixture was diluted with EtOAc (25 mL) and washed with water (20 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to give the intermediate (S)-2-chloro-3-ethynyl-4-((1-(methylthio)propan-2-yl)amino)benzonitrile. This intermediate was dissolved in NMP (2 mL), treated with KOtBu (1 M in THF) (1.430 mL, 1.430 mmol) and heated at 60° C. The reaction was monitored by LCMS, and after 45 min, additional KOtBu (1 M in THF) (1.430 mL, 1.430 mmol) was added and heating continued for another 1 h. Upon cooling, the reaction mixture was diluted with EtOAc (25 mL) and washed with water (20 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 5-30% EtOAc-hexane gradient to give (S)-4-chloro-1-(1-(methylthio)propan-2-yl)-1H-indole-5-carbonitrile (0.056 g, 42% yield): MS (ESI): m/z 265 (M+H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][NH:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@H]2C[NH:22][C:21](=[O:24])[CH2:20]2)C=CC=CC=1>CO>[C:21]([CH2:20][N:10]1[CH2:11][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]1=[O:12])(=[O:24])[NH2:22]
Reactant: O=C1C[C@H](c2ccccc2)CN1
Reactant: O=C1C[C@@H](c2ccccc2)CN1
Solvent: CO
Product: NC(=O)CN1C[C@H](c2ccccc2)CC1=O

Procedure:
Substituting pyrrolidinone 1 in Example 1 by 4(S)-phenyl-2-pyrrolidinone (1a) S-enantiomeric N-carbamoylmethyl-4(S)-phenyl-2-pyrrolidinone (4a) was obtained. [α]D20=−8.3° (c=3, MeOH). 1H NMR (CDCl3), δ: 2.61 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (1H, quintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 and 6.21 (1H and 1H, br.s and br.s, NH2); 7.20-7.40 (5H, m, C6H5).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:25]2[C:30](Cl)=[N:29][CH:28]=[CH:27][N:26]=2)[NH:16][C:17](=O)[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C(NC(C2CCC2)=O)C2C(Cl)=NC=C[N:48]=2)C=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:26]3[CH:27]=[CH:28][N:29]=[C:30]([NH2:48])[C:25]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC1CCCC1)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCC1
Product: Nc1nccn2c(CC3CCCC3)nc(-c3cccc(OCc4ccccc4)c3)c12

Procedure:
N-[(3-Benzyloxyphenyl)-(3-chloropyrazin-2-yl)-methyl]-2-cyclopentyl-acetamide: Prepared according to the procedures for Cyclobutanecarboxylic Acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]Amide, White solid, MS (ES) 436.32 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([N:27](C(OCC(Cl)(Cl)Cl)=O)[C:28](OCC(Cl)(Cl)Cl)=[O:29])=[N:19]1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([NH:27][C:28]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:29])=[N:19]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ncccc12
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1noc2ncccc12)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 58.9 %

Procedure:
A mixture of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (738 mg, 3.00 mmol), bis(2,2,2-trichloroethyl) isoxazolo[5,4-b]pyridin-3-ylimidodicarbonate (486 mg, 1.00 mmol), diisopropylethylamine (0.348 ml, 2.00 mmol) and dimethyl sulfoxide (5 ml) was stirred at 70° C. for 5 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from tetrahydrofuran to yield 240 mg (59.0%) of the desired product.
Reaction SMILES: [BH3-][C:2]#[N:3].[Na+].N[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:7]=1.[CH2:25]=O>C(O)(=O)C>[CH3:25][N:3]([CH3:2])[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:7]=1
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1N
Reactant: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1N(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
According to Scheme 15 Step 2: NaBH3CN (7.26 mmol, 456 mg) was added to a solution of ethyl 3-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (3.63 mmol, 1.00 g) and formaldehyde (109 mmol, 8.84 g) in acetic acid (10 mL). The reaction mixture was stirred for 4 hours at room temperature and was then extracted with AcOEt. After neutralization of the aqueous phase, it was extracted with AcOEt. The organic phase was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10 to 0:100) as eluent to afford ethyl 3-(dimethylamino)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (1.98 mmol, 600 mg, 54%) as an oil.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([O:23]C)=[O:22])=[CH:12][CH:11]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>CO>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([OH:23])=[O:22])=[CH:12][CH:11]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc(C2CCCC2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc2ccccc2n1Cc1ccc(C2CCCC2C(=O)O)cc1
Yield: 62.6 %

Procedure:
A mixture of methyl 2-[4-[(2-propyl-1H-benzimidazol-1-yl)methyl]phenyl]cyclopentane-1-carboxylate (530 mg, 1.41 mmol), 1N NaOH (2.8 mL), and MeOH (5.0 mL) was heated under reflux for 6 h. The mixture was concentrated, diluted with water (10 mL), and extracted with ether (discarded). The aqueous phase was neutralized with 1N HCl (2.8 mL) and the white precipitate was collected by filtration. Recrystallization from EtOH gave 320 mg (63%) of product, mp 179°-180° C.