Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH2:18][C:19]#[N:20].O>C1C=CC=CC=1>[CH:4]([CH:18]([C:11]1[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[CH3:9])[C:19]#[N:20])=[O:5]
Reactant: CCOC=O
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(C)c(C(C#N)C=O)c(C)c1

Procedure:
To a stirred mixture of sodium methoxide (2.78 g, 51 mmol) and ethyl formate (4.0 g, 54 mmol) in 100 mL of benzene was added 2,4,6 trimethylphenylacetonitrile (8.0 g, 50 mmol) over 5 min. After stirring for an additional hour it was treated with water (100 mL) and the layers were separated. The aqueous layer was separated and acidified with 10% HCl and extracted with ethyl acetate. After drying the solvent was removed in vacuo to afford a-formyl-2,4,6-trimethylphenylacetonitrile as colorless crystals melting at 120-122° C.
Reaction SMILES: [N:1]1[C:6](C)=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][S:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].ClCCCN1CCCC1>C(#N)C.CN(C)C=O>[N:1]1([CH2:2][CH2:8][CH2:9][S:10][C:12]2[CH:17]=[CH:16][C:15]([C:18]3([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)c1ccc(C2(C#N)CCOCC2)cc1
Reactant: Cc1cccc(C)n1
Agent: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#CC1(c2ccc(SCCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
2,6-Lutidine (3.33 ml, 28.6 mmol) was added to a solution of 4-[4-(methylsulfinyl)phenyl]tetrahydro-2H-pyran-4-carbonitrile (2.3 g, 9.23 mmol) in acetonitrile (70 ml). The mixture was cooled in an ice-acetone bath and trifluoroacetic anhydride (3.87 ml, 27.69 mmol) added slowly. The solution was stirred at this temperature under nitrogen for 3 hours. The reaction mixture was then concentrated in vacuo and the residue taken up in methanol (7 ml). Triethylamine (7 ml) was added at 0° C. and the mixture stirred at 0° C. for 30 minutes. N,N-Dimethylformamide (10 ml) was added at 0° C., followed by potassium carbonate (2.8 g, 20.31 mmol) and 1-(3-chloro-propyl)-pyrrolidine (2.72 g, 18.46 mmol) in N,N-dimethylformamide (10 ml). The mixture was then warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in water (50 ml) and extracted with ethyl acetate (2×150 ml). The organic layers were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 95:5:0.5 by volume) to provide the title compound (2.62 g, 86%) as a solid. 1H NMR (400 MHz, CDCl3) δ 1.77-1.80 (m, 4H), 1.84-1.91 (m, 2H), 2.01-2.14 (m, 4H), 2.48-2.52 (m, 4H), 2.58 (t, 2H), 2.99 (t, 2H), 3.89 (t, 2H), 4.06-4.10 (m, 2H), 7.34-7.39 (m, 4H). LRMS APCI+ m/z 331 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.[K].[O:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].[I-].[Na+]>>[NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:17]2[C:18](=[O:20])[CH2:19][O:15][C:16]2=[O:21])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1COC(=O)N1
Reactant: Nc1ncccc1OCCCCCl
Agent: [I-]
Agent: [K]
Agent: [Na+]
Product: Nc1ncccc1OCCCCN1C(=O)COC1=O

Procedure:
Using 15.05 g (75 mmol) of 2-amino-3-(4-chlorobutyloxy)pyridine, 10.44 g (75 mmol) of oxazolidine-2,4-dione potassium salt and 11.24 g (75 mmol) of sodium iodide, the same procedure as in Reference Example 11 was followed, to yield 12.34 g (62.0%, yellow powder) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.C[Mg]Br.[CH2:15]1COC[CH2:16]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:15][CH3:16])[CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: C[Mg]Br
Product: CCc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), was added 1.0 Methyl magnesium bromide in THF (32 mL, 32.0 mmol) dropwise at 0° C. and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 2 N HCl and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 4-bromo-2-ethylbenzoic acid as a colorless liquid that was used in the next step without purification (0.4 g): 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 2.95 (q, J=4.0 Hz, 2H), 1.32 (t, J=4.0 Hz, 3H); ESIMS m/z 228.97 ([M+H]+).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B.[OH-:29].[Na+].OO>O1CCCC1.O>[CH2:1]([O:17][CH2:18][CH:19]([O:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [OH-]
Reactant: C=CCCCCC(COCCCCCCCCCCCCCCCC)OC
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(CCCCCCO)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8-(hexadecyloxy)-7-methoxy-1-octene in 100 ml of tetrahydrofuran was added a solution of 112.3 ml of 1.0M borane in tetrahydrofuran at 0° C. over a 1 hour period. The mixture was stirred on addition 3 hours at 25° C. The solution was recooled to 0° C. and a solution of 187.3 ml of 3M sodium hydroxide was slowly added followed by 216 ml of 30% hydrogen peroxide. After 30 minutes, the mixture was poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was purified by chromatography giving 20 g of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:13])=[C:7]([CH2:9][C:10](Cl)=[O:11])[CH:8]=1.[CH3:14][NH:15][CH3:16]>CCOCC>[CH3:14][N:15]([CH3:16])[C:10](=[O:11])[CH2:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[Br:13]
Reactant: COc1ccc(Br)c(CC(=O)Cl)c1
Reactant: CNC
Solvent: CCOCC
Product: COc1ccc(Br)c(CC(=O)N(C)C)c1
Temperature: 25 °C

Procedure:
5-Methoxy-2-bromophenylacetyl chloride (60 g, 0.23 mol) is dissolved in anhydrous Et2O (400 mL), stirred and cooled in an ice bath. A 2 M solution of dimethylamine (228 mL, 0.46 mol) is added dropwise and the mixture allowed to warm to room temperature and stirred for 2 hours. Additional Et2O (500 mL) is added. The organic solution is washed with 1 N HCl (2×500 mL), saturated NaHCO3 (500 mL) and brine (500 mL). The organic layer is dried (Na2SO4) and concentrated by rotary evaporator. The residue is purified using flash chromatography (hexanes/EtOAc, from 7:3 to 1:9). Trituration of the crude product with Et2O/hexanes gives N,N-dimethyl-5-methoxy-2-bromophenylacetamide as a white crystalline solid (m.p. 88–90° C.).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[C:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CN(P(N(C)C)(N(C)C)=O)C.Br[CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1.CCOC(C)=O>CN(C=O)C>[CH:25]1([CH2:24][N:2]([CH3:1])[CH2:3][C:4]#[C:5][CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[O:29][CH:28]=[CH:27][O:26]1
Reactant: BrCC1OCCO1
Reactant: CNCC#CCN1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN(CC#CCN1CCCC1)CC1OC=CO1

Procedure:
A solution of N-Methyl-4-(1-pyrrolidinyl)-2-butynamine (83.4 mg, 0.548 mmol), TEA (153 μL, 1.098 mmol), HMPA (114 μL, 0.657 mmol), and 2-(bromomethyl)-1,3-dioxolane (68 μL, 0.657 mmol) in DMF (2 mL) was stirred at 50 ° C. for 20 h or until complete by TLC. The mixture was poured into EtOAc (20 mL) then washed with 1N NaOH saturated with NaCl (3×20 mL). The organic layer was dried over Na2SO4, and the EtOAc removed in vacuo to give a crude orange oil (102.8 mg, 79% yield). This oil was vacuum distilled to give N-(2,5-dioxolylmethyl)-N-methyl-4-(1-pyrrolidinyl)-2-butynamine as a clear oil: bp 90° C. (0.2 mm Hg); MS (CI-NH3), m/e 239 (MH+); 1H NMR (CDCl3) δ1.74 (br s, 4 H), 2.33 (s, 3 H), 2.58 (br H), 3.37 (s, 2 H), 3.38 (s, 2 H), 3.79 (m, 2 H), 3.92 (m, 2 H), 4.90 (t, J=4.6 Hz, 1 H).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=O)[CH3:3].C(O)C.[S-:18][C:19]#[N:20].[K+]>O>[CH2:2]([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:20]=[C:19]1[SH:18])[CH3:3]
Reactant: N#C[S-]
Reactant: CCNCC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCn1cc(-c2ccc(O)cc2)nc1S
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred and refluxing mixture of 21.5 parts of 2-(ethylamino)-1-(4-hydroxyphenyl)ethanone hydrochloride, 60 parts of ethanol and 75 parts of water is added dropwise a solution of 12 parts of potassium thiocyanate in a small amount of water. Upon completion, stirring is continued overnight at reflux temperature. Another portion of 4 parts of potassium thiocyanate in small amount of water is added and the whole is stirred for 8 hours at reflux temperature. The reaction mixture is concentrated. The product is filtered off and crystallized from a mixture of ethanol and water, yielding 10 parts (91%) of 4-(1-ethyl-2-mercapto-1H-imidazol-4-yl)phenol; mp. 251.7° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]I)[CH:6]=[CH:7][CH:8]=1.[C-:15]#[C-:16].[Na+].[Na+]>>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:15]#[CH:16])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(CCCI)c1
Reactant: [C-]#[C-]
Agent: [Na+]
Product: C#CCCCc1cccc(C(F)(F)F)c1

Procedure:
The title compound was synthesized using 3-(3-trifluoromethylphenyl)-1-iodopropane and sodium acetylide by conducting the reactions similar to those mentioned in Reference example 29.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[F:15][C:16]1[CH:48]=[CH:47][C:19]2[N:20]=[C:21]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]3[CH2:39][O:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:25])[S:22][C:18]=2[CH:17]=1>CO>[ClH:1].[ClH:1].[F:15][C:16]1[CH:48]=[CH:47][C:19]2[N:20]=[C:21]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH:27]3[CH2:39][O:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:25])[S:22][C:18]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2nc3ccc(F)cc3s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1nc2ccc(F)cc2s1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 90 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(6-fluorobenzo[d]thiazol-2-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (122 mg, 0.203 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 83.9 mg (90%) of the title compound as a white solid. LC-MS: RT=4.61 min, [M+H]+=388.1.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].N1C=CC=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1C(F)(F)F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
A solution of 2-(trifluoromethyl) aniline (693 mg, 4.30 mmol) and pyridine (438 μL, 5.87 mmol) in DCM (40 mL) was treated with 4-bromobenzene sulfonyl chloride (1.0 g, 3.91 mmol) and stirred at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1N HCl, sat. NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-20% EtOAc in cyclohexane) and triturating with pentane gave 4-bromo-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (719 mg, 48% yield) as a colourless crystalline solid. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.2 Hz, 1H), 7.65-7.47 (m, 6H), 7.29-7.20 (m, 1H), 6.85 (br s, 1H), LCMS (m/z, Method A) ES+ 380.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:7][CH2:6][CH:5]([OH:8])[CH2:4][O:3]1.O[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][C:2]1([CH3:9])[O:7][CH2:6][CH:5]([O:8][N:11]2[C:15](=[O:16])[C:14]3[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]2=[O:21])[CH2:4][O:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC1(C)OCC(O)CO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(ON2C(=O)c3ccccc3C2=O)CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Forbes, D. C. et. al. Synthesis, 1998;6:879-82). 1H NMR (400 MHz; DMSO-d6) δ 4.91 (d, 1H, J=5.1), 3.70-3.75 (m, 2H), 3.41-3.46 (m, 3H), 1.30 (s, 3H), 1.24 (s, 3H); MS (APCI+)=132.9. To a stirring solution of 2,2-dimethyl-[1,3]dioxan-5-ol (1.50 g, 11.35 mmol), N-hydroxyphthalimide (1.85 g, 11.35 mmol) and triphenylphosphine (2.98 g, 11.35 mmol) in anhydrous tetrahydrofuran (30 mL) at 0° C. was added diethyl azodicarboxylate (2.3 mL, 14.75 mmol). The resultant solution was allowed to warm to room temperature. After stirring for 3 hours, the mixture was concentrated in vacuo and charged with chloroform affording white solids. The solids were filtered off and filtrate was collected and concentrated. The residue was purified via silica column chromatography (4:1 hexanes/ethyl acetate) affording 2-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-isoindole-1,3-dione as clear crystals (1.74 g, 55% over 2 steps): 1H NMR (400 MHz; DMSO-d6) δ 7.83 (s, 4H), 4.11-4.12 (m, 1H), 4.04-4.09 (m, 2H), 3.92-3.96 (m, 2H), 1.32 (s, 3H), 1.25 (s, 3H); MS (APCI+)=278.0.
Reaction SMILES: F[C:2]1C=CC(N2C3C(=CC=C(CCCC(O)=O)C=3)C=N2)=C[CH:3]=1.[CH2:23]([C:25]12[CH2:51][CH2:50][C:47]3([CH2:49][O:48]3)[CH2:46][CH:26]1[CH2:27][CH2:28][CH2:29][C:30]1[C:31]2=[CH:32][C:33]2[CH:34]=[N:35][N:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:37]=2[CH:38]=1)[CH3:24].[CH2:52]([Mg]Br)[CH3:53].[NH4+].[Cl-]>[Cu]I.CCOC(C)=O.O.C1COCC1>[CH2:23]([C@:25]12[CH2:51][CH2:50][C@@:47]([CH2:49][CH2:2][CH3:3])([OH:48])[CH2:46][C@@H:26]1[CH2:27][CH2:28][CH2:29][C:30]1[CH:38]=[C:37]3[C:33](=[CH:32][C:31]=12)[CH:34]=[N:35][N:36]3[C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1)[CH3:24].[CH2:23]([C@@:25]12[CH2:51][CH2:50][C@:47]([CH2:49][CH2:52][CH3:53])([OH:48])[CH2:46][C@H:26]1[CH2:27][CH2:28][CH2:29][C:30]1[CH:38]=[C:37]3[C:33](=[CH:32][C:31]=12)[CH:34]=[N:35][N:36]3[C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1)[CH3:24]
Reactant: CCC12CCC3(CO3)CC1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: O=C(O)CCCc1ccc2cnn(-c3ccc(F)cc3)c2c1
Reactant: CC[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC[C@@]1(O)CC[C@]2(CC)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@H]2C1
Product: CCC[C@]1(O)CC[C@@]2(CC)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@@H]2C1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A 50 mL 3 necked round bottom flask with stir bar, nitrogen line, septum and thermometer was charged with rac-(2′R,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2′-oxirane](14, R1=4-Fluorophenyl, R2=Ethyl) (0.225 g, 0.576 mmol), THF (10 mL) and copper(I) iodide (0.016 g, 0.086 mmol). The mixture was stirred for about 10 min then cooled to about −5° C. Ethylmagnesium bromide (3 M in ether, 0.576 mL, 1.73 mmol) was added keeping the internal temperature below about 0° C. After about 15 min sat. aqueous NH4Cl (3 mL), water (25 mL) and EtOAc (25 mL) were added to the mixture. The layers were separated then the organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-20% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield (3S,4aR,12bR)-12b-Ethyl-9-(4-fluoro-phenyl)-3-propyl-1,2,3,4,4a,5,6,7,9,12b-decahydro-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-ol; compound with (3R,4aS,12bS)-12b-ethyl-9-(4-fluoro-phenyl)-3-propyl-1,2,3,4,4a,5,6,7,9,12b-decahydro-9,10-diaza-benzo[3,4]cyclohepta[1,2-f]inden-3-ol (16, R1=4-Fluorophenyl, R2=Ethyl, R3=Propyl) (Example 4) (0.187 g, 77%); LC/MS, method 2, Rt=3.84 min, MS m/z 421 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=0.6 Hz, 1H), 7.92 (s, 1H), 7.83-7.77 (m, 2H), 7.54 (s, 1H), 7.45-7.35 (m, 2H), 3.83 (s, 1H), 3.22-3.15 (m, 1H), 2.95-2.89 (m, 1H), 2.22-2.14 m, 1H), 2.12-1.93 (m, 3H), 1.88-1.71 (m, 2H), 1.68-1.59 (m, 1H), 1.56-1.48 (m, 2H), 1.44-1.24 (m, 8H), 0.88 (t, J=6.6 Hz, 3H), 0.35 (t, J=7.3 Hz, 3H)
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[O:12])[C:3]1=[O:15]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Cc1cc(N)no1
Solvent: Brc1ccccc1
Product: Cc1cc(NC(=O)c2c(O)cc(C)n(C)c2=O)no1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 66.5 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 79 mg of 3-amino-5-methylisooxazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 6.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 141 mg of 1,6-dimethyl-4-hydroxy-N-(5-methylisooxazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 27) represented by the formula:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li])CCC.CC(C)([O-])C.[K+].[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:36][CH3:37])=[C:27]([C:29]([CH3:35])([CH3:34])[CH2:30][C:31](=[O:33])[CH3:32])[CH:28]=1>C1COCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:36][CH3:37])=[C:27]([C:29]([CH3:34])([CH3:35])[CH2:30][C:31]([CH2:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)([OH:33])[CH3:32])[CH:28]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(C)(O)Cc1cc2ccccc2[nH]1
Temperature: -20 °C
Reaction time: 0.03 h
Yield: 31.2 %

Procedure:
To a solution of 2-methylindole (130 mg) in THF (2 mL) stirred under argon cooled on dry ice/acetone was added n-butyl lithium (2M in pentane, 1.6 mL). After 2 minutes, potassium tert-butoxide (1M in THF, 2 mL) was added and the mixture was allowed to warm to approximately −20° C. After 5 minutes, precipitate was noted and the mixture was cooled to −70° C. 4-(5-Fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 17) (440 mg) in THF (1.5 mL) was added all at once. The cooling bath was removed and the mixture was stirred for 10 minutes and then quenched with EtOH (0.5 mL). The mixture was diluted with EtOAc, washed with water, dried, filtered, and evaporated. Chromatography over silica gel (EtOAc-hexanes (1:9)) gave product which solidified on trituration with hexanes-ether. The solid was recrystallized from ether-hexanes, collected by filtration and dried under vacuum to give 0.11 g of the title compound, m.p. 118° C.-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1.C(=O)=O.C(#N)C>C1COCC1>[Cl:1][C:2]1[C:11]([C@H:12]([OH:14])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(=O)c1cc2ccc(F)cc2nc1Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H](O)c1cc2ccc(F)cc2nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A solution of 1-(2-chloro-7-fluoroquinolin-3-yl)ethanone (164 g, 733 mmol) in THF (1.34 L) was added to a solution of (+)-DIP-Cl (517.5 g, 2.2 eq) in THF (3.5 L) at −45° C. (dry ice and acetonitrile) dropwise. The reaction was slowly warmed up to rt overnight. The reaction was then quenched with acetone (750 mL) and 10% Na2CO3 (750 mL) at 0° C. and stirred at rt for 1 h before the addition of EtOAc (3.5 L). The mixture was warmed up to rt and washed with 10% Na2CO3 and water. The organic layer was dried with brine, concentrated and treated with hexane (1.0 L) and water (1.8 L). The mixture was stirred at rt for 40 min and filtered. The white solid was washed with water and hexane, dried in the air over night (143 g). This material was dried on the roto-evaporator at 60° C. for 4 h under high vacuum (2 mm Hg) to give a white powder of (R)-1-(2-chloro-7-fluoroquinolin-3-yl)ethanol (122 g, 73.7%). Chiral HPLC on AD column (isopropanol in hexane, 10%) showed ee>99%. Mass Spectrum (ESI) m/e=226 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Na+].[I-:12].C(Cl)(=O)C.[OH-].[Na+]>C(#N)C.C1COCC1>[I:12][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: Ic1ccnc2[nH]ccc12
Temperature: 80 °C
Reaction time: 96 h
Yield: 47.4 %

Procedure:
To a solution of 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 84.3 mmol) and NaI (40 g, 168 mmol) in acetonitrile (150 mL) was slowly added acetyl chloride (12.6 mL, 176 mmol). The mixture was allowed to stir at 80° C. for 4 days, and then the excess acetonitrile was removed in vacuo. 300 mL of 10% K2CO3 (aq) was added to the residue and the mixture extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with 10% sodium bisulfite (aq) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product (22.2 g). To a solution of this crude product in THF (150 mL) was added 1M NaOH (100 mL). The mixture was stirred at room temperature for 2 hr prior to evaporation of the solvent in vacuo, dilution with water and extraction with CH2Cl2. The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting brown solid was purified by chromatography over silica gel and recrystallized from acetonitrile to give pure 4-Iodo-1H-pyrrolo[2,3-b]pyridine (9.75 g, 48%). MS (ES+): 245 [MH+].