Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([C:5](=[NH:7])[NH2:6])[CH2:4][CH2:3]1.[OH-:8].[Na+]>CC#N.O>[CH:2]1([C:5]2[N:6]=[CH:4][C:2]([CH:5]=[O:8])=[CH:3][N:7]=2)[CH2:4][CH2:3]1
Reactant: N=C(N)C1CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=Cc1cnc(C2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a mixture of a1 (ca. 0.095 mol) in CH3CN (300 mL) was added cyclopropanecarboximidamide hydrochloride (12.5 g, 0.105 mol), then sodium hydroxide (7.6 g, 0.19 mol) in water (7.6 mL) was added drop-wise at 0° C. After addition was complete, the resulting mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated to remove CH3CN under reduced pressure and the residue water phase was extracted with DCM (3×300 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a red oil, which was purified by column chromatography on silica gel (petroleum ether:EtOAc=2:1) to afford 2-cyclopropylpyrimidine-5-carbaldehyde (7.6 g, yield: 53.5%). 1H NMR (CDCl3 400 MHz): δ 10.06 (s, 1H), 8.99 (s, 2H), 2.41-2.35 (m, 1H), 1.32-1.21 (m, 4H).
Reaction SMILES: S(C)(C)=O.[H-].[Na+].[CH3:7][O:8][C:9]([O:26][CH3:27])([CH2:13][CH2:14][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][C:21](=[O:24])[O:20]1)[CH2:10][CH:11]=O.CO[CH2:30][CH2:31][O:32]C>O>[O:24]=[C:21]1[O:20][CH:19]([CH2:18][CH2:17][CH2:16][C:15](=[O:25])[CH2:14][CH2:13][C:9]([O:26][CH3:27])([O:8][CH3:7])[CH2:10]/[CH:11]=[CH:30]/[C:31](=[O:32])[CH2:11][CH2:10][CH2:9][CH2:13][CH3:14])[CH2:23][CH2:22]1
Reactant: COCCOC
Reactant: COC(CC=O)(CCC(=O)CCCC1CCC(=O)O1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(=O)/C=C/CC(CCC(=O)CCCC1CCC(=O)O1)(OC)OC
Reaction time: 0.08 h

Procedure:
To a mixture of 70 parts of sulfinylbismethane with approximately 2 parts of a 50% dispersion of sodium hydride in mineral oil is added 11 parts of dimethyl (2-oxoheptyl) phosphonate. The resultant mixture is added, with stirring during 1 hour, to a solution of 10 parts of tetrahydro-β,β-dimethoxy-ε,5-dioxo-2-furannonanal in 52 parts of 1,2-dimethoxyethane at 0°-5° under nitrogen. Stirring is continued for 5 minutes longer, whereupon the reaction mixture is poured into 5 volumes of water, and the mixture thus obtained is extracted with benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is taken up in a 50:50 (by volume) mixture of ethyl acetate and hexane. The resultant solution is chromatographed on silica gel. Elution with a 75:25 (by volume) mixture of ethyl acetate and hexane affords, upon removal of solvent by vacuum distillation, (E)-1-(tetrahydro-5-oxofuran-2-yl)-7,7-dimethoxyhexadec-9-ene-4,11-dione as the residue, an oil. It has the formula ##STR11##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([CH3:17])[CH:16]=[C:4]2[N:3]=1.O.[NH2:19][NH2:20]>O1CCOCC1.O>[CH3:17][C:15]1[CH:16]=[C:4]2[N:3]=[C:2]([NH:19][NH2:20])[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]2[N:14]=1
Reactant: NN
Reactant: Cc1cc2nc(Cl)cc(N3CCOCC3)n2n1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2nc(NN)cc(N3CCOCC3)n2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
There was dissolved, in 1,4-dioxane (3 mL), 5-chloro-2-methyl-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (179 mg, 0.708 mM), then hydrazine monohydrate (343 μL, 7.08 mM) was added to the solution, and the mixture was stirred at 90° C. overnight. This reaction liquid was then diluted with water and the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (88.7 mg, yield: 51%).
Reaction SMILES: C(O)(=O)C.[N+:5]([O-:8])(O)=[O:6].[CH3:9][C:10]1([CH3:28])[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([CH3:27])=[CH:22][C:23]([CH3:26])=[C:24]([CH3:25])[C:12]=2[O:11]1>C(OC(=O)C)(=O)C>[CH3:9][C:10]1([CH3:28])[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([CH3:27])=[C:22]([N+:5]([O-:8])=[O:6])[C:23]([CH3:26])=[C:24]([CH3:25])[C:12]=2[O:11]1
Reactant: Cc1cc(C)c2c(c1C)OC(C)(C)C2c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C)C2c1ccccc1
Yield: 48.1 %

Procedure:
The mixed solution of acetic anhydride (3 ml) and acetic acid (3 ml) was cooled and nitric acid (3 ml) was added cautiously with stirring. Then a solution of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydrobenzofuran (3.7 g, 13.9 mmol) in acetic anhydride (3 ml) was added dropwise and the mixture was stirred for 30 minutes. The reaction mixture was poured into ice-cold water and the product was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 9:1) and crystallized from methanol to obtain the desired compound (2.08 g, yield: 48.1%), m.p. 155°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.[Cl:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Cl)[N:23]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[C:24]([NH:20][CH2:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[N:23]=1
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Clc1nc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)c2nc[nH]c2n1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (0.100 g, 0.33 mmol), 2,6-dichloropurine (0.062 g, 0.33 mmol, 1 eq) and DIEA (0.07 mL, 0.4 mmol, 1.2 eq) in ethanol (5 mL). 2-Chloro-N-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=615 nM] was obtained after purification as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.44 (1 H, s), 8.15 (1 H, s), 8.04 (1 H, dd, J=8.5, 1.2 Hz), 7.96 (1 H, d, J=6.7 Hz), 7.60 (1 H, d, J=7.3 Hz), 7.61 (1 H, t, J=7.9 Hz), 7.54 (1 H, d, J=6.7 Hz), 7.50 (1 H, t, J=6.7 Hz), 7.44 (1 H, t, J=7.3 Hz), 4.62 (2 H, d, J=26.9 Hz) Mass Spectrum (ESI) m/e=455.0 and 457.0 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14](O)=[O:15])[N:7]=3.CC[N:21]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH2:21])=[O:15])[N:7]=3
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (8.27 g, 26.7 mmol), EDCI (6.66 g, 34.8 mmol), HOBt (4.69 g, 34.8 mmol) and ammonium chloride (4.29 g, 80.2 mmol) in DMF (80 mL) was added triethylamine (7.49 mL, 53.5 mmol) and the reaction mixture stirred at 45° C. for 1.5 h. The reaction mixture was concentrated in vacuo and the residue triturated with water (250 mL). The precipitated product was collected by filtration and dried in vacuo at 45° C. for 16 h to give 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a buff coloured solid (7.67 g, 93%). 1H NMR (400 MHz, d6-DMSO) 8.40 (1H, d, J=8.7 Hz), 7.80 (1H, s), 7.42 (1H, br s), 7.32 (1H, dd, J=8.7, 2.0 Hz), 7.27 (1H, d, J=2.1 Hz), 7.15 (1H, br s), 4.50-4.46 (4H, m). LCMS: RT=3.07 min, M+H+=308/310. 1H NMR showed product to contain 5% 8-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].CCOC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:12]([O:10][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: COc1ccc(O)c(F)c1
Reactant: O=C(O)c1cc(Br)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ccc(Br)cc2C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A three-neck RBF equipped with a reflux condenser and overhead stirrer was charged with 2-fluoro-4-methoxyphenol (14.24 g, 100 mmol), 2,5-dibromobenzoic acid (25.5 g, 91 mmol), EtOAc (0.446 mL, 4.55 mmol), copper (I) triflate toluene complex (2:1) (0.484 g, 2.27 mmol) and toluene (300 mL). Cesium carbonate (59.4 g, 182 mmol) was carefully added portion-wise. The mixture was stirred for 10 minutes at RT then heated at 95° C. for 3 hours. The toluene was cooled to RT then extracted twice with 300 ml of water. The combined water extracts were acidified with 6 N HCl at which time a precipitate formed. The mixture was extracted with EtOAc (3×500 mL) and the combined organic fractions were dried over sodium sulfate and concentrated in vacuo. The resulting solid was triturated with minimal 1:1 Hexanes:EtOAc and filtered. The collected solid was dried in vacuo to afford 5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a grey solid. The mother liquors were set aside for later recrystallizatio. MS m/z=341.0 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]=[O:13])[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[Mg]Br.OS(O)(=O)=O>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([OH:13])[C:24]1[S:23][CH:27]=[CH:26][CH:25]=1)[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2
Reactant: Br[Mg]c1cccs1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C=O)cc2OC1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(O)c3cccs3)cc2OC1C(F)(F)F
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
The title product from Example 170 Step 1 (100 mg, 0.31 mmol) was dissolved in 1.0 mL of Et2O and cooled to −30° C. To this solution was added 0.31 mL thiophene-2-yl magnesium bromide solution (1.0 M in THF). After 10 minutes, the reaction mixture was pipetted over ice and diluted with ether and a dilute solution of H2SO4. The organic extracts were washed with a saturated solution of NaHCO3, dried over MgSO4, filtered, and evaporated under reduced pressure to dryness to provide 112 mg of a yellow oil. This oil was used as is without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:12][CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH:4]([N:12]([C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:25]=1[Cl:24])[CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: C#CCNC(Cc1ccccc1)C(=O)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN(C(=O)c1ccc(Cl)cc1Cl)C(Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-Phenyl-2-prop-2-ynylamino-propionic acid methyl ester (75 mg, 0.346 mmol) in anhydrous CH2Cl2 (2 mL) was cooled to 0° C. in an ice bath, then triethylamine (0.1 mL) and 2,4-dichlorobenzoyl chloride (0.06 mL, 0.45 mmol) were added. The mixture was stirred at room temperature for 3 h. Excess of benzoyl chloride was quenched by adding ice-cold water and then the reaction mixture was partitioned between water and CH2Cl2. The organic layer was separated, dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 2-[(2,4-Dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester as a syrup, 125 mg (93%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.Cl[CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[F:22].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[C:15]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1O
Reactant: Fc1cnccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 150 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of 1.59 g of 2-hydroxy-5-(trifluoromethyl)benzaldehyde, 1.22 g of 4-(chloromethyl)-3-fluoropyridine, 3.48 g of potassium carbonate and 7 ml of DMF was stirred at 80° C. for 1 hour and subsequently at 150° C. for 2 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.27 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]-pyridine (hereinafter, referred to as “Present Active Compound 8”).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]2[CH:12]([NH2:13])[CH:11]([CH2:14][CH2:15][O:16][CH3:17])[CH2:10][NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][C:27]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH:12]([NH:13][CH2:28][C:27]3[CH:30]=[C:31]([CH:34]([CH3:36])[CH3:35])[CH:32]=[CH:33][C:26]=3[O:25][CH3:24])[CH:11]([CH2:14][CH2:15][O:16][CH3:17])[CH2:10][NH:9]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COCCC1CNC(C(c2ccccc2)c2ccccc2)C1N
Reactant: COc1ccc(C(C)C)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCCC1CNC(C(c2ccccc2)c2ccccc2)C1NCc1cc(C(C)C)ccc1OC
Reaction time: 18 h
Yield: 62 %

Procedure:
A solution of 109 mg (0.35 mmol) of [(2SR, 3SR, 4RS)-2-diphenylmethyl-3-amino-4-(2-methoxyethyl)pyrrolidine] (the product of Example 27B) in 35 ml of dichloroethane was treated with 63 mg (0.35 mmol) of 2-methoxy-5-isopropylbenzaldehyde and 104 mg (0.49 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred for 18 hours and then quenched with 30 ml of saturated aqueous sodium bicarbonate. The reaction mixture was extracted with methylene chloride and the organic phase was washed with brine, dried and evaporated. The residue was chromatographed on silica gel eluting with 97/2/1 (methylene chloride/methanol/ammonia) to afford 102 mg (62%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:1]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1cc(C2CO2)ccn1
Reactant: CN1CCc2[nH]c3ccc(C(C)(C)C)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(C(C)(C)C)ccc3n2CC(O)c2ccncc2)C1
Reaction time: 0.17 h

Procedure:
To a solution of 8-tert-butyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 4.1 mmol) in DMF (6 mL) was added sodium hydride (495 mg, 12.3 mmol) under nitrogen at 0° C. and stirred for 10 min. A solution of 4-(oxiran-2-yl)pyridine (898 mg, 7.4 mmol) in DMF (2 mL) was added dropwise into the reaction mixture at RT and stirred for 12 h. The progress of reaction was monitored by TLC and LCMS. The reaction mass was poured in ice-cold water and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was re-crystallized with hexane to yield 2-(8-tert-butyl-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.7 (d, 2H), 7.3 (s, 1H), 7.2 (d, 1H), 7.19 (d, 2H), 7.17 (d, 1H), 4.7 (t, 1H), 4.0 (d, 2H), 3.5 (dd, 2H), 2.82 (m, 1H), 2.7 (m, 2H), 2.58 (m, 1H), 2.4 (s, 3H), 1.4 (s, 9H). Separation by chiral HPLC provides enantiomers II-68a-b.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=O)[CH:5]=[CH:4][N:3]=[CH:2]1.C1(C)C=CC(S([CH2:28][N+:29]#[C-])(=O)=O)=CC=1.[Na].C(O)C>C(COC)OC>[C:28]([CH:13]1[C:14]2[C:10](=[C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:12]1)#[N:29]
Reactant: O=C1CCc2c(OCCn3ccnc3)cccc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CCc2c(OCCn3ccnc3)cccc21
Yield: 30.7 %

Procedure:
To a solution of 2.68 g 4-[β-(1H-imidazol-1-yl)ethoxy]-1-indanone and 3.3 g of (p-toluenesulfonyl)methylisocyanide in 80 ml of dimethoxyethane, 0.36 g of sodium dissolved in 13.5 of absolute ethanol and 29 ml of dimethoxyethane are added as described in Ex. 3. 2.9 g of crude product are isolated and under purification by silica-gel chromatography allows to isolate 0.86 g (32%) of the nitrile in the form of oil which solidifies along the time (M.P. 115°-117° C.) and is chromatographically pure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)[C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:9].[CH2:24]([N:27]([CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH:31]=O)[CH2:25][CH3:26].C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:33]([N:27]([CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29][CH2:30][CH2:31][N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:8](=[O:9])[N:7]([CH2:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)[CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:14]1)[CH2:34][CH3:35]
Reactant: O=C(NCC1CCNCC1)N(Cc1ncc[nH]1)Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCN1CCC(CNC(=O)N(Cc2ncc[nH]2)Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
Under an argon atmosphere, to a methanol (2.3 mL) solution of the compound (73 mg) obtained in Example 10, 4-(dipropylamino)butanal (39 mg) and trimethyl orthoformate (49 mg) were added at 0° C. The reaction solution was stirred at room temperature for 2 hours. To the reaction solution, sodium borohydride (17 mg) was added at 0° C., followed by stirring for one hour. The reaction solution was concentrated under reduced pressure, and then an aqueous 5N sodium hydroxide solution (10 mL) was added to the residue. The aqueous layer was extracted twice with chloroform (30 mL). The combined organic layer was dried over anhydrous magnesium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (dichrolomethane:methanol:28% aqueous ammonia=10:1:0→80:10:1) to obtain the title compound (37 mg) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=O.[CH3:13][N:14]1[CH:18](P(OCC)(=O)OCC)[C:17](=[O:27])[NH:16][C:15]1=[O:28]>>[CH3:13][N:14]1[C:18](=[CH:4][C:3]2[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])[C:17](=[O:27])[NH:16][C:15]1=[O:28]
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Reactant: Cc1cccc([N+](=O)[O-])c1C=O
Product: Cc1cccc([N+](=O)[O-])c1C=C1C(=O)NC(=O)N1C
Yield: 80 %

Procedure:
Reaction of 2-methyl-6-nitrobenzaldehyde with diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to procedure D provides the title compound as a mixture of geometrical isomers, m.p. 194°-197° C. in 80% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:4]=1[CH:5]=[CH:6][CH2:7]Cl.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:7][CH:6]=[CH:5][C:4]3[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:3]=3[O:2][CH3:1])[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: COc1cccc(C=CCCl)c1OC
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1cccc(C=CCN2CCc3nc(N)sc3CC2)c1OC
Yield: 39 %

Procedure:
Prepared from 2,3-dimethoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 39% of theory, Melting point: 87°-9 1° C. (ether).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([CH3:27])=[CH:10][C:11]([CH3:26])([CH3:25])[NH:12]2)(=[O:4])[CH:2]=[CH2:3].[CH2:28](Br)[CH:29]=[CH2:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][CH2:6][C:7]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([CH3:27])=[CH:10][C:11]([CH3:26])([CH3:25])[N:12]2[CH2:30][CH:29]=[CH2:28])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CC(=O)OCc1c(-c2ccccc2OC)ccc2c1C(C)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1c2ccc(-c3ccccc3OC)c(COC(=O)C=C)c2C(C)=CC1(C)C
Temperature: 60 °C
Reaction time: 96 h
Yield: 41 %

Procedure:
A mixture of 5-acryloyloxymethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 1-7, 50 mg, 0.14 mmol), allylbromide (111 μL, 1.28 mmol) and potassium carbonate (78 mg, 0.56 mmol) was suspended in anhydrous N,N-dimethylformamide (2 mL), and the reaction mixture was stirred at 60° C. for 4 days. After cooling down, it was diluted with ethyl acetate (25 mL). The whole was washed with water (30 mL, twice) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (23 mg) as a pale yellow oil. (Yield 41%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([C:14](=[O:15])[NH:13][CH2:12][CH:11]2[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([C:14](=[O:15])[N:13]([CH3:26])[CH2:12][CH:11]2[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCC2c1cccnc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1CC(c2cccnc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a cooled (−60° C.) solution of 1-oxo-4-pyridin-3-yl-2,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester (diastereomer 1) (343 mg, 1.03 mmol) in THF (7 ml) was added dropwise 1M LHMDS in THF (1.34 ml, 1.34 mmol). After stirring for 1 h at −60° C., iodomethane (0.084 ml, 1.34 mmol) in THF (1 ml) was added. The cooling bath was removed and the reaction mixture was allowed to warm to RT and stirred for 3 h. A further portion of 1M LHMDS in THF (0.75 ml, 0.75 mmol) was added to the cooled (−60° C.) reaction mixture. After 30 minutes, iodomethane (0.042 ml, 0.67 mmol) in THF (0.5 ml) was added, the cooling bath was removed and the reaction mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with NH4Cl saturated solution (5 ml) and extracted with EtOAc (2×25 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-5% MeOH in DCM afforded the title compound as a yellow oil.