Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]3[N:19]=[C:18]([C@@H:20]4[CH2:25][C@@H:24]5[C@@H:22]([CH2:23]5)[N:21]4[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:17][C:16]=3[CH:33]=1)[CH:6]=[N:5]2.CC([O-])=O.[K+].[B:39]1(B2OC(C)(C)C(C)(C)O2)[O:43]C(C)(C)C(C)(C)[O:40]1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([O:28][C:26]([N:21]1[C@H:20]([C:18]2[NH:17][C:16]3[CH:33]=[C:12]([C:7]4[CH:6]=[N:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([B:39]([OH:43])[OH:40])[CH:3]=5)[N:8]=4)[CH:13]=[CH:14][C:15]=3[N:19]=2)[CH2:25][C@@H:24]2[C@H:22]1[CH2:23]2)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3cnc4cc(Br)ccc4n3)cc2[nH]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3cnc4cc(B(O)O)ccc4n3)cc2[nH]1
Temperature: 83 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
Pd(Ph3P)4 (23.28 mg, 0.020 mmol) was added to a degassed solution of (1R,3S,5R)-tert-butyl 3-(6-(6-bromoquinoxalin-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (102 mg, 0.201 mmol), KOAc (49.4 mg, 0.504 mmol) and bis(pinacolato)diboron (113 mg, 0.443 mmol) in dioxane (2 mL) and the reaction was stirred at 83° C. for 16 h. The reaction mixture was partitioned between EtOAc (20 mL) and sat. NH4Cl(aq.) (5 mL). The organic layer was dried (MgSO4), filtered and concentrated to an orange oil, which was purified by prep HPLC (H2O-MeOH with 0.1% TFA buffer) to yield 2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-ylboronic acid (57 mg, 0.121 mmol, 60.0% yield) as orange solid. LC-MS retention time 1.94 min; m/z 472 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].F[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:7][O:6][C:4](=[O:5])[CH:3]([NH:2][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(N)c1ccccc1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(C(=O)OC)c2ccccc2)c([N+](=O)[O-])c1
Yield: 89.6 %

Procedure:
A solution of methyl 2-amino-2-phenylacetate hydrochloride (2.5 g, 12.38 mmol, 1.00 equiv) in DMF (30 mL), methyl 4-fluoro-3-nitrobenzoate (5 g, 25.13 mmol, 2.00 equiv), and DIEA (5 g, 38.76 mmol, 3.13 equiv) was reacted overnight at 30° C. in a 100-mL round-bottom flask. The reaction was then quenched by the addition of 200 mL of water, and the solids were collected by filtration. Purification via silica gel column (petroleum ether/EtOAc (50:1)) yielded 3.82 g (90%) of methyl 4-(2-methoxy-2-oxo-1-phenylethylamino)-3-nitrobenzoate as a yellow solid. LC-MS (ES, m/z): 345 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].S(Cl)(Cl)=O.[CH3:31][O:32][CH2:33][CH2:34][NH2:35].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26]
Reactant: COCCN
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1
Reaction time: 2 h

Procedure:
5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (1.00 g, 2.77 mmol) was suspended in anhydrous DCM (20 ml) and thionyl chloride (0.5 ml, 6.85 mmol) added. The reaction was heated under reflux for 3 h then evaporated to dryness. The residue was dissolved in anhydrous DCM and spit into 4 aliquots, one aliquot was added to a solution of methoxyethylamine (0.075 ml, 1.00 mmol) and triethylamine (0.14 ml, 1.00 mmol) in DCM (5 ml). After stirring for 2 h the reaction was washed with water (2 ml) then evaporated to dryness. Crude product was purified by silica chromatography using DCM as eluent then crystallised from DCM:diethyl ether to provide crystalline title compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[C:13](=[C:14]([CH2:18][NH:19][C:25](=[O:27])[CH3:26])[CH:15]=[CH:16][CH:17]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CNC(C)=O)c1C(=O)OC
Temperature: 4 °C
Yield: 77.8 %

Procedure:
Triethylamine (1.87 g, 18 mmol) was added slowly to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The resulting mixture was cooled in an ice bath to 4° C. Acetyl chloride (0.73 g, 9 mmol) was added dropwise at a rate such that the temperature stayed between 4-7° C. After addition was complete, the mixture was stirred in the ice bath for an additional 30 minutes and then allowed to warm to room temperature and maintained for 2 hours. The reaction mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the product was purified by chromatography (dichloromethane/ethyl acetate 6 to 4) to afford 1.65 g (80%) of the product as an oil: 1H NMR (CDCl3) δ 7.86 (d, J=7.7 Hz, 1H), 7.62 (d, J=7.6 Hz); 7.46 (t, J=7.7 Hz); 6.29 (b, 1H), 4.39 (d, J=6.1 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 1.96 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)(=O)[CH3:2].Cl.[NH2:14][OH:15].C([O-])(=O)C.[K+]>C(O)C>[C:1](=[N:14][OH:15])([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)CCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(=NO)c1ccc2c(c1)CCC2
Yield: 91.5 %

Procedure:
Anhydrous aluminum trichloride (25 g) is added dropwise to a stirred mixture of acetylchloride (11.8 g), indane (24 g) and dry benzene (100 ml) stirred at 5-8° C. The stirring is continued for 6 hours at this temperature until the evolution of hydrogen chloride is over; then, the mixture is partitioned with ice (200 g) and 6N hydrochloric acid (100 ml), the organic phase is separated, the aqueous phase is extracted with benzene. The organic benzene layers are collected, washed until neutral, dried on MgSO4 and the excess solvent is evaporated under vacuum. The residue (28.5 g) is distilled in high vacuum (1 mmHg) and the fractions with b.p. 80°-85° C. are collected affording 16 g of 5-acetylindane. I.R.=1680 cm-1. H-NMR (CDCl3 /TMS): 7.1-7.8 (m, 3H, Ar); 2.9 (t, 4H); 2.55 (s, 3H, CH3); 1.9-2.4 (m, 2H). A solution of 5-acetylindane (15 g) in ethanol (50 ml) is treated with a solution of hydroxylamine hydrochloride (15 g) and potassium acetate (21.5 g) in ethanol (50 ml) for 20 minutes at the reflux temperature. The excess of the solvent is evaporated in vacuum and the mixture is diluted with water. The precipitate is collected by filtration affording 15.01 g of 5-acetylindane oxime m.p. 104° C. I.R.=3200 cm-1. H-NMR (CDCl3 /TMS): 8.15 (s, 1H, N--OH); 2.3 (s, 3H, CH3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.CS[C:11]1[NH:16][C:15](=[O:17])[N:14]2[N:18]=[CH:19][CH:20]=[C:13]2[N:12]=1>C1(C)C(C)=CC=CC=1>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][CH:11]2[NH:16][C:15](=[O:17])[N:14]3[N:18]=[CH:19][CH:20]=[C:13]3[NH:12]2)[N:8]=[CH:7]1
Reactant: CSc1nc2ccnn2c(=O)[nH]1
Reactant: NCCc1c[nH]cn1
Solvent: Cc1ccccc1C
Product: O=C1NC(NCCc2c[nH]cn2)Nc2ccnn21
Yield: 49.1 %

Procedure:
A mixture of 135 mg of free histamine and 180 mg of 2-methylthio-4-oxo-3H-pyrazolo(1,5-a)-1,3,5-triazine in 10 ml of xylene is refluxed for 22 hrs. After evaporation of the solvent in vacuo, the pale pink residue is triturated with water and alcohol, filtered, washed with ether and dried to yield 120 mg of purified product. TLC (silica gel CHCl3 /MeOH/triethylamine=3:1:0-5) Rf=0.14.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:28][O:27]2)=[CH:22][N:21]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:28][CH:26]([C:23]3[CH:22]=[N:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)[OH:27])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: COc1ccc(C2CO2)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 5.0 mmol) was dissolved in DMF (8 mL). Sodium hydride (600 mg, 15 mmol) was added portionwise under nitrogen at 0° C. 2-Methoxy-5-oxiranyl-pyridine (1.130 g, 7.5 mmol) was diluted in DMF (2 mL) was added dropwise under nitrogen atmosphere and the reaction mixture stirred at RT for 3 h. By monitoring TLC & NMR after consumption of starting material, the reaction mixture was then quenched with ice water and extracted with EtOAc (3×40 mL). The combined organic layer was washed with water (4×30 mL) and dried over anhydrous sodium sulfate and concentrated to obtain 1.0 g of 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(6-methoxy-pyridin-3-yl)-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.11 (s, 1H), 7.55 (d, 1H), 7.18 (s, 1H), 7.16 (d, 1H), 6.98 (d, 1H), 6.72 (d, 1H), 4.98 (t, 1H), 4.11 (m, 2H), 3.93 (s, 3H), 3.60 (q, 2H), 2.88 (d, 1H), 2.78 (m, 2H), 2.69 (d, 1H), 2.51 (s, 3H), 2.44 (s, 3H). Separation by chiral HPLC provided enantiomers 51a and 51b.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](O)=[CH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:2].C(O)(=O)C.[CH3:25][NH2:26]>CCO>[CH2:1]([O:3][C:4](=[O:20])[C:5]([NH:26][CH3:25])=[CH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)C(O)=CC(=O)c1c[nH]c2ccc(Cl)cc12
Reactant: CN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=CC(=O)c1c[nH]c2ccc(Cl)cc12)NC
Yield: 37.5 %

Procedure:
To a solution of 0.59 g (2.0 mmol) of 4-(5chloroindol-3-yl)-2-hydroxy-4-oxo-2-butenoic acid ethyl ester prepared in Example 1(1) in 95% EtOH (10 ml) was added 0.55 g (6.0 mmol) of methylamine acetate. After refluxing for 2.5 hours, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The ethyl acetate was washed with water, dried, and then concentrated. The resulting residue was chromatographed on silica gel (ethyl acetate as eluant) to give 0.23 g of the titled compound as oil. Yield: 38%.
Reaction SMILES: [CH2:1]([C:5]1[CH2:6][C@@H:7]2[C@H:10]([CH:11]=1)[C:9](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH2:2][CH2:3]C.O[CH:21](CCC=C)C(CC(C)C)C(O)=O>>[CH2:1]([C:5]1[CH2:6][C@@H:7]2[C@H:10]([CH:11]=1)[C:9](=[CH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2)[CH:2]([CH3:3])[CH3:21]
Reactant: C=CCCC(O)C(CC(C)C)C(=O)O
Reactant: CCCCC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Product: CC(C)CC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1

Procedure:
The compound of interest (3.7 g, 67%) was obtained as an oil substance (E/Z mixture) in the same way as in paragraph (10-c) using 3-hydroxy-2-isobutyl-6-heptenoic acid (4.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14]OS(C)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O)(=O)=O)=CC=1.[F:38][C@@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>[I-].[K+].C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:41]3[CH2:42][CH2:43][C@@H:39]([F:38])[CH2:40]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: F[C@@H]1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CC[C@@H](F)C1
Yield: 102.9 %

Procedure:
Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.16 g, 0.44 mmole), anhydrous acetonitrile (2 mL), potassium carbonate (0.21 g, 1.54 mmol), potassium iodide (0.007 g, 0.04 mmol) and (3R)-3-fluoropyrrolidine 4-methylbenzenesulfonate (salt) (See Intennediate 51) (0.21 g, 0.79 mmol) to give the title compound as a pale orange oil (0.16 g): MS (m/e) (79Br/81Br): 353, 355(M+1)
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=1.Cl>O1CCOCC1>[CH3:13][C:9]([C:7]1[NH:8][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=1)([CH3:12])[C:10]#[N:11]
Reactant: COc1cccc(C(C)(C)C#N)n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C#N)c1cccc(=O)[nH]1
Temperature: 190 °C
Yield: 380.7 %

Procedure:
To a 20 dram microwave vial was added 2-(6-methoxypyridin-2-yl)-2-methylpropanenitrile (7 g, 40 mmol) and 4N HCl in dioxane (15 mL). The reaction was then sealed and heated in a microwave reactor at 190° C. for 30 min. This reaction was repeated six times using the procedure above. These reactions were combined and filtered. The resultant white solid was washed with 20% EtOAc/hexanes and then dried in vacuo to afford 2-methyl-2-(6-oxo-1,6-dihydropyridin-2-yl)propanenitrile (24.7 g, 77%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Cl[C:11]1[C:12]2[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=2[N:14]=[CH:15][N:16]=1>CN(C=O)C.O>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]2[N:14]=[CH:15][N:16]=[C:11]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:12]=2[N:20]=1
Reactant: Oc1cccnc1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2ncnc(Oc3cccnc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of pyridin-3-ol (0.048 g, 0.500 mmol) in DMF (1.67 ml) was added NaH (0.027 g, 55% dispersion in mineral oil, 0.630 mmol) at 0° C. After stirring for 30 min at room temperature, the reaction mixture was cooled to 0° C. and 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1 g, 0.500 mmol) was added to the mixture. After stirring for 2 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine (0.090 g, 70%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.46 (1H, dd, J=8.0 and 4.8 Hz), 7.66-7.69 (1H, m), 7.86 (1H, d, J=8.8 Hz), 8.31 (1H, d, J=8.8 Hz), 8.61 (1H, d, J=4.4 Hz), 8.65 (1H, d, J=2.8 Hz), 8.80 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.S(=O)(=O)(O)O.[OH-].[K+]>>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH:14]=[CH:15][C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(C=Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 5 °C

Procedure:
2-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(C2CCC(C)(C)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCC(c2ccc(O)cc2)CC1
Yield: 84.8 %

Procedure:
A solution of 4-(4,4-dimethylcyclohexyl)anisole (2.76 g, 12.64 mmol), boron tribromide (4.42 mL, 15.2 mmol), in methylene chloride was stirred at room temperature overnight. The reaction mixture was treated with wet ice and diluted with methylene chloride. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The product was chromatographed on silica gel, using a toluene/ethyl acetate (18:1), to afford the title compound (2.19 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OC(=O)C)C.O>[C:24]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
5-nitroindole (50 mg, 0.31 mmol) and potassium carbonate (128 mg, 0.93 mmol) were suspended in. dimethylformamide (1.0 ml). Then, benzoyl chloride (0.04 ml, 0.345 mmol) was added and stirred at room temperature for 2 hours. After completing the reaction, water and ethylacetate (respectively 5 ml) were added to extract, washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified through a flash column chromatography (an eluent: ethyl acetate/n-hexane=1/1, v/v). As a result, the present compound (35 mg, productive yield 43%) was obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC>COC>[C:1]1([Li:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Agent: COC
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
Here 5 g (30 mmol) fluorene, dissolved in dimethyl ether, was reacted for three hours with 18.8 ml of butyllithium (1.6M in hexane). The solvent was evaporated to yield yellow fluorenyl lithium. Then 11.4 g (45 mmol) of Ph2SiCl2, i.e. diphenyl dichloro silane, was dissolved in 200 ml of pentane and the solid fluorenyl lithium was added in one portion to the pentane solution. After stirring for one hour, the mixture was filtered, the precipitated LiCl was eluated with 50 ml of ether, and the solvent evaporated from the combined organic layers to yield a yellow powder characterized by GC/MS as FlSiPh2Cl, i.e. fluorenyl-diphenyl chlorosilane. Crystallization in pentane yields colorless crystals of the product, from which a H-NMR-spectra could be obtained.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=O)[O:2]1.ClCC1C(CC#[N:22])=CC=CC=1>>[OH:2][CH2:1][C:10]1[C:5]([CH2:4][C:3]#[N:22])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1Cc2ccccc2CO1
Reactant: N#CCc1ccccc1CCl
Product: N#CCc1ccccc1CO
Yield: 1.6 %

Procedure:
After completion of the reaction, the concentration of 3-isochromanone was analyzed by GC analysis and then the yield of 3-isochromanone was calculated. As a result, the yield was found to be 95% based on α-chloro-α′-cyano-o-xylene. At this time, the conversion ratio of α-chloro-α′-cyano-o-xylene was 100% and the by-product compound (α-hydroxy-α′-cyano-o-xylene) where the halogen moiety was hydrolyzed was produced in a yield of 1.6%.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:20][CH:21]1[CH2:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[NH:23][C:22]1=[O:32])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]([CH2:11][N:23]1[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26][CH2:27][CH:21]([NH:20][CH:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:22]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2CCC1NC(CCc1ccccc1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCc2ccccc2)CCc2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (4.0 g) in dry dimethylformamide was added under a nitrogen atmosphere to a stirred suspension of sodium hydride [from the 60% mineral oil dispersion (0.42 g) washed with petroleum ether (3×80 ml)] in dry dimethylformamide (100 ml) at room temperature to which tetrabutylammonium bromide (3.1 g) had been added. Stirring was continued for an additional 30 minutes at room temperature, when a solution of benzyl bromoacetate (2.2 g) in dry dimethylformamide (10 ml) was added. After an additional 30 minutes at room temperature, the reaction mixture was heated to 50°, and maintained at that temperature for 18 hours. The reaction mixture was cooled to room temperature, and the solvent removed under high vacuum. Water (150 ml) was added and the solution extracted with ethyl acetate (2×300 ml). The combined ethyl acetate solutions were washed with water (100 ml), dried over magnesium sulfate, and the solvent removed under reduced pressure to give a brown oil which was chromatographed on silica gel (250 g). Elution with toluene/ethyl acetate (1:1; 600 ml) gave an oil, characterized as isomer A of the title compound; NMR (CDCl3) 5.12(s, 4H), 4.50 (q, 2H). Elution with an additional 2 liters of the solvent mixture gave an oil characterized as isomer B of the title compound; NMR(CDCl3) δ5.17(s,2H), 5.03(d,2H), 4.60 (q, 2H).
Reaction SMILES: [C:1]([CH:4]([C:14]1[N:22]2[C:17]([C:18](=[O:34])[NH:19][C:20]([CH2:23][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[CH:29][CH:28]=[CH:27]4)=[N:21]2)=[C:16]([CH3:35])[N:15]=1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[OH:3][CH:1]([CH:4]([C:14]1[N:22]2[C:17]([C:18](=[O:34])[NH:19][C:20]([CH2:23][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[CH:29][CH:28]=[CH:27]4)=[N:21]2)=[C:16]([CH3:35])[N:15]=1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CC(=O)C(CCCc1ccccc1)c1nc(C)c2c(=O)[nH]c(Cc3ccc4ncccc4c3)nn12
Agent: [BH4-]
Agent: [Na+]
Product: Cc1nc(C(CCCc2ccccc2)C(C)O)n2nc(Cc3ccc4ncccc4c3)[nH]c(=O)c12

Procedure:
7-(1-Acetyl-4-phenylbutyl)-2-(quinolin-6-ylmethyl)-5-methylimidazo[5,1-f][1,2,4]-triazin-4(3H)-one is reacted analogously to Example 12 with sodium borohydride to give 7-[1-(1-hydroxyethyl)-4-phenylbutyl]-2-(quinolin-6-ylmethyl)-5-methylimidazo-[5,1-f][1,2,4]triazin-4(3H)-one.