Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:32])[C:11]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])=[CH:23][CH:22]=4)=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:13][C:14]=3[C:5]2=[N:4][N:3]1COCC[Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:32])[C:11]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([CH3:30])([CH3:31])[C:28]#[N:29])=[CH:25][CH:26]=4)=[C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[O:13][C:14]=3[C:5]2=[N:4][NH:3]1
Reactant: CC(C)(C#N)c1ccc(-c2c(-c3ccccc3)oc3c(ccn4c(=O)n(COCC[Si](C)(C)C)nc34)c2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C#N)c1ccc(-c2c(-c3ccccc3)oc3c(ccn4c(=O)[nH]nc34)c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
To a stirred solution of 2-{4-[3,6-dioxo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,6-dihydro-3H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalen-7-yl]-phenyl}-2-methyl-propionitrile (55 mg, 0.1 mmol) in DCM (2 mL), cooled in an ice bath, was added TFA (1.5 mL) at RT. After 16 h, the reaction mixture was evaporated to dryness, the resultant residue was dissolved in THF (3 mL) and benzyltrimethylammonium hydroxide solution (0.06 mL, 40% in MeOH) was added. The reaction mixture was stirred at RT for 1.5 h. EtOAc and water were added and the mixture was acidified by the addition of 1 M HCl (1 mL). The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, EtOAc) to afford the title compound (20 mg, 47%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.05 (s, 1H), 7.72 (d, J=7.3 Hz, 1H), 7.46-7.38 (m, 5H), 7.33-7.22 (m, 5H), 1.73 (s, 6H). LCMS (Method E): RT=4.22 min, [M+H]+=423.
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+].[Na+].[I-].C(O)CCO.[H][H].[CH2:27](Cl)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]CCC>CN(C=O)C.O>[CH2:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:1]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCCCCCCCCCl
Agent: CCCCCCCCCCOCCCO
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: OCCCO
Product: CCCCCCCCCCOCCCCCCCCCC
Reaction time: 18 h

Procedure:
3-Hydroxypropyl decyl ether (Compound 17) To a mixture of NaH (2.6 g, 70 mmol) and anhydrous NaI (9.9 g, 70 mmol) in dry DMF (80 mL) under N2 was added dropwise a solution of 1,3-propanediol (4.75 mL, 70 mmol) in DMF (20 mL). The mixture was stirred until hydrogen evolution had ceased, decyl chloride (1.34 g, 7.6 mmol) was added and stirring was continued at 50° C. for 18 hours. Then, the reaction mixture was poured into H2O (300 mL) and extracted with diethyl ether (3×250 mL). The organic extracts were combined, washed with sat. NaCl (100 mL), dried (MgSO4) and evaporated to dryness. The residue was subjected to silica-gel column chromatography [eluent: ethyl acetate/hexane, 30/70, v/v] to furnish decyl ether Compound 17 as a colourless oil.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([CH2:15][N+:16]([O-:18])=[O:17])(=[O:14])=[O:13])=[C:7]([CH3:19])[CH:6]=1)(=O)C.Cl.O>C(O)C>[NH2:4][C:5]1[CH:6]=[C:7]([CH3:19])[C:8]([S:12]([CH2:15][N+:16]([O-:18])=[O:17])(=[O:14])=[O:13])=[C:9]([CH3:11])[CH:10]=1
Reactant: CC(=O)Nc1cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 73 %

Procedure:
(4-Acetamido-2,6-dimethylphenylsulfonyl)nitromethane (11.5 g, 40 mM) is added in one portion to a boiling mixture of concentrated hydrochloric acid (22 mL), water (110 mL) and ethanol (45 mL). The mixture is stirred at reflux until a clear solution is formed (about 20 minutes) and then for a further 10 mins. The hot reaction mixture is then poured into an excess of ice-cold saturated sodium bicarbonate solution. The aqueous mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and the solvent removed by evaporation to give (4-amino-2,6-dimethylphenylsulfonyl)nitromethane, as a solid, m.p. 132°-133° C. [after recrystallisation from ethanol] in 73% yield; NMR(d6 -DMSO, 200 MHz): 2.39(6H, s), 6.19(4H, s), 6.35(2H,s); microanalysis, found: C,44.5; H,4.9; N,11.6%; C9H12N2O4S requires: C,44.3; H,4.9; N,11.5%.
Reaction SMILES: [C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C>>[C:4]([O:6][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])(=[O:5])[CH2:3][CH2:2][C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)=[O:7]
Reactant: CC1(C)CC(OC(=O)CCC(=O)[O-])CC(C)(C)N1
Reactant: CCCCCCCCCCCCBr
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)CCC(=O)OC1CC(C)(C)NC(C)(C)C1

Procedure:
The product is prepared as described in Example 4b by reacting 30.9 g (0.12 mol) of mono(2,2,6,6-tetramethyl-4-piperidyl) succinate with 29.9 g (0.12 mol) of 1-bromododecane in the presence of 12.1 g (0.12 mol) of triethylamine. The product obtained has a boiling point of 195° C./5.3 mbar.
Reaction SMILES: [CH3:1][CH:2]([NH:6][CH2:7][C:8]1[S:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH2:3][O:4][CH3:5].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>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.CO.O.O1CCOCC1>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:11]4[S:12][C:8]([CH2:7][NH:6][CH:2]([CH3:1])[CH2:3][O:4][CH3:5])=[CH:9][CH:10]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: COCC(C)NCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(C)COC)s4)cc23)CC1
Yield: 35.2 %

Procedure:
[5-({[1-methyl-2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid (60 mg, 0.262 mmol) was transferred to a CEM microwave tube with methanol. The methanol was evaporated under a stream of N2. To this was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.19 mmol), potassium carbonate (160 mg, 1.16 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol), dioxane (1.5 mL), and water (0.5 mL). The vial was capped and reacted in a CEM microwave at 150° C. for 30 min. This solution was loaded onto a 2 g SCX SPE cartridge primed with 3 mL of methanol. The cartridge was then sequentially eluted with water (3 mL), methanol (9 mL), and 2M NH3 in MeOH (6 mL). The NH3 in MeOH fractions were dried under a stream of N2 at 40° C. The crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP with UV (230 nm) and MS detection. The desired fractions were passed thru two sequential 500 mg Pharmasil CHQAX cartridge primed with 1 mL of methanol and 1 mL of water. The solvents were evaporated under a stream of N2 at 60° C. to give 34.7 mg of the title compound (34%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>>[N:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: [Na+]
Product: [N-]=[N+]=NCC(=O)c1ccc(Cl)cc1Cl

Procedure:
In a manner similar to Preparation 3 react 2-bromo-1-(2,4-dichlorophenyl)ethanone with sodium azide to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C=O.[C:17](O)(=O)C(O)=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH3:17])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: O=C(O)C(=O)O
Agent: C=O
Solvent: O=CO
Product: CN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 11: 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.125 g, 0.628 mmol), formic acid (1.82 mL), aqueous formaldehyde (40%, 1.63 mL). 65° C.; over night. The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether (0.126 g). M.p. 159-162° C.; MS m/z (relative intensity, 70 eV) 213 (M+, 27), 141 (13), 113 (15), 58 (32), 57 (bp).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][N+:9]([O-])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C[Si](C)(C)[C:15]#[N:16].C(N(CC)CC)C>C(#N)C>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:15]#[N:16])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccnc(C#N)c1

Procedure:
A solution of 4-(acetylaminomethyl)pyridine N-oxide (17.5 g), trimethylsilanecarbonitrile (53 ml) and triethylamine (43 ml) in acetonitrile (180 ml) was refluxed for 7 hours with stirring. After evaporation of the solvent, the residue was diluted with water and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (430 g) by eluting with a mixture of ethyl acetate and methanol (50:1) followed by recrystallization with a mixture of ethyl acetate and diisopropyl ether to give 4-(acetylaminomethyl)-2-pyridinecarbonitrile (8.66 g).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:15])=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25]O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([C:4]1[C:5]([O:15][CH2:25][CH2:24][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:6][O:7][C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: C=CCc1c(O)noc1-c1ccccc1
Product: C=CCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 91.7 %

Procedure:
4-Allyl-3-hydroxy-5-phenylisoxazole (1.00 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.96 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (1.57 g, 91%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH:12]([CH2:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:12]([CH2:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CCCC(Br)C(=O)OCC
Product: CCCC(Oc1ccccc1[N+](=O)[O-])C(=O)OCC
Yield: 104.1 %

Procedure:
Starting from 2-nitrophenol (1.0 g, 1 eq, 7.19 mmol) and ethyl 2-bromopentanoate (2.97 ml, 3.0 eq, 21.54 mmol) the procedure of step (i), preparation 17 was followed to obtain ethyl 2-(2-nitrophenoxy)pentanoate (2.0 g) as crude which was used for step (ii).
Reaction SMILES: [F:1][C:2]1[C:19]([CH3:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([OH:14])[C:8]=1[CH3:15])=O>C1COCC1>[F:13][C:12]1[CH:11]=[CH:10][C:9]([OH:14])=[C:8]([CH3:15])[C:7]=1[NH:6][CH2:4][C:3]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH:18]=[C:19]([CH3:20])[C:2]=1[F:1]
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2C)c1F
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2C)c1F
Temperature: 60 °C
Yield: 68.4 %

Procedure:
To a solution of 2-fluoro-N-(6-fluoro-3-hydroxy-2-methyl-phenyl)-5-(3-fluorophenyl)-3-methyl-benzamide (404 mg, 1.1 mmol, 1.0 eq) in THF (10 mL) under N2 was added a solution of BH3 (1M in THF, 5.5 mL, 5.5 mmol, 5.0 eq) at room temperature. The reaction mixture was heated at 60° C. for 3 h, then cooled to room temperature and quenched with 1 M HCl. Water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The crude residue obtained was purified by column chromatography (petroleum ether:EtOAc, 100:1 to 15:1) to give the title compound as a yellow oil (269 mg, 69%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[N+:24]([O-])([OH:26])=[O:25]>O>[CH3:2][N:3]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[CH:21]=2)[CH2:16]1)[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: CN(CCc1ccc([N+](=O)[O-])cc1)C1Cc2ccccc2C1
Agent: Cl
Solvent: O
Product: CN(CCc1ccc([N+](=O)[O-])cc1)C1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
2-[N-Methyl-N-(4-nitrophenethyl)amino]indane hydrochloride (1.2 g) was added portionwise over 10 minutes to fuming nitric acid (20 ml, density=1.5 g/ml) cooled to -5°. Stirring was continued for a further 2 minutes before the reaction mixture was poured into ice/water. The water-containing mixture was extracted with methylene chloride and the organic extract was washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated to dryness in vacuo. The residue was rectystallised from ethanol to give the title compound, yield 0.78 g, m.p. 138°-140°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:24]1[CH2:25][CH2:26][N:21]([C:18]2[C:17]([CH3:27])=[CH:16][C:15]([CH:12]3[CH2:13][CH2:14]3)=[CH:20][N:19]=2)[CH2:22][CH2:23]1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2Br)CC1
Yield: 95.1 %

Procedure:
Using 2-bromo-4-chlorobenzoic acid (1 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (0.92 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.75 g) was obtained.
Reaction SMILES: Cl.[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH:20]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21]1>CN(C=O)C.O>[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH:19][S:23]([CH:20]3[CH2:22][CH2:21]3)(=[O:25])=[O:24])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1)C1CC1
Reaction time: 1.5 h
Yield: 63.8 %

Procedure:
To a mixture of (1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.300 g, 0.952 mmol, Example #6, Step C) in DMF (9 mL) was added TEA (0.462 mL, 3.33 mmol) and cyclopropanesulfonyl chloride (0.097 mL, 0.95 mmol). After about 1.5 h at ambient temperature, the reaction was diluted with water (10 mL) and extracted with DCM (3×15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. To the crude material was added MeOH (˜50 mL) and a small amount of insoluble material (<0.01 g) was removed by filtration. Silica gel (2 g) was added to the filtrate and the mixture was concentrated under reduced pressure. The mixture was purified by silica gel chromatography eluting with a step-wise gradient of DCM/MeOH/NH4OH 990:9:1 to 980:18:2 to give an off-white solid that was dried in a vacuum oven at about 70° C. The solid was dissolved in hot MeOH, filtered while hot to remove particulates and then the filtrate was sonicated while cooling to provide a fine suspension which was concentrated under reduced pressure and dried in a vacuum oven at about 100° C. to give N-((1S, 3R)-3-(6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.21 g, 64%): LC/MS (Table 2, Method a) Rt=1.51 min; MS m/z: 347 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH2:22][O:23][CH3:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.Cl.[F:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[NH:35][C:34](=[O:37])[C:33]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[CH:32]2>>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH2:22][O:23][CH3:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([N:41]3[CH2:42][CH2:43][CH:38]([C:33]4[C:34](=[O:37])[NH:35][C:36]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][C:27]=5[F:26])[CH2:39][CH2:40]3)=[O:19])[CH2:15][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Reactant: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)O)C1=O
Agent: Cl
Product: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C1=O
Yield: 56 %

Procedure:
[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-acetic acid (100 mg, 0.25 mmol) and 8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (85 mg, 0.30 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10$$ -tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 56% yield. High resolution MS m/e (M+H)+=624.1631.
Reaction SMILES: C([Si](C)(C)[C:6]1[N:10]([CH3:11])[C:9]([C:12]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)([OH:35])[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:18](=[O:27])[CH:17]=[C:16]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[CH:8][N:7]=1)(C)(C)C.O>C1COCC1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:34][C:30]1[CH:29]=[C:28]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:12]([C:36]4[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=4)([OH:35])[C:9]4[N:10]([CH3:11])[CH:6]=[N:7][CH:8]=4)[CH:14]=3)[N:19]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:18](=[O:27])[CH:17]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)cnc1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.9 %

Procedure:
A solution of 6-[[2-(tert-butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-(4-chloro-phenyl)-hydroxy-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one (4.24 g crude) in THF (100 mL) was treated with tetrabutylammonium chloride (1 M in THF, 10.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, poured into H2O (200 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with 1N HCl (100 mL), aqueous NaHCO3 (100 mL), and brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a light green foam. Purification by flash column chromatography (silica, EtOAc:pet. ether:NH4OH 1:1:.01) gave 4-(3-Chloro-phenyl)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (2.3 g, 68%) as a light yellow solid.
Reaction SMILES: C([O-])([O-])OCC.C(OC(=O)C)(=O)C.[C:14]([NH:17][CH:18]1[CH2:22][CH2:21][N:20]([C:23]2[C:40]([F:41])=[CH:39][C:26]([C:27]([C:29](=[CH:35]OCC)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:28])=[C:25]([Cl:42])[N:24]=2)[CH2:19]1)(=[O:16])[CH3:15].[CH:43]1([NH2:46])[CH2:45][CH2:44]1>>[C:14]([NH:17][CH:18]1[CH2:22][CH2:21][N:20]([C:23]2[C:40]([F:41])=[CH:39][C:26]([C:27]([C:29](=[CH:35][NH:46][CH:43]3[CH2:45][CH2:44]3)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:28])=[C:25]([Cl:42])[N:24]=2)[CH2:19]1)(=[O:16])[CH3:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Cl
Reactant: NC1CC1
Agent: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Cl

Procedure:
Ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxo-propionate (1.4 g) prepared in Reference Example 10-(3) was allowed to react with 3-acetylaminopyrrolidine to give ethyl 3-[6-(3-acetylamino-1-pyrrolidinyl)-2-chloro-5-fluoropyridin-3-yl]-3-oxopropionate (0.78 g) as a oil. This compound (0.74 g) was treated with ethyl orthoformate and acetic anhydride, and the resulting oil, ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-chloro-5-fluoronicotinoyl]-3-ethoxyacrylate, was allowed to react with cyclopropylamine to give ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-chloro-5-fluoronicotinoyl]-3-cyclopropylaminoacrylate (0.43 g) as an amorphous powder, m.p. 71°-75° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CS(C)=O>[C:11]([C:7]1[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
8.40 g (40.7 mmol) 2,6-di-tert-butylphenol was dissolved in 100 ml dried DMSO. 8 g (58 mmol) potassium carbonate and 8.5 g (54 mmol) p-chloronitrobenzene were added into the DMSO solution. The DMSO solution was heated to 100˜120° C. for 12 hrs with stirring. Then the reaction mixture was allowed to cool to room temperature and poured into distilled water. The aqueous solution was acidified to pH 2˜4 and yellow precipitate was collected by filtration. The yellow precipitate was washed with water and dried. The crude yield was 92%. The yellow precipitate was purified by recrystallizing in cyanomethane, mp 157˜160° C. Elemental Anal. Calcd.: C, 73.40; H, 7.64; N, 4.28. Found: C, 73.25; H, 7.58; N, 4.25%.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]2[C:21]3[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:20]=3[O:19][C:18]([CH3:29])([CH3:28])[CH2:17]2)=[N+:13]([O-:15])[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[C:26]([C:23]1[CH:24]=[CH:25][C:20]2[O:19][C:18]([CH3:29])([CH3:28])[CH2:17][CH:16]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N+:13]=3[O-:15])[C:21]=2[CH:22]=1)#[N:27]
Reactant: CC1(C)CC(c2ccc(OCc3ccccc3)c[n+]2[O-])c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(c2ccc(O)c[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 31.1 %

Procedure:
0.21 g of 5-benzyloxy-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide in 90 ml of methanol was hydrogenated over 10% palladium-on-carbon at room temperature and under atmospheric pressure for 30 minutes. The catalyst was removed by filtration and the filtrate was evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (19:1) for the elution to give 0.05 g of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-hydroxypyridine N-oxide in the form of an off-white solid of melting point 224° C. (from ethyl acetate).