Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([NH:30][CH2:31][CH3:32])=[C:24]([N+:27]([O-])=O)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.[Fe]>[NH2:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[NH:30][CH2:31][CH3:32])[N:20]=[CH:19][N:18]=[C:17]2[N:14]1[CH2:15][CH2:16][N:11]([C:9](=[S:10])[NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:13]1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Yield: 92 %

Procedure:
To a suspension of 4.26 g (9.44 mmol) of N-benzyl-4-(7-ethylamino-6-nitro-4-quinazolinyl)-1-piperazinethiocarboxamide obtained in Example 361 in 100 ml of ethanol and 10 ml of water were added 4.26 g (76.3 mmol) of iron powder and 430 mg (1.59 mmol) of ferric chloride hexahydrate under ice-cooling, followed by heating under reflux in an atmosphere of argon for 4 hours. After the iron powder was separated by filtration using Celite, the solvent was evaporated, and the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:26](=[CH:27][CH:28]=5)[CH2:25][NH:24][CH2:23][CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>C(Cl)Cl>[C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:26](=[CH:27][CH:28]=5)[CH2:25][N:24]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH2:23][CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CCNC6)sc4n3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN1CCc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(1-phenylcyclopropyl)-2-(1,2,3,4-tetrahydroisoquinolin-6-yl)thiazolo[5,4-b]pyridine (97 mg, 0.252 mmol), triethylamine (0.053 mL, 0.377 mmol), and methyl 2-bromoacetate (0.024 mL, 0.254 mmol) in DCM (2.0 mL) was stirred at 25° C. for 30 min. Additional methyl 2-bromoacetate (0.024 mL, 0.254 mmol) was then added, and the resulting mixture was stirred at 25° C. for 30 min. The resulting suspension was then concentrated onto silica gel and chromatographically purified (0-100% EtOAc/hexanes) to provide methyl 2-(6-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate as a white solid. MS (ESI) m/z: Calculated: 455.2; Observed: 456.0 (M++1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[I:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([O:12][CH2:14][CH2:15][O:16][CH3:17])[CH:3]=1
Reactant: Oc1cc(I)cc(C(F)(F)F)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(I)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A mixture of 3-iodo-5-(trifluoromethyl)phenol (5 g, 17.36 mmol, 1.00 equiv), 1-bromo-2-methoxyethane (3.6 g, 25.90 mmol, 1.49 equiv) and potassium carbonate (7.2 g, 52.09 mmol, 3.00 equiv) in N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 h. The resulting mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to give 5.1 g (85%) of 1-iodo-3-(2-methoxyethoxy)-5-(trifluoromethyl)benzene as a yellow oil. 1H-NMR (300 MHz, DMSO-d6): δ 7.63-7.60 (m, 2H), 7.28 (s, 1H), 4.21-4.18 (m, 2H), 3.66-3.64 (m, 3H), 3.33 (s, 3H) ppm. LCMS (method D, ESI): RT=1.67 min.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.N[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(#N)C>[C:9]1([C:3]2=[CH:2][C:1]([O:6][C:4]2=[O:5])=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CC#N
Product: O=C1C=C(c2ccccc2)C(=O)O1
Yield: 29.2 %

Procedure:
Following the general procedure of Example I, 150 mmols of maleic anhydride were reacted with 25 mmols of distilled aniline in 60 mL of acetonitrile and in the presence of 38 mmols of concentrated HCl and 2.5 mmols of cuprous oxide. The process resulted in a 29.2% yield of 3-phenylmaleic anhydride.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15]Cl)[O:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:18]=[N+]=[N-].[Na+]>CN(C)C=O>[Si:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][NH2:18])[O:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1coc(CCl)cc1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1coc(CN)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (20 ml) was dissolved (5-tert-butyldimethylsilyloxy-4-oxo-4H-pyran-2-yl)methyl chloride (2.00 g). Sodium azide (1.00 g) was added to the resulting solution and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, followed by washing once with water and then once with saturated aqueous NaCl solution. The organic layer thus extracted was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was dissolved in methanol (100 ml), followed by the addition of 10% palladium-carbon (50% wet w/w, 800 mg). The resulting mixture was stirred overnight under a hydrogen gas stream of normal pressure. The reaction mixture was subjected to Celite filtration, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a silica gel column (methylene chloride methanol=100:3), whereby the title compound (290 mg) was obtained as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=2)[C:6](=[O:14])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(=O)Nc2ccccc21
Reactant: Fc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-3,4-dihydroquinoxalin-2(1H)-one (0.13 g, 0.68 mmol) in DMF (3.5 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (0.75 mL, 0.75 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with 4-fluorobenzyl bromide (0.089 mL, 0.72 mmol), and stirred at room temperature for 3 hours. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:14][O:15][C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[NH4+:27]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:14][O:15][C:16]([CH3:21])([CH3:20])[C:17]([NH2:27])=[O:18])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Cc1nc(-c2ccc(Cl)cc2)oc1COC(C)(C)C(=O)O
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)cc2)oc1COC(C)(C)C(N)=O
Reaction time: 16 h
Yield: 49 %

Procedure:
4.44 g (14.5 mmol) of 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid were dissolved in 40 ml of dry dichloromethane and 1 drop of dimethylformamide was added. 1.96 (16 mmol) of thionyl chloride were added and the mixture was heated to reflux for 4 hours. The cooled solution of the resulting acid chloride was added while stirring to 70 ml of aqueous ammonium hydroxide solution (specific gravity 1.880) and crushed ice. After stirring for 16 hours the suspension was extracted with 200 ml of dichloromethane. The organic phase was separated and washed twice with 100 ml of water each time. The organic phase was dried over magnesium sulphate and filtered, and the solvent was then removed by evaporation under reduced pressure. Recrystallization of the crude solid from ethyl acetate gave 2.2 g (49%) of 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionamide of melting point 177°-178° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[C:8]=1[F:16])(=O)=O.[C:19]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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:22]([O:21][C:19](=[O:20])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[C:8]=2[F:16])=[CH:29][C:28]=1[F:36])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1F
Reactant: N#Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1F
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1F
Temperature: 90 °C
Yield: 92.9 %

Procedure:
A solution of 7 g of 4-cyano-2,3-difluorophenyl trifluoromethanesulfonate in 400 mL of dioxane is admixed at ambient temperature with 8.67 g of N-Boc 4-amino-3-fluorophenylboronic acid, 7.235 g of sodium carbonate in solution in 100 mL of distilled water, and then 3.38 g of tetrakistriphenylphosphinepalladium. The reaction mixture is heated at 90° C. for 3 h and then concentrated to dryness under reduced pressure. The solid obtained is taken up in ethyl acetate; this organic phase is washed a number of times with distilled water and then with saturated sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The solid obtained is chromatographed on a silica column (eluent: cyclohexane/ethyl acetate, 90/10 by volume). Evaporation to dryness under reduced pressure of the fractions containing the expected product gives 7.89 g of tert-butyl(4′-cyano-3,2′,3′-trifluorobiphenyl-4-yl)carbamate in the form of a cream-white solid, whose characteristics are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)C)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[NH2:9]
Reactant: CC(=O)Nc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(F)cc(Br)c1
Temperature: 100 °C
Yield: 74.6 %

Procedure:
To a solution of N-(3-bromo-5-fluorophenyl)acetamide (Intermediate 181, 8.7 g, 37.4 mmol) in ethanol (30 mL) was added concentrated hydrochloric acid (80 mL). The reaction was heated to 100° C. for 1 hr. It was cooled to room temperature and neutralized with 5N sodium hydroxide. The crude product was extracted with ethyl acetate (2×100 mL), the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel with a gradient of 5-10% ethyl acetate in hexanes gave 5.3 g (75%) of the product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([Cl:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+].[N:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CS(C)=O>[Cl:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:29]1[CH2:30][CH2:31][CH:26]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:27][CH2:28]1
Reactant: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
4-Chloro-5-fluoro-2-nitrophenyl methyl ether (2.19 g, 10.7 mmol) was dissolved in DMSO (10 mL). K2CO3 (2.2 g, 16 mmol) and 1,4′-bipiperidine (1.8 g, 11 mmol) were added and the reaction mixture was allowed to stir overnight at rt. The mixture was then poured into H2O and extracted with EtOAc (2×) and then the combined organics were extracted with H2O (5×). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step C (2.69 g, 71%). MS (M+H, ES+) 354.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[S:5][CH:6]=1.[CH2:16]1[O:18][CH2:17]1.O>C1COCC1.[Li+].CC([N-]C(C)C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[S:5][C:6]=1[CH2:16][CH2:17][OH:18]
Reactant: C1CO1
Reactant: CCc1ccc(Cc2cc(Br)cs2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(Br)c(CCO)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Under a nitrogen stream, to 4-bromo-2-((4-ethylphenyl)methyl)thiophene (2.80 g, 10.0 mmol) in anhydrous THF (40 ml), LDA (2.0 M, 5.50 ml, 11.0 ml) was added dropwise at −78° C. over 5 minutes. After the reaction mixture was stirred at 0° C. for 30 minutes, a THF solution of ethylene oxide (10 ml) was added dropwise at −78° C. The reaction mixture was warmed to room temperature and stirred for 3 hours. After addition of water, the reaction mixture was extracted with ether. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:9)) to give the titled compound (2.55 g, 78%).
Reaction SMILES: Cl.CS([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:18][CH:17]=3)=[C:13]([C:32]3[CH:37]=[CH:36][C:35]([O:38]S(C)(=O)=O)=[CH:34][CH:33]=3)[S:12][C:11]=2[CH:43]=1)(=O)=O.[OH-].[Na+].CC(C)=O>C(O)C>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:31])[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:20][CH:21]=3)=[C:13]([C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)[S:12][C:11]=2[CH:43]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12

Procedure:
A 4 g. portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride, was combined with 100 ml. of denatured alcohol and 10 ml. of 5 N sodium hydroxide, and stirred under reflux for 1.5 hours under a nitrogen atmosphere. The reaction mixture was then evaporated to dryness under vacuum, and the residue was dissolved in 200 ml. of water and washed with 300 ml. of diethyl ether. The water layer was degassed under vacuum, and then nitrogen was bubbled through it to remove all traces of ether. The mixture was then acidified with 1 N hydrochloric acid, and then made basic with excess sodium bicarbonate. The precipitate was collected by filtration and washed with cold water to obtain 2.4 g. of crude product. It was purified on a 2×30 cm. column of silica gel, eluting first with 700 ml. of 5% methanol in chloroform, followed by 1 liter of 10% methanol in chloroform. The impurities came off first, and the product-containing fractions were combined and evaporated under vacuum to obtain 1.78 g. of yellow oil. The oil was dissolved in 6 ml. of acetone, seeded and chilled in a freezer to obtain 1.2 g. of purified product, m.p. 143°-147°. The identity of the product was confirmed as follows: nmr spectrum (100 mHz in dmso-d6) δ1.20-1.65 (6H, m, N(CH2CH2)2CH2); 2.30-2.45 (4H, m, N(CH2CH2)2CH2); 2.60 (2H, t, J=6 Hz, OCH2CH2N): 4.06 (2H, t, J=6 Hz, OCH2CH2N); 6.68 (2H, d, J=9 Hz, aromatic o to OH); 6.85 (1H, q, JH4-H5 =9 Hz, JH5-H7 =2 Hz, H5 of benzothiophene ring); 6.90 (2H, d, J=9 Hz, aromatic o to OCH2CH2N); 7.18 (2H, d, J=9 Hz, aromatic m to OH); 7.25 (1H, d, J=9 Hz, H4 of benzothiophene ring); 7.66 (2H, d, J=9 Hz, aromatic o to CO); 9.72 (2H, broad s, OH). Ultraviolet spectrum in ethanol: λmax (ε): 290 nm. (34,000). Electron impact mass spectrum M+ at m/e 473.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>C(O)C>[Cl:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:1][C:2]3[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: CCO
Product: COC(=O)c1cc(Nc2ccnc3cc(Cl)ccc23)cc(C(=O)OC)c1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
1,3-dimethyl 5-aminobenzene-1,3-dicarboxylate (2.09 g, 10 mmol) and 4,7-dichloroquinoline (1.98 g, 1 eq) were refluxed in 200 mL of ethanol for 3 h. The reaction mixture was then cooled to room temperature and the precipitate was removed by filtration and washed successively with a saturated aqueous solution of NaHCO3, water, ethanol and then petroleum ether to yield expected compound as a yellow powder (2.90 g, 78% yield). m/z (ESI) 371.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[C:4]([CH3:13])[N:3]=1.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:22]([NH:21][CH2:20][C:19]3[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:27])[F:26])=[CH:25][CH:24]=3)=[O:23])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1cc2c(N)cccc2c(C)n1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc2c(C)n1

Procedure:
Prepared from 1,3-dimethylisoquinolin-5-amine (Description 83) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 374 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[C:39]([N:42]1[C:50]2[C:45](=[CH:46][C:47]([NH2:51])=[CH:48][CH:49]=2)[CH2:44][CH2:43]1)(=[O:41])[CH3:40]>C(O)C>[C:39]([N:42]1[C:50]2[C:45](=[CH:46][C:47]([NH:51][C:7]3[N:8]=[CH:9][C:10]4=[C:2]([CH3:1])[N:3]=[C:4]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[N:5]4[N:6]=3)=[CH:48][CH:49]=2)[CH2:44][CH2:43]1)(=[O:41])[CH3:40]
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Reactant: CC(=O)N1CCc2cc(N)ccc21
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: CC(=O)N1CCc2cc(Nc3ncc4c(C)nc(-c5ccccc5)n4n3)ccc21
Yield: 30.6 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), 1-acetyl-5-amino-2,3-dihydro-(1h)-indole (30.5 mg, 0.17 mmol) and ethanol (2.5 mL) to afford N-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (20 mg) as a yellow solid. MS m/z 385 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][C:21]=2[O:30][CH3:31])=[C:14]([CH3:32])[N:13]=1>C1COCC1.CCOC(C)=O>[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([CH2:24][OH:25])=[CH:22][C:21]=2[O:30][CH3:31])=[C:14]([CH3:32])[N:13]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1Cl
Temperature: 25 °C

Procedure:
A solution of diisobutylaluminium hydride (1M in hexanes, 5.44 mL) was added over 10 min to a suspension of the product from example 21 step (iii) (0.5 g) in THF (10 mL) at 0° C. The mixture was allowed to warm to rt and stirred for Ih. EtOAc (10 mL) was added cautiously and then the reaction mixture was added to ice/water (100 mL). The mixture was stirred for 30 min and then diluted with EtOAc (50 mL). The organic phase was separated and the aqueous was extracted with EtOAc. The combined organic phase was dried, filtered and evaporated to afford the subtitle compound, 0.39 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:19])([O-])[CH3:17].[K+].C(I)C(C)C>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:15][CH:16]([CH3:19])[CH3:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)CI
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)CC1CN(Cc2ccccc2)CCC1=O
Reaction time: 0.25 h

Procedure:
1-benzylpiperidin-4-one (10 g, 53.0 mmole) was added to the stirred suspension of potassium tert. butoxide (7.0 g, 59.0 mmole) in tetrahydrofuran (50 ml) at 10° C. The reaction mixture was stirred for 15 min, isobutyl iodide (10.0 g, 54.0 mmole) was added at 10° C. The resulting mixture stirred for 16 hr at room temperature, refluxed for 3 hr and concentrated to dryness. The residue was triturated with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated to give crude product, which was purified through column chromatography. Elute from 10% ethyl acetate in hexane afforded 1-benzyl-3-isobutylpiperidin-4-one. Yield 1.0 g (9%), C16H23NO, m/z 246 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[NH2:38])=[CH:31][CH:30]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:41])[C:37]([CH3:39])([CH3:40])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)N)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1Oc1ccc(N2C(=O)NC(C)(C)C2=O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 189.1 %

Procedure:
In a 50 mL round-bottomed flask N-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-2-methylalaninamide (Intermediate 80, 144.4 mg) was dissolved in dichloromethane (5 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (27.7 mg, 0.227 mmol), triethylamine (0.158 mL, 1.134 mmol) and triphosgene (67.3 mg, 0.227 mmol) were added. The reaction mixture was stirred at 0° C. After 20 min, the solvent was evaporated under vacuum to afford a yellow solid which was purified via silica gel chromatography (Biotage system, 10 g SNAP column) using as eluent a gradient Cyclohexane/EtOAc from 2:1 to 1:3 in 20 CV; then 1:3 for 5 CV. The collected fractions afforded the title compound as a white solid (139.7 mg).