Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH:5]1([NH2:8])[CH2:7][CH2:6]1.C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1.O>O1CCOCC1>[CH:5]1([NH:8][C:11](=[O:10])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)=[N:22][O:23][C:24]=3[CH3:25])=[N:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of cyclopropylamine (69 mg, 84 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 3 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (100 mg, 91%) which was obtained as a white solid. MS: m/e=368.0 [M+H]+.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][NH3+:18].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O>>[Cl:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][NH:18][CH2:24][C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[CH:10][C:9]([C:13]#[N:14])=[CH:8]2
Reactant: N#Cc1ccc2c(Cl)c(OCC[NH3+])ccc2c1
Reactant: O=Cc1cccs1
Agent: [Cl-]
Product: N#Cc1ccc2c(Cl)c(OCCNCc3cccs3)ccc2c1
Yield: 35 %

Procedure:
Prepared from 2-[(1-chloro-6-cyanonaphthalen-2-yl)oxy]ethanaminium chloride and thiophen-2-carbaldehyde in 35% yield as a whitish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:24])=[C:6]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:38]([CH2:40][CH2:41][CH2:42]Cl)[CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.CCOCC>[CH3:1][O:2][C:3]1[N:4]([CH2:42][CH2:41][CH2:40][N:38]([CH3:39])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:5]([CH3:24])[C:6]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Reactant: CN(CCCCl)Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC1=NC(c2cccc([N+](=O)[O-])c2)=C(C(=O)OC(C)C)C(C)N1CCCN(C)Cc1ccccc1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methyethyl ester (2.0 g, 6.0 mmol) in dimethylformamide (7.0 ml) was treated with finely ground potassium carbonate (1.7 g, 12.0 mmoles), N-benzyl-3-chloro-N-methylpropylamine (2.37 g, 12.0 mmol) and a catalytic amount of 18-crown-6. The reaction was heated at 70°-75° C. under argon overnight. The reaction was allowed to cool down to room temperature and was diluted with ether. It was filtered, and the filtrate was washed with water, brine and was dried over anhydrous magnesium sulfate. Evaporation of solvent provided a brown oil which was purified by flash chromatography (20% acetone in hexanes) to yield the title compound (1.51 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[C:10](=[O:35])[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29](C#N)[N:28]=2)[C:12]([CH3:25])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]>C(O)(C)(C)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[C:10](=[O:35])[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([OH:4])[N:28]=2)[C:12]([CH3:25])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccnc(C#N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccnc(O)n1
Yield: 51.7 %

Procedure:
A mixture of 4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carbonitrile trifluoroacetate (0.2 g, 0.00035 mol) potassium fluoride on aluminum oxide (0.25 g) in t-butanol (5.0 mL) was refluxed for 4 h under argon atmosphere. The reaction mixture was cooled, filtered the precipitate and washed with ethanol. The combined filtrate and washings were concentrated to dryness and the residue was purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m/z=452) were combined and freeze dried to afford the title compound (0.05 g) as a white powder:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:34])=[O:35])[N:18]=3)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCS(C)(=O)=O)c4ccc(OC(F)F)cc34)nc12
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (105 mg, 0.138 mmol) in dichloromethane (4 mL) was added drop-wise trifluoroacetic acid (2 mL) at room temperature and the reaction mixture was stirred for 2 hours. The solvent was removed under reduced pressure and the residue was purified by preparative-TLC (silica gel, EtOAc as eluent) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (50 mg, 72%) as a white solid. MS: (M+H)+=521.1; 1H NMR (300 MHz, DMSO): δ 12.85 (brs, 1H), 9.13 (s, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.93 (t, 1H, J=7.8 Hz), 7.47 (d, 1H, J=9.0 Hz), 7.24 (s, 1H), 4.72 (d, 2H, J=6.6 Hz), 3.28-3.18 (m, 2H), 3.02 (s, 3H), 2.40-2.38 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=O)[CH3:12])=[C:6](I)[CH:5]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1C#C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:11]([C:18]1[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:23])=[CH:12]2)=[O:15]
Reactant: C#Cc1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(NC(C)=O)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Product: COC(=O)c1ccc2[nH]c(-c3c(Cl)cccc3Cl)cc2c1
Temperature: 100 °C

Procedure:
To a solution of 4-acetylamino-3-iodo-benzoic acid methyl ester (0.17 g) in TMG (1.5 mL) and dioxane (1.5 mL) were added 1,3-dichloro-2-ethynyl-benzene (0.1 g), 10 mol % of Pd(PPh3)2Cl2, and 10 mol % of CuI. The reaction mixture was heated to 100° C. overnight. The solvent were evaporated and the resulting mixture was purified by column chromatography (SiO2, 2:3, EtOAc/Hexane) to give 2-(2,6-dichloro-phenyl)-1H-indole-5-carboxylic acid methyl ester: MS (m/z) 320.0 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.ClC1C=CC=C(C(OO)=[O:29])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:2][C:3]1[C:4]([S:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:29])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2ccccc2nc1SCc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccccc2nc1S(=O)Cc1ccccn1
Yield: 67.2 %

Procedure:
In a mixture of 36 ml of chloroform and 18 ml of methanol was dissolved 2.6 g of 3-methyl-2-(2-pyridylmethylthio)quinoxaline hydrochloride. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was added 1.77 g of m-chloroperbenzoic acid (purity 70%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture under chilling. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (chloroform/methanol), and recrystallized from ethyl/hexane to give 1.63 g of 3-methyl-2-(2-pyridylmethylsulfinyl)quinoxaline as an orange crystalline powder, m.p. 85°-88° C. (decompn.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].CCN(C(C)C)C(C)C.[CH2:30](Cl)[O:31][CH2:32][CH2:33][O:34][CH3:35]>CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:20])=[N:4][O:5][C:6]=1[N:7]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:9])=[O:10]
Reactant: COCCOCCl
Reactant: Cc1noc(NS(=O)(=O)c2csc3ncccc23)c1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)thieno[2,3-b]-pyridine-3-sulfonamide (0.76 g, 2.3 mmoles) (see Example 3), DIEA (0.6 ml, 35 mmoles) and EtOAc (100 ml) was added MEM-Cl (0.3 ml, 2.5 mmoles). The orange-brown solution was stirred 3 hours at ambient temperature, then washed with saturated NaHCO3 (200 ml). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.92 g (95%) of the title compound as a brown solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH3:21].Cl>ClCCCl.O>[C:5]([C:16]1[CH:17]=[CH:18][C:19]2[C:14](=[CH:13][CH:12]=[C:11]([O:20][CH3:21])[C:10]=2[Br:9])[CH:15]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1ccc2ccccc2c1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc2cc(C(C)=O)ccc2c1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 43 g of anhydrous AlCl3 and 24.6 g (0.313 mole) of acetyl chloride in 200 ml of 1,2-dichloroethane at 10° C. was cooled to 0° C. and added dropwise under stirring with a solution of 59.25 g (0.250 mole) of 1-bromo-2-methoxy-naphthalene in 150 ml of 1,2-dichloroethane. The resulting solution was stirred for 15 minutes then poured into a cold solution of 300 ml of water and 100 ml of 2 N hydrochloric acid. The organic phase was separated, washed first with 100 ml of 1 N hydrochloric acid and then with 100 ml of water, dried under vacuum and the obtained residue was crystallized from 2-butanol. Yield 68.11 g (98%).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:38]=[C:37](B4OCC(C)(C)CO4)[CH:36]=[CH:35][C:34]=3[O:47][CH3:48])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:50]1[S:54][C:53]([C:55]([O:57][CH3:58])=[O:56])=[CH:52][C:51]=1[CH3:59].N#N.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:19]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:38]=[C:37]([C:50]4[S:54][C:53]([C:55]([O:57][CH3:58])=[O:56])=[CH:52][C:51]=4[CH3:59])[CH:36]=[CH:35][C:34]=3[O:47][CH3:48])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(B2OCC(C)(C)CO2)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: COC(=O)c1cc(C)c(Br)s1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(-c2ccc(OC)c(-c3ccc(N4CCC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (4S,5R)-3-({6-azetidin-1-yl-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]pyridin-2-yl}methyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (27 mg, 0.040 mmol) and methyl 5-bromo-4-methyl-2-thiophene carboxylate (18.74 mg, 0.080 mmol) in THF (0.5 mL) was degassed with N2 at 25° C. 1N K2CO3 (0.5 mL) was added followed by 1,1-bis(di-tert-butylphosphino) ferrocene palladium dichloride (2.60 mg, 3.99 mmol) and the reaction was stirred vigorously at 25° C. under N2 overnight. The reaction was diluted with water and extracted with EtOAc (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by preparative TLC (20×20, 1000 μm, hexanes/EtOAc (70/30)) to give methyl 5-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}-4-methylthiophene-2-carboxylate. LCMS calc.=719.2. found=720.2 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.86 (s, 1H); 7.73 (s, br, 2H); 7.62 (s, 1H); 7.47 (d, J=8.6 Hz, 1H); 7.35 (d, J=8.6 Hz, 1H); 7.33-7.23 (m, 1H); 7.03 (d, J=8.6 Hz, 1H); 6.31 (d, J=8.3 Hz, 1H); 5.74-5.31 (m, 1H); 4.87 (d, J=16.2 Hz, 1H); 4.24 (s, br, 1H); 4.23-3.97 (m, 5H); 3.88 (s, 3H); 3.87 (s, 3H); 2.47-2.41 (m, 2H); 2.33 (s, 3H); 0.75-0.53 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:23])[N:14]([CH2:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH3:25][O:26][NH2:27]>>[CH3:25][O:26][N:27]=[C:18]([CH2:17][C:16]([CH3:21])([CH3:22])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH3:23])[CH3:19]
Reactant: CON
Reactant: CC(=O)CC(C)(C)Cn1c(C)nc2c(N)nc3ccccc3c21
Agent: Cl
Product: CON=C(C)CC(C)(C)Cn1c(C)nc2c(N)nc3ccccc3c21

Procedure:
By the general method described in Part F Example 30, 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one was reacted with O-methylhydroxylamine hydrochloride to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one O-methyloxime as about a 4.9 to 1 mixture of E and Z isomers as light yellow needles after recrystallization from aqueous methanol, mp 193-195° C.
Reaction SMILES: [N:1]([C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][CH2:5]1)=[C:2]=[O:3].Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[NH2:35][C:21]1[N:22]=[C:23]([C:25]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][N:31]([C:2]([NH:1][C:4]4([C:7]([F:10])([F:9])[F:8])[CH2:6][CH2:5]4)=[O:3])[CH2:32]3)=[CH:27][CH:26]=2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: O=C=NC1(C(F)(F)F)CC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3(C(F)(F)F)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from 1-isocyanato-1-(trifluoromethyl)cyclopropane, and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=476.2.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1>C1COCC1>[OH:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11][CH2:12]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCC(O)CC1
Temperature: 25 °C

Procedure:
To a heated (40° C.) solution of tert-butyl 2-bromoacetate (7.38 mL, 49.9 mmol) in THF (10 mL) was added dropwise a solution of piperidin-4-ol (5.050 g, 49.9 mmol) and TEA (6.96 mL, 49.9 mmol) in THF (50 mL). The mixture was refluxed for 2 hours and then cooled to RT and filtered through a pad of Celite® brand filter aid. The filtrate was evaporated and the residue diluted with EtOAc (50 mL), washed with water (50 mL), brine (10 mL), and the organic layer dried over Na2SO4, filtered and evaporated. The material was purified via flash chromatography using a linear gradient of 0% to 10% of 1% NH4OH in MeOH in DCM. The title compound was isolated as an off-white solid (4.865 g, 45% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H-].[Na+].[CH3:21]I>CN(C=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:21])[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCOCC1)c1ccc(N)cc1

Procedure:
N-methylation of N-(4-nitrophenyl)morpholine-4-carboxamide was effected by allowing it to react with sodium hydride and methyl iodide in DMF, and the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain N-(4-aminophenyl)-N-methylmorpholine-4-carboxamide. F: 236.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12](OCC)(OCC)OCC.O>C(O)C>[Cl:10][CH2:11][C:12]1[O:9][C:3]2[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: CCOC(CCl)(OCC)OCC
Solvent: CCO
Solvent: O
Product: ClCc1nc2cc(Br)ccc2o1
Temperature: 25 °C

Procedure:
2-Amino-4-bromophenol (1.6 g) prepared according to U.S. Pat. No. 4,157,444 was dissolved in ethanol (5 ml) and 2-chloro-1,1,1-triethoxyethane (1.9 g) was added. The resulting solution was warmed on a steambath for 1.5 hour. After cooling the reaction mixture to room temperature, cold water (5 ml) was added. The precipitated solid was collected and air-dried to obtain the product (1.12 g; m.p. 63°-65° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]2[C:3]=1[C:4](=[O:31])[O:5][CH2:6]2.[C:32](OC(=O)C)(=[O:34])[CH3:33].O>N1C=CC=CC=1>[C:32]([O:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]2[C:3]=1[C:4](=[O:31])[O:5][CH2:6]2)(=[O:34])[CH3:33]
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1c(C)c2c(c(OC(C)=O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate (10.0 g) was dissolved in pyridine (50.0 ml) followed by the addition of acetic anhydride (10.0 ml). The mixture was stirred at room temperature for 90 minutes, then poured into water and extracted with ethyl acetate. The organic solution was dried and evaporated to give morpholinoethyl E-6-(1,3-dihydro-4-acetoxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15](=[O:29])[CH2:16][C:17]1[C:18](=[O:28])[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([OH:27])[CH:21]=2>>[CH3:13][O:14][C:15](=[O:29])[CH2:16][C:17]1[C:18](=[O:28])[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([O:27][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12])[CH:21]=2
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)Cc1cc2ccc(O)cc2[nH]c1=O
Product: COC(=O)Cc1cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2[nH]c1=O

Procedure:
The title compound is prepared according to the procedure of Example 75 except that (3-bromopropyl)-carbamic acid tert-butyl ester is used in place of (2-bromoethyl)-carbamic acid tert-butyl ester and that (7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester is used in place of (7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=[N:17][OH:18])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)C(=NO)CCC2(C)C
Temperature: 70 °C

Procedure:
7-Methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (1.48 g, 7.24 mmol) (Winstein, S.; Heck, R. F, J. Org. Chem., 1972, 37, 825.) was dissolved in Ethanol (20 mL) then Hydroxylamine hydrochloride (0.61 g, 8.8 mmol) and Sodium acetate (1.20 g, 14.6 mmol) were added along with Water (20 mL). The mixture was warmed to 70° C. for 6 h, cooled and partitioned between 50 mL DCM, 10 mL satd. sodium bicarbonate and 40 mL water. The pH was 6-7. The phases were separated and the aq. extracted 2×50 mL DCM. The organic extracts were dried over sodium sulfate and concentrated in vacuo. 7-Methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one oxime was isolated as a yellow solid (1.55 g, 98%) and used without purification. 1H-NMR (CDCl3): 7.42 (d, 1H, J=2.4 Hz), 7.27 (d, 1H, J=8.5 Hz), 7.23 (s, 1H), 6.91 (dd, 1H, J=2.4, 8.5 Hz), 3.81 (s, 3H), 2.85 (t, 2H, J=6.8 Hz), 1.73 (t, 2H, J=6.8 Hz), 1.27 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[Sn](CCCC)(CCCC)CCCC>>[CH3:21][N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:2]1[CH:20]=[CH:19][C:5]([N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Product: Cn1cccc1-c1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
As shown in scheme 1, 4-bromo-N,N-diphenylaniline (11) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12). n-butyl lithium is reacted with 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12), and then tributylstannylchloride is added thereto to obtain 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13). 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13) is reacted with 4-bromobenzaldehyde by Stille coupling reaction to obtain 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a). Finally, 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[4-(5-(4-(diphenyl-amino)phenyl)-1-methyl-1H-pyrrol-2-yl)]phenyl)acrylic acid (15a) is synthesized.