Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1>C(O)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([N+:1]([O-:4])=[O:2])[CH:7]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)ccc1O
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of 400 ml concentrated nitric acid, at 0° C., was added dropwise a solution of 4-fluorophenol (204 g, 1.8 mole) in acetic acid (200 ml) over 2 hours. Stirring was continued for another 2 hours at 5° C. The reaction mixture was poured onto ice, and the resulting yellow solids were collected and washed with water. The solids were recrystallized from methanol-water (5:1) to afford 198 g of the title compound. The NMR spectrum showed absorption at 7.17 (dd, 1H, J=9, 5 Hz), 7.44-7.52 (m, 1H) and 7.80 (dd, 1H, J=8, 3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(OC)(OC)OC.[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([O:22][CH2:21][CH2:20][O:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture that consists of 7.35 g of 4-oxocyclohexylcarboxylic acid ethyl ester, 28 ml of trimethyl orthoformate, 64 ml of ethylene glycol and 100 mg of p-toluenesulfonic acid in 120 ml of dichloromethane is stirred for 12 hours at 25° C. Then, 2 ml of triethylamine is added. It is washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product that is obtained is purified by column chromatography on silica gel. 9.22 g of product is obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[O:12][CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[O:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CCOC(=O)c1coc(C2CCN(S(C)(=O)=O)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)N1CCC(c2nc(C(=O)O)co2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
Ethyl 2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxylate (590 mg, 1.951 mmol) was dissolved in THF/methanol mixture (9:1) and 1M lithium hydroxide (3.90 ml, 3.90 mmol) was added slowly. The reaction mixture was stirred at RT for 1 h, diluted with water and pH was adjusted to 1.5. The mixture was extracted three times with ethyl acetate. Ethyl acetate phases were combined and evaporated to yield the title compound (74.7%). 1H-NMR (400 MHz; DMSO): δ 1.68-1.81 (m, 2H), 2.06-2.15 (m, 2H), 2.85-2.96 (m, 5H), 2.99-3.10 (m, 1H), 3.51-3.59 (m, 2H), 8.67 (s, 1H), 13.02 (bs, 1H).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]([CH3:14])[C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])C.[OH-].[Li+]>O1CCCC1.O>[CH3:14][CH:5]([C:6]([NH:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[O:7])[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)C(C)C(=O)NCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 1.48 g (6.52 mmol) 2-Methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid ethyl ester in 40 ml of tetrahydrofurane, 20 ml of water and 1.09 g (26 mmol) of lithium hydroxide were added and the mixture was stirred overnight at room temperature. After concentration in vacuo water (50 ml) was added and the mixture was extracted with dichloromethane (three times 30 ml). The aqueous phase was acidified with 8 N hydrochloric acid and extracted with dichloromethane (four times 30 ml). The combined organic layers from the second extraction were dried (MgSO4) and evaporated in vacuo to give 1.09 g (84%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].COC1N=C([N:19]2[C:24](=[O:25])[CH:23]=[CH:22][NH:21][C:20]2=[S:26])C=CN=1.C[N:28]([CH3:31])[CH:29]=O>>[CH2:1]([O:8][C:29]1[N:19]=[CH:24][C:23]([CH2:22][C:23]2[C:24](=[O:25])[NH:19][C:20](=[S:26])[NH:21][CH:22]=2)=[CH:31][N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: OCc1ccccc1
Reactant: COc1nccc(-n2c(=O)cc[nH]c2=S)n1
Agent: [H-]
Agent: [Na+]
Product: O=c1[nH]c(=S)[nH]cc1Cc1cnc(OCc2ccccc2)nc1
Temperature: 80 °C

Procedure:
To a solution of benzyl alcohol (20 ml) in dry dimethylformamide (20 ml) was added sodium hydride ((60% in oil) 2.3 g) over 0.5 h under argon. A slurry of 2-methoxypyrimidyl thiouracil (3.6 g) in dry dimethylformamide (10 ml) was added in one portion and the solution heated to 80° C. for 2.5 h. After cooling, the solvent was removed under reduced pressure and the residue partitioned between diethyl ether and water. The aqueous layer was washed with further diethyl ether and then acidified to pH4 with glacial acetic acid. The solid so formed was filtered, washed with water and diethyl ether and dried in vacuo to give the desired material. 1H-NMR (d6-DMSO) δ 3.49 (2H, s), 5.36 (2H, s), 7.2-7.5 (6H, m), 8.50 (2H, s); MS (APCI+) found (M+1)=327; C16H14N4O2S requires 326.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][NH:3]1.[H-].[Na+].[CH2:9](Br)[C:10]#[CH:11].C(=O)(O)[O-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:11]([N:3]1[C:2](=[O:1])[CH2:6][S:5][CH2:4]1)[C:10]#[CH:9]
Reactant: C#CCBr
Reactant: O=C1CSCN1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCN1CSCC1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 10.3 g of 4-oxothiazolidine in 500 ml of anhydrous dimethylformamide under N2 was added 6.0 g of sodium hydride (50% in oil). After 30 min., 15 ml of a solution of 80% propargyl bromide in toluene was added and the mixture was allowed to stir for another hour. The mixture was then poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic fractions were washed twice with water, then once with brine, dried (MgSO4), filtered and concentrated. The residue was distilled at 0.1/mm Hg, 95°-98° C., to provide 9.248 g of 3-propargyl-4-oxothiazolidine as an oil which solidified upon refrigeration, mp 29°-31°.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1[S:9][C:10]([CH2:25][CH3:26])=[C:11]([C:23]#[N:24])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=O)C.O.[NH2:28]N>C(O)(=O)C>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:11]([C:23]#[N:24])=[C:10]([CH2:25][CH3:26])[S:9][C:8]=2[C:6]2[NH:28][N:2]=[CH:4][N:5]=2)=[CH:14][CH:15]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CCc1sc(C(=O)N=CN(C)C)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCc1sc(-c2ncn[nH]2)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Temperature: 90 °C

Procedure:
Dissolve 3-(4-tert-butyl-phenyl)-4-cyano-5-ethyl-thiophene-2-carboxylic acid dimethylaminomethyleneamide (261 mg, 0.71 mmol) in 2 mL of glacial acetic acid, add hydrazine monohydrate (50 μL, 1.03 mmol) and heat to 90° C. under nitrogen. After 90 minutes cool the reaction slightly, pour into 50 mL of ice-water and stir for twenty minutes. Filter off the resulting solid and rinse with 10 mL of water. Vacuum-dry overnight to give the title compound, 206 mg (86%). MS(ES+, m/e)=337 (M++1); HPLC=00%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[C:3]=1C(OC)=O.OC1C2CCCCC=2NC(=O)C=1C(O)=O>>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[CH:3]=1
Reactant: COC(=O)c1c(O)c2c([nH]c1=O)CCCC2
Agent: O=C(O)c1c(O)c2c([nH]c1=O)CCCC2
Product: O=c1cc(O)c2c([nH]1)CCCC2

Procedure:
Using the general method of Example 1 Part E, a mixture of methyl 1,2,5,6,7,8-hexahydro-4-hydroxy-2-oxoquinoline-3-carboxylate and 1,2,5,6,7,8-hexahydro-4-hydroxy-2-oxoquinoline-3-carboxylic acid (1.92 g total) was hydrolyzed and decarboxylated to provide 1.38 g of 5,6,7,8-tetrahydro-4-hydroxy-2(1H)-quinolinone as a white solid, m.p. >300° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:7][CH:8]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:12])[CH:11]=1)(=[O:3])[CH3:2].Br[CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:22][CH2:23][NH:24][C:25]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CC(=O)OCc1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc(OCCNC(=O)OC(C)(C)C)c(OCc2ccccc2)cn1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a solution of 6.1 g of (5-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)methyl acetate in 50 mL of dimethyl sulfoxide, 5.0 g of tert-butyl (2-bromoethyl)carbamate and 10 g of potassium carbonate were added, and the mixture was stirred at 80 to 90° C. for 6 hours 30 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=99:1 to 98:2 obtain 3.8 g of (5-(benzyloxy)-4-(2-((tert-butoxycarbonyl)amino)ethoxy)pyridin-2-yl)methyl acetate as a brown oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH3:24])([CH3:23])[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[C:19](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=4.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:44][C:45]1([CH3:52])[O:49][C@H:48](CO)[CH2:47][O:46]1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1.C1COCC1>[CH3:44][C:45]1([CH3:52])[O:49][C@H:48]([CH2:1][O:2][C:3]2[C:8]3[C:9]([CH3:24])([CH3:23])[C:10]4[NH:11][C:12]5[C:17]([C:18]=4[C:19](=[O:20])[C:7]=3[CH:6]=[CH:5][CH:4]=2)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=5)[CH2:47][O:46]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: COc1cccc2c1C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@@H](COc2cccc3c2C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)O1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 7-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound W3, 15 mg, 0.05 mmol) and triphenylphosphine (40 mg, 3 eq.) were added with THF (1 ml), further added dropwise with ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (20 mg, 3 eq.) and 2.19 N toluene solution of diethyl azodicarboxylate (68 μL, 3 eq.), and the mixture was stirred at 50° C. for 2 hr. After cooling, the reaction solution was added with ethyl acetate, washed with brine, dried over sodium sulfate, and filtered. The residues obtained after concentration under reduced pressure were purified by preparative TLC (ethyl acetate/dichloromethane), and the resulting solid was washed with dichloromethane to obtain the target compound (brown powder, 5 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH:23]([C:29]#[N:30])C(OCC)=O)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].O>CS(C)=O.CCOC(C)=O>[C:29]([CH2:23][C:15]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[CH2:13][N:11]([CH3:12])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:30]
Reactant: CCOC(=O)C(C#N)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CN(Cc1cc([N+](=O)[O-])ccc1CC#N)C(=O)OCc1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
36B (2.609 g, 6.34 mmol) was dissolved in DMSO (40 mL), lithium chloride (0.538 g, 12.68 mmol) and water (0.114 mL, 6.34 mmol) were added. The reaction mixture was stirred at 130° C. for 2 h, then cooled to rt, diluted with EtOAc (250 mL), washed with water (2×100 mL), brine (1×100 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-70% EtOAc/hexanes) to give 36C (1.803 g, 5.31 mmol, 84% yield) as a yellowish film. MS (ESI) m/z: 340.1 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 8.20 (1H, d, J=7.07 Hz), 8.09 (1H, br. s.), 7.67 (1H, d, J=5.05 Hz), 7.29-7.46 (5H, m), 5.19 (2H, s), 4.59 (2H, br. s.), 3.91 (2H, br. s.), 2.94 (3H, br. s.).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>>[C:14]([C:6]1[N:2]([CH3:1])[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:5]=1[CH3:7])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1cc(C)cn1C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2)n1C
Temperature: 25 °C
Yield: 56.2 %

Procedure:
Ethyl 1,4-dimethylpyrrole-2-acetate (37.0 g, 0.19 mol), benzoyl chloride (54.3 g, 0.38 mol), and triethylamine (52.9 ml, 0.38 mol) were dissolved in xylenes (750 ml), and the reaction mixture was refluxed for 18 h under argon. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. Purification on a Florisil® column (hexane followed by hexane-ethyl acetate, 4:1) gave ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate (30.45 g, 57%) as a solid. ##STR18##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1.[CH:16](=O)[CH3:17]>>[CH2:16]([N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1)[CH3:17]
Reactant: CC=O
Reactant: O=C1Nc2ccccc2C12CCCNC2
Product: CCN1CCCC2(C1)C(=O)Nc1ccccc12

Procedure:
The compound was prepared according to PROCEDURE 1, Method A by reaction with spiro[indoline-3,3′-piperidin]-2-one and acetaldehyde (5 equivalents). Yield: 45 mg (26%). 13C NMR of the HCl-salt (CD3OD): δ 9.6, 19.8, 31.3, 46.3, 54.2, 54.3, 55.1, 111.5, 123.9, 124.4, 130.4, 131.3, 142.6, 182.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([CH3:22])=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1.[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH3:25])[C:13]([CH3:22])=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: CI
Reactant: COc1ccc(-c2nc(-c3cccnc3)c(C)[nH]2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(-c3cccnc3)c(C)n2C)c(OC)c1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(2,4-dimethoxyphenyl)-5-methyl-4-(3-pyridyl)imidazole (0.80 g) in N,N-dimethylformamide (12 ml) was added sodium hydride (0.13 g, 60% suspension in oil), and the mixture was stirred for 10 minutes. Then methyl iodide (0.34 ml) was added thereto, and the reaction was stirred at ambient temperature for 5 hours. The solution was poured into water (100 ml), and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and chromatographed on silica gel (25 g) eluting with chloroform. The fractions were collected and evaporated, and the residue was triturated with a mixture of ethyl acetate and diisopropyl ether (1:1 V/V) to give 2-(2,4-dimethoxyphenyl)-1,5-dimethyl-4-(3-pyridyl)imidazole (70 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[C:11]([C:22]([NH2:24])=[O:23])=[C:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[C:18]=1[CH:19]1[CH2:21][CH2:20]1)#[N:9].C(N(CC)CC)C.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(#N)C>[C:8]([C:10]1[C:11]([C:22]([NH2:24])=[O:23])=[C:12]2[CH2:17][N:16]([S:40]([C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:45])=[CH:39][CH:38]=3)(=[O:42])=[O:41])[CH2:15][CH2:14][N:13]2[C:18]=1[CH:19]1[CH2:20][CH2:21]1)#[N:9]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1c(C(N)=O)c2n(c1C1CC1)CCNC2
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#Cc1c(C(N)=O)c2n(c1C1CC1)CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 42.8 %

Procedure:
A suspension of 7-cyano-6-cyclopropyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt [200 mg, Example 44(b)] in dry acetonitrile (50 mL) was treated with dry triethylamine (0.16 mL), then with 4-(trifluoromethyl)benzenesulfonyl chloride (142 mg). After stirring at 60° C. for 2.5 hours the reaction mixture was allowed to cool to room temperature and evaporated. The residue was treated with ethyl acetate (40 mL) and water (40 ml). The organic phase was separated, dried over sodium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give 7-Cyano-6-cyclopropyl-2-(4-trifluoromethylbenzenesulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide (109 mg) as a white solid, m.p. 253–256° C.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][CH:17]([F:20])[CH2:18]O.C(N(CC)CC)C>ClCCl>[F:16][CH:17]([F:20])[CH2:18][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:11])=[O:10]
Reactant: OCC(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCC(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 74.6 %

Procedure:
In a flask under argon was placed triflic anhydride (10.22 mL, 61 mmol) and dichloromethane (10 mL) and it was cooled to −70° C. To this cooled mixture was added slowly a solution of 2,2-difluoroethanol (5.00 g, 61 mmol) and triethylamine (8.5 mL, 61 mmol) in dichloromethane (10 mL). After the addition was complete, the mixture was warmed to 25° C. and then concentrated in vacuo. This material was distilled at 60° C. and 50 mm Hg which afforded trifluoro-methanesulfonic acid 2,2-difluoro-ethyl ester (9.74 g, 75%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][C:21]([O:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[CH:22][CH:23]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CN(C)CCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cn1
Yield: 20.3 %

Procedure:
Following general procedure D, (6-bromo-4-(6-(2-(dimethylamino)ethoxy)pyridin-3-ylamino)quinolin-3-yl)(cyclopropyl)methanone (100 mg, 0.22 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (95 mg, 0.33 mmol) to afford the desired product (24 mg, 20%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.25 (s, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.94 (s, 2H), 7.80 (s, 1H), 7.56 (dd, J=8.5, 2.8 Hz, 1H), 7.18 (s, 2H), 6.93 (d, J=8.5 Hz, 1H), 4.54 (t, J=5.5 Hz, 2H), 3.04 (t, J=5.5 Hz, 2H), 2.95-2.86 (m, 1H), 2.54 (s, 6H), 1.23-1.14 (m, 2H), 1.17-1.08 (m, 2H); ESI MS m/z 537 [C28H26Cl2N4O3+H]+; HPLC>99% (AUC), tR=11.42 min.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([F:15])[C@H:13]([N:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][C:17]2=[O:31])[O:12][C@@H:11]1[CH2:32]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:34]([O:41]CC)([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37]>>[C:1]([O:9][C@H:10]1[C@H:14]([F:15])[C@H:13]([N:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][C:17]2=[O:31])[O:12][C@@H:11]1[CH2:32][P:34]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])=[O:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C(Nc1ccn([C@@H]2O[C@H](CBr)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c(=O)n1)c1ccccc1
Product: CCOP(=O)(C[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)OCC
Yield: 44 %

Procedure:
A solution of compound 4 (0.08 g, 0.16 mmol) in 10 mL of (EtO)3P was stirred at 140° C. for 24 h and the solvent was evaporated under reduced pressure. The residue was dissolved in 10 mL of MeOH and adsorbed on silica gel and then purified on silica gel column chromatography (Hexane:EtOAc=1:2 to 1:4 v/v) to give compound 5 (0.04 g, 0.07 mmol) in 44% yield. 1H NMR (CDCl3, 400 MHz) δ 8.97 (br, 1H), 8.08 (d, J=7.2, 2H), 8.04 (d, J=7.6, 1H), 7.92 (d, J=7.2, 2H), 7.60 (m, 3H), 7.50 (m, 4H), 5.98 (d, J=18.4, 1H), 5.65 (d, J=4.8, 0.5H), 5.52 (d, J=4.8, 0.5H), 5.45 (m, 1H), 4.76 (m, 1H), 4.11 (m, 4H), 2.42 (m, 2H), 1.32 (m, 6H); MS calcd for C27H29FN3O8P m/z 574.2 (M+H)+, found 574.3.
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(C)(C)C>FC(F)(F)C(O)=O.ClCCl.ClCCCl>[CH3:15][O:14][C:12]([C:11]1[CH:10]=[C:9]([C:8]#[C:7][C:6]([OH:19])=[O:5])[CH:18]=[CH:17][CH:16]=1)=[O:13]
Reactant: COC(=O)c1cccc(C#CC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(C#CC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
The mixture of methyl 3-(3-(tert-butoxy)-3-oxoprop-1-yn-1-yl)benzoate (9-1) (139 mg, 0.53 mmol) in a mixture of trifluoroacetic acid and dichloromethane (v:v=95:5, 1.5 mL) was stirred at room temperature for 2 h. The mixture was diluted with 1,2-dichloroethane and the whole was evaporated to dryness. The residue was triturated with hexane and the solid was collected by decantation and dried under vacuum to give the title compound 9-2 (102 mg, 94% yield) as a light brown solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH:21](Br)([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([O:17][CH:21]([CH3:23])[CH3:22])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)Br
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Oc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 2 h
Yield: 35.9 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.035 g, 0.099 mmol) in dichloromethane (1 mL) was treated with isopropyl bromide (0.037 g, 0.297 mmol), DBU (0.048 g, 0.205 mmol) and stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.014 g of a clear oil. MS calculated for C16H19BrF3NO2+H: 394, observed: 394.