Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:41]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=4)(=[O:43])=[O:42])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3cccc(F)c3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added 3-fluoro benzenesulfonyl chloride (35 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 50 mg (44.99%); 1H NMR (CDCl3, 300 MHz): δ 9.57 (s, 1H), 8.025-8.051 (d, 1H, J=7.8 Hz), 7.952-7.980 (d, 1H, J=8.4 Hz), 7.94 (m 1H,), 7.75 (d, 2H, J=9 Hz,), 7.63 7.674 (dd, 1H, J=9, 2.1 Hz), 7.56-7.61 (m, 1H), 7.438-7.466 (d, 2H, J=8.4 Hz), 7.38-7.42 (m, 1H), 6.99-6.996 (d, 1H, J=1.8 Hz), 1.80 (s, 6H); MS: m/z 565 (M+).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[NH:12])[NH2:11])=[CH:5][CH:4]=1.Cl.[CH2:14]([N:21]1[CH2:27][CH2:26][C:25](=O)[CH:24]([C:29](OCC)=[O:30])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]CC.[Na+]>>[CH2:14]([N:21]1[CH2:22][CH2:23][C:24]2[C:29](=[O:30])[NH:12][C:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][CH:7]=3)=[N:11][C:25]=2[CH2:26][CH2:27]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(CC(=N)N)cc1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(Cc2nc3c(c(=O)[nH]2)CCN(Cc2ccccc2)CC3)cc1
Yield: 43 %

Procedure:
Under nitrogen, 2-(4-methylphenyl)ethanimidamide hydrochloride (360 mg, 1.95 mmol) and ethyl 1-benzyl-5-oxoazepane-4-carboxylate hydrochloride (500 mg, 1.61 mmol) were added to a freshly-prepared solution of sodium ethoxide (from sodium (120 mg, 5.22 mmol) dissolved in ethanol (15 ml)) and the mixture refluxed overnight. The reaction mixture was concentrated in vacuo and the residue treated with water. The mixture was acidified with 2M HCl solution, then rebasified using saturated aqueous NaHCO3 solution and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by purified by column chromatography on silica gel, eluting with DCM:MeOH, 98:2 to 94:6, to afford the title compound as a solid in 43% yield, 250 mg.
Reaction SMILES: N#N.C(N(CC)C1C=CC=CC=1)C.B.[C:15]([C:18]1[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=1)[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)=O)(=[O:17])[CH3:16].Cl>C1(C)C=CC=CC=1.CO>[OH:17][C@H:15]([C:18]1[CH:19]=[C:20]([CH:36]=[CH:37][CH:38]=1)[CH2:21][N:23]1[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]1)[CH3:16]
Reactant: CC(=O)c1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: B
Agent: Cl
Agent: N#N
Solvent: CO
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](O)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
Under a positive pressure of N2 1-1.5M solution of (S)-Methyl oxazaborolidine (0.5 mL, 5.0 mmol) was diluted in 2 mL of toluene and treated with 3.6 mL of borane-N,N-diethylaniline. The tert-butyl 4-(3-acetylbenzoyl)piperazine-1-carboxylate from above in 3 mL of anhydrous toluene was added to the above solution over 1 hour and stirred for an additional hour. The mixture was stirred at 20° C. for another hour. To the mixture was added 6 mL MeOH, 12 mL 1N HCl and the resultant mixture stirred for 20 min. The mixture was diluted with 50 mL toluene and washed with saturated NaCl (50 mL). The organic extracts were dried over Na2SO4, filtered and concentrated at reduced pressure. The residue was heated at reflux in Et2NH for 1 hour. Purification by reverse-phase HPLC to afforded (S)-tert-butyl 4-(3-(1-hydroxyethyl)benzyl)piperazine-1-carboxylate as 1.08 g of white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].B>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: COc1ccc(Br)c(C#N)c1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CN)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
2-Bromo-5-methoxybenzonitrile (10.0 g, 47.2 mmol) was dissolved in dry tetrahydrofuran (100 mL) in a flame-dried flask and cooled in an ice bath. A solution of borane in tetrahydrofuran (75 mL, 75 mmol, 1.0 M) was added dropwise over a period of 30 minutes. The reaction mixture was stirred overnight at rt, then quenched slowly with ice water and Na2CO3 (saturated aqueous solution). After removal of THF, the residue was extracted with large amounts of EtOAc three times. The combined organic layers were washed with water, dried, and concentrated to give the crude, which was purified by silica gel column chromatography to give the desired product as a white powder (3.65 g, 36%). LCMS for C8H10BrNO (M+H)+: m/z=216.9, 219.0.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1N

Procedure:
18 g (99 mmol) of the compound from Example 1 b) are stirred under reflux in 200 ml of methanol with 20 ml of thionyl chloride for 48 h. The reaction solution is evaporated in a rotary evaporator, the residue is taken up in 400 ml of satd. Na2CO3 solution, the solution is extracted 3 times with EA, and the combined organic phases are washed with dilute Na2CO3 solution and satd. NaCl solution, dried over Na2SO4 and concentrated. Chromatography on SiO2 with EA/Hep 9:1 and 7:3 yields 11.5 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:31]([N:39]2[CH2:50][CH2:49][N:48]3[C:41](=[CH:42][C:43]4[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=43)[C:40]2=[O:53])=[N:32][CH:33]=[CH:34][C:35]=1B(O)O)(=[O:27])[CH3:26].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:39]2[CH2:50][CH2:49][N:48]3[C:41](=[CH:42][C:43]4[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=43)[C:40]2=[O:53])=[N:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:27])[CH3:26]
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 110 °C
Reaction time: 4 h
Yield: 22.5 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 226a (279 mg, 0.80 mmol), (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl) methyl acetate 199e (1.53 g, 3.2 mmol), Pd2(dba)3 (73.2 mg, 0.080 mmol), tricyclohexyl-phospine (44.6 mg, 0.16 mmol), cesium carbonate (521.6 mg, 1.6 mmol), 1,4-dioxane (10 mL), and water (8 drops). After three cycles of vacuum/argon flush, the mixture was stirred at 110° C. for 4 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 40:1 ethyl acetate/methanol to afford 226b as a yellow solid (120 mg, 23%). MS-ESI: [M+H]+ 667.3
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].C(O)(=O)C.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18]>C(O)C>[F:18][C:17]([F:19])([F:20])[C:16]([F:25])([C:21]([F:22])([F:23])[F:24])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:1][C:2]#[N:3]
Reactant: FC(F)(F)C(F)(CCCCCCBr)C(F)(F)F
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: N#CSCCCCCCC(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 97 %

Procedure:
In accordance with scheme (45) above, 8-Bromo-1,1,1,2-tetrafluoro-2-trifluoromethyl-octane (20 grams) can be dissolved in 30 mL of ethanol containing 7.6 grams of potassium thiocyanate. Acetic acid (0.2 mL) can be added to form a mixture and the mixture heated to reflux for 4 hours. The mixture can be allowed to cool to room temperature overnight, concentrated under vacuum, and partitioned between methylene chloride (200 mL) and water (100 mL). The organic layer can be dried over magnesium sulfate, filtered, and concentrated under vacuum to afford 18.2 grams (97%) 1,1,1,2-tetrafluoro-8-thiocyanato-2-trifluoromethyl-octane by NMR analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](I)[CH3:18].C1CCCCC1.C(OCC)(=O)C>CS(C)=O>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:17][CH3:18])[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NC1CC=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCN(C(=O)OC(C)(C)C)C1CC=CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of cyclohex-3-enyl-carbamic acid tert-butyl ester (Kampferer, P.; Vasella, A. Helvetica Chimica Acta 2004, 87, 2764-2789) (4.34 g, 22 mmol) in 20 ml of DMSO was added sodium hydride (880 mg, 60% dispersion, 22 mmol) and after one hour of stirring ethyl iodide (1.78 ml, 22 mmol). After further stirring for 2 hours at room temperature the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and brine and extracted three times with ethyl acetate. The organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and after chromatography (silica, cyclohexane/ethyl acetate=12/1) the title compound (Rf=0.30, 2.88 g, 58% yield) was obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[C:17]1([C:23]2([C:26](O)=[O:27])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:26]([C:23]3([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:25][CH2:24]3)=[O:27])=[CH:11][CH:10]=2)[O:5]1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(NC(=O)C3(c4ccccc4)CC3)cc2)OC1(C)C

Procedure:
Intermediate 26 was prepared in analogy to GP 5 by reaction of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with 1-phenyl-cyclopropanecarboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[O:20][CH2:21][CH2:22][NH:23][C:24](=O)[CH3:25]>C(#N)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[C:4]2[C:24]([CH3:25])=[N:23][CH2:22][CH2:21][O:20][C:3]=12
Reactant: CC(=O)NCCOc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1F
Solvent: CC#N
Product: CC1=NCCOc2c(F)cc3c(ccn3S(=O)(=O)c3ccccc3)c21
Temperature: 200 °C
Yield: 5.3 %

Procedure:
To N-(2-{[6-fluoro-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethyl)acetamide (Intermediate 30, 0.020 g, 0.053 mmol) in acetonitrile (20 mL) phosphoryl chloride (0.5 mL) was added and the reaction mixture was heated at 200° C. for 30 minutes in a microwave heater. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (1 mg). MS m/z 359 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]#[N:16])[CH:10]=[N:11][CH:12]=1>CO.[Pd]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15]#[N:16])[CH:10]=[N:11][CH:12]=1
Reactant: CN1CCC[C@H]1c1cncc(C=CC#N)c1
Agent: [Pd]
Solvent: CO
Product: CN1CCC[C@H]1c1cncc(CCC#N)c1
Yield: 75.3 %

Procedure:
(S)-3-(5-(1-Methylpyrrolidin-2-yl)pyridin-3-yl)acrylonitrile (preparation 2) (185 mg, 0.87 mmol) and 5% Pd/C (50 mg) in MeOH (5 mL) were stirred under an atmosphere of hydrogen for 72 hours. The reaction mixture was filtered through Celite then the solvent evaporated. The crude product was purified by flash chromatography (5% [20% ammonia in MeOH] in DCM) to give the title compound as a pale yellow oil (141 mg, 75%).
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=O)[CH2:2][CH3:3].Cl.[CH2:11]([O:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[K+]>CO.O>[CH2:11]([O:18][N:19]=[C:1]([CH2:2][CH3:3])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NOCc1ccccc1
Reactant: CCC(=O)CC(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC(CC(=O)OC)=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of 26.03 g (0.2 mol) of methyl propionylacetate in 300 ml of methanol, 100 ml of water and 35.12 g (0.22 mol) of benzyloxyamine hydrochloride, 19.69 g (0.24 mol) of potassium acetate were added and the mixture was stirred for 15 hours at room temperature. After distilling methanol off under reduced pressure, followed by adding 200 ml of water and extracting three times with 200 ml of ethyl acetate, the mixture was washed with water and a saturated aqueous sodium chloride and then dried over with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 47.06 g yield: 100%) of a crude methyl 3-benzyloxyiminovalerate as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[N:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:31])=[N:4][CH:5]=1)[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: Cc1cc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (R)-2-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (17 mg, 0.049 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.50 mL) and aq. H2O2 (30%, 0.50 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (7 mg). MS 364.3 (M+H); UV 210.2, 275.0, 323.7 nm; t 0.458 min.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12].C(=O)(O)[O-].[K+].S(O[CH:27]([C:41]#[N:42])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:29]=1)(=O)(=O)C>O1CCCC1.CN(C)C=O.CCOCC>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH:27]([C:41]#[N:42])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:29]=1)=[O:12]
Reactant: CC(C)C(C(=O)O)C1=Cc2ccccc2C1
Reactant: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)C1=Cc2ccccc2C1

Procedure:
A mixture of 2-(2-indenyl)-3-methylbutanoic acid (3.4 mmol), potassium bicarbonate (3.4 mmol) in 10 ml of tetrahydrofuran/dimethylformamide (1/1) is stirred for a few minutes and then α-cyano-m-phenoxybenzyl mesylate (3.4 mmol) in 5 ml of tetrahydrofuran/dimethylformamide (1/1) is added. The reaction is worked up by diluting with ether, washing with water and sat. NaCl, drying and evaporating under vacuum to remove solvent to yield α-cyano-m-phenoxybenzyl 2-(2-indenyl)-3-methylbutanoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[C:33]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)#[N:34]>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:38]3[CH2:39][CH2:40][CH:35]([C:33]#[N:34])[CH2:36][CH2:37]3)[CH:32]=[CH:31][CH:30]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2nc(-c3ccc(C(C)(C)C(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: N#CC1CCNCC1
Product: Cc1cc(-c2nc(-c3ccc(C(C)(C)C(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCC(C#N)CC2)c1

Procedure:
Analogously to the process described in Example 9, 125 mg (0.247 mmol) of the compound from Example 3A and 55 mg (0.495 mmol) of 4-cyanopiperidine were used to obtain 66 mg (50% of theory) of the title compound.
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[C:7]([NH2:11])[N:8]([CH3:10])[N:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12]1([O:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[C:12]1([O:18][C:19](=[O:20])[NH:11][C:7]2[N:8]([CH3:10])[N:9]=[C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1nc(C2CCC2)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Product: Cn1nc(C2CCC2)cc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5-Cyclobutyl-2-methyl-2H-pyrazol-3-ylamine (0.156 g, 1.03 mmol) in dimethylformamide (3 ml) cooled to 0° C., is treated with phenylchloroformate (0.13 ml, 1.03 mmol) dropwise and left to stir at 0° C. for 1 hour. The reaction mixture is partitioned between ethylacetate and 1.0 M hydrochloric acid solution, and the organic phase washed with water, dried over magnesium sulphate and evaporated to yield (5-Cyclobutyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester. [M+H] 272.22
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([NH2:37])[CH:34]=[N:35][CH:36]=2)[CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:37][C:33]1[CH:34]=[N:35][CH:36]=[C:31]([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH:32]=1)=[C:3]([CH3:24])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH3:23])(=[O:22])=[O:21])=[N:5]2
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (75.0 mg, 0.20 mmol) and 5-morpholinopyridin-3-amine in toluene to give 5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.19 (1H, dd, J=7.9, 1.3 Hz), 7.89 (1H, d, J=2.3 Hz), 7.86 (1H, d, J=2.3 Hz), 7.78 (1H, td), 7.68 (1H, td, J=7.7, 1.2 Hz), 7.49 (1H, ddd, J=9.4, 2.4, 1.3 Hz), 7.42 (1H, dd, J=7.5, 1.3 Hz), 7.02-7.15 (2H, m), 6.55 (1H, t, J=2.3 Hz), 3.79 (4H, t, J=4.8 Hz), 3.09-3.22 (7H, m), 1.88 (3H, s). Mass Spectrum (ESI) m/e=511.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:21](OCC)(OCC)OCC.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[N:12]1([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:21]1
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nn1cnc2cnc3ccccc3c21
Temperature: 130 °C
Reaction time: 23 h

Procedure:
A suspension of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (6.50 g, 23.7 mmol) in 100 mL of toluene was treated with triethyl orthoformate (8.68 mL, 52.2 mmol) and pyridine hydrochloride (0.14 g, 1.2 mmol) and heated to 130° C. under an atmosphere of nitrogen. After 23 h, the reaction mixture was concentrated under reduced pressure to yield a red/brown oil. The oil was dissolved in CHCl3 (150 mL) and washed with water (2×50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 6.74 of tert-butyl N-(1H-imidazo[4,5-c]quinolin-1-yl)carbamate as a red/orange oil.
Reaction SMILES: [NH3:1].[C:2]1([S:12](Cl)(=[O:14])=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1>CCOCC>[C:2]1([S:12]([NH2:1])(=[O:14])=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: N
Solvent: CCOCC
Product: NS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Ammonia was passed (for 5 min) into a stirred solution of 1-naphthalenesulfonyl chloride (5.0 g, 22 mmol) and anhydrous Et2O (400 ml) at -78°. The resulting mixture was stirred at -78° for 1 hr, allowed to warm to room temperature, and stirred overnight. The Et2O was removed under vacuum to leave a white powder which was washed with water and dried under vacuum to give 3.2 g (70%) of the title compound as a white powder, m.p. 152°-153° C.