Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[CH:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][CH2:36][C:37]1[N:38]=[CH:39][N:40]([C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]3=[O:54])=[CH:44][CH:43]=2)[CH:41]=1>CN(C=O)C>[C:1]([C:3]1[S:7][C:6]([C:8]([NH:35][CH2:36][C:37]2[N:38]=[CH:39][N:40]([C:42]3[CH:43]=[CH:44][C:45]([N:48]4[CH:53]=[CH:52][CH:51]=[CH:50][C:49]4=[O:54])=[CH:46][CH:47]=3)[CH:41]=2)=[O:10])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(C(=O)O)s1
Reactant: NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C#Cc1ccc(C(=O)NCc2cn(-c3ccc(-n4ccccc4=O)cc3)cn2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-ethynyl-thiophene-2-carboxylic acid (83 mg, 0.54 mmol) and TEA (0.15. mL, 1.1 mmol) in DMF (4 mL), HATU (228 mg, 0.60 mmol) was added. After being stirred at room temperature for 30 min, a solution of 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one prepared above (145 mg, 0.54 mmol) and TEA (0.15 mL, 1.1 mmol) in DMF (8 mL) was added. The mixture was stirred at room temperature overnight. It was then purified by HPLC to give the title compound (65 mg). MS 401 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:36]([NH:35][CH2:33][CH3:34])=[O:37])[CH2:17][CH2:18]1)=[N:7]2
Reactant: CCN=C=O
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: CCNC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)CC1

Procedure:
Prepared according to Procedure P using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and ethylisocyanate to give 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-N-ethylpiperazine-1-carboxamide. 1H NMR (DMSO-d6) δ ppm 1.03 (t, J=6.4 Hz, 3H), 2.08 (br s, 3H), 3.05-3.11 (m, 6H), 3.25 (br s, 4H), 3.44-3.45 (m, 4H), 3.68-3.69 (m, 4H), 6.49 (br s, 1H), 6.59-6.56 (m, 1H), 7.13-7.18 (m, 1H), 7.28-7.30 (m, 1H), 7.53 (s, 1H), 7.78 (s, 1H), 8.36 (s, 1H). Mass Spectrum (ESI) m/e=512.1 (M+1).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5](O)[C:4]1=[O:14].[BrH:15]>>[NH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:15])[CH:10]=2)[NH:5][C:4]1=[O:14]
Reactant: Br
Reactant: NC1Cc2ccccc2N(O)C1=O
Agent: Cl
Product: NC1Cc2cc(Br)ccc2NC1=O
Temperature: 25 °C

Procedure:
The title compound was prepared from 3-amino-1-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline hydrochloride (Davis, A. L., et al., J. Med. Chem., 7, 632 (1964)) according to procedures similar to those described in McCord, T. J., et al., J. Het. Chem., 9, 119 (1972), as follows. To 48% aqueous HBr solution (70 mL) was added 3-amino-1-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline hydrochloride (2.0 g, 9.3 mmol). The resulting mixture was stirred at reflux for 2 h. HPLC/MS indicated a nearly 1:1 mixture of desired product and its 8-bromo isomer plus a small amount of dibromo product. After cooling to RT, precipitate was filtered and treated with excess saturated aqueous Na2CO3 solution to make a basic (pH=10) mixture. This heterogenous mixture was extracted repeatedly with CH2Cl2. During these extractions, a substantial amount of solid remained undissolved and suspended in the aqueous layer. The combined organic extracts were dried over Na2SO4 and evaporated under vacuum. The resulting residue was chromatographed on silica gel eluted with 10% MeOH in CH2Cl2 to obtain the title compound (0.15 g). Additional title compound (0.56 g) was obtained by filtering the heterogenous aqueous layer and washing the filtered solid with water, then Et2O, and then 10% MeOH in Et2O before drying under vacuum.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.C([Li])CCC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]3[CH:37]=[C:38]4[C@:43]([CH:45]=[O:46])([CH2:44][C:35]=3[CH:34]=[N:33]2)[CH2:42][N:41]([S:47]([C:50]2[CH:51]=[C:52]([CH3:56])[CH:53]=[CH:54][CH:55]=2)(=[O:49])=[O:48])[CH2:40][CH2:39]4)=[CH:28][CH:27]=1.O>O1CCCC1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]3[CH:37]=[C:38]4[C:43]([C@H:45]([C:6]5[N:7]=[CH:8][CH:9]=[CH:10][N:11]=5)[OH:46])([CH2:44][C:35]=3[CH:34]=[N:33]2)[CH2:42][N:41]([S:47]([C:50]2[CH:51]=[C:52]([CH3:56])[CH:53]=[CH:54][CH:55]=2)(=[O:49])=[O:48])[CH2:40][CH2:39]4)=[CH:28][CH:27]=1
Reactant: Cc1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C=O)C2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)CC3([C@@H](O)c3ncccn3)C2)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
To a stirred solution of 2-(tributylstannyl)pyrimidine (428 μl, 1.351 mmol) in dry tetrahydrofuran (5 mL) was added butyllithium (2.5 M in hexanes) (554 μl, 1.384 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hours. A solution of (R)-1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (200 mg, 0.443 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and the reaction mixture was stirred for 1.5 hours at −78° C. Water (25 mL) was added and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was partitioned between acetonitrile (25 mL) and hexanes (15 mL). The hexane layer was discarded. The acetonitrile layer was concentrated in vacuo to give a pale orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrimidin-2-yl)methanol (75 mg) as a colourless oil. LCMS (Method F, ES-API): RT 2.27 min, m+H=532.2.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[CH2:14]=O>>[CH2:14]1[O:4][C:3]([CH2:2][C:1]([OH:13])=[O:12])([CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:7])[O:6]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C=O
Product: O=C(O)CC1(CC(=O)O)OCOC1=O

Procedure:
reacting citric acid with paraformaldehyde to form anhydromethylene citric acid;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].[C:15]([CH2:23][C:24]([CH3:26])=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>CO>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:5][C:24]([CH3:26])=[CH:23][C:15](=[O:22])[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(=O)c1cccnc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)NC(C)=CC(=O)c1cccnc1
Yield: 78.9 %

Procedure:
To a solution of L-tyrosine methyl ester (4.00 g, 20.51 mmol) in methanol (150 ml) is added 1-nicotinoylacetone (3.68 g, 22.56 mmol), then the mixture is heated to reflux for 24 h. The solvent is evaporated under a vacuum. To the residue is added ethanol (50 ml), then the ethanol is distilled off under atmospheric pressure. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (5.51 g, 79%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17](O)=[O:18])=[CH:16][C:9]=23)[C:5]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2].[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]([NH:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:18])=[CH:16][C:9]=23)[C:5]([C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[N:4]1)[CH3:2]
Reactant: NCCN1CCOCC1
Reactant: CCn1cc(-c2ccnc3[nH]c(C(=O)O)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CCn1cc(-c2ccnc3[nH]c(C(=O)NCCN4CCOCC4)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described in Example 15a using 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid and 4-(2-aminoethyl)-morpholine afforded the title compound. ESMS [M+H]+: 490.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>C(O)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:13](=[O:14])[CH2:12][C:11]([CH3:10])=[O:15]
Reactant: COc1ccccc1N
Reactant: C=C1CC(=O)O1
Solvent: CCO
Product: COc1ccccc1NC(=O)CC(C)=O
Temperature: 85 °C

Procedure:
2.4 kg/h (19.5 mol/h) of 2-methoxyaniline, 1.98 kg/h (23.1 mol/h) of diketene (purity 98%) and 6.9 kg/h of aqueous 30% strength ethanol are reacted separately but simultaneously as described in Example 1. The product stream of about 0.3 l, produced under reflux at about 85° C. and kept to a constant volume by pumping out, is cooled down to about 15° C., and the reaction product is crystallized out and separated from the 5.8 kg/h of mother liquor by filtration. The light-colored solids are washed with 5.8 kg/h of aqueous 30% strength ethanol and dried, leaving 3.8 kg/h (18.3 mol/h) of 2'-methoxyacetoacetanilide, corresponding to 94% of yield based on amine. The purity of the product is better than 99.5%.
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:20]=1)[CH2:14][N:15]=[N+]=[N-])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>CO.CCOCC>[CH2:22]([O:21][C:19]1[CH:18]=[C:13]([CH:12]=[C:11]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:20]=1)[CH2:14][NH2:15])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: [H][H]
Reactant: CCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCC)c1
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCCCOc1cc(CN)cc(OCCCCCCCCC)c1
Yield: 62.26 %

Procedure:
A thick walled glass bottle containing a stir bar was flushed with nitrogen gas. 5% Palladium on activated carbon (0.53 g, 10% by mass) was added and wetted with a solution of 50% methanol/ether (about 10 mL). A solution of 3,5-dinonoxybenzylazide (5.3 g, 12.68 mmol) in 50% methanol/ether (about 40 mL) was added. The mixture was hydrogenated with hydrogen gas at 40 psi for approximately 1 hour. The mixture was then filtered through celite with a controlled vacuum using.50% methanol/ether. The solvent was removed from the filtrate under reduced pressure and then the trace solvent was removed with using high vacuum. The starting material was still present in the resulting organic oil, so hydrogenation and celite filtration were repeated until there is no azide remained (3 times). There was a 7.3 g yield or a 62.26% yield of the derivative. The NMR characterization data for this derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.3, 6H, CH2CH3), 1.1-1.55 (m, 28H, CH2(CH2)6), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.78 (s, 2H,), 3.95 (t, J=6.6, 4H,), 6.33 (t, J=2.2, 1H, ArH), 6.44 (d, J=2.2, 2H, ArH).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([O:22][CH:23]([CH3:25])[CH3:24])[CH:16]=2)[CH2:11][CH2:10]1>C(O)=O>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:21]=[CH:20][C:18]([NH:19][CH:1]=[O:3])=[C:17]([O:22][CH:23]([CH3:25])[CH3:24])[CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)Oc1cc(C2CCN(C)CC2)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(C)Oc1cc(C2CCN(C)CC2)ccc1NC=O
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A solution of 12.3 g of acetic anhydride is added slowly to 19 ml of formic acid at ambient temperature. After one hour of stirring, a solution of 6.0 g of 4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline in 28 ml of formic acid is added dropwise. The mixture is stirred at ambient temperature for 2 h and then concentrated under vacuum and taken up with water. The aqueous phase is neutralized with a saturated sodium bicarbonate solution and extracted three times with 100 ml of dichoromethane. The organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product is triturated with ethyl ether and the solid is filtered off, so as to obtain 5.0 g of N-[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]formamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[C:15]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH2:27][NH:22][C:15](=[O:16])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(I)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCC(=O)c1ccc(Br)c(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a solution of 1-bromo-2-fluoro-4-iodobenzene (44.22 g, 0.147 mol) in tetrahydrofuran (160 mL) was added isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 73.5 mL) at 0° C. and the mixture stirred at 0° C. for 3 hours. This solution was cannulated into a solution of 1-BOC-2-piperidone (24.4 g, 0.122 mol) in tetrahydrofuran (240 mL) at −78° C. and the mixture stirred at −78° C. for 1 hour. The solution was warmed to ambient temperature and stirred for one hour before quenching with water. Hydrochloric acid (2N, 120 mL) was added and the mixture stirred at ambient temperature for 10 minutes. The mixture was concentrated and the residue partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over magnesium sulfate and filtered. Concentration afforded the crude product which was recrystallized from hexane and dichloromethane to give 33.95 g of the title compound as a white solid. 1HNMR (CDCl3) δ 1.44 (s, 9H), 1.52-1.63 (m, 2H), 1.70-1.83 (m, 2H), 2.96 (t, J=7.1 Hz, 2H), 3.16 (q, J=6.4 Hz, 2H), 4.58 (s, 1H), 7.59-7.71 (m, 3H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH3:22][Si:23]([C:26]#C)([CH3:25])[CH3:24]>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.O1CCCC1>[CH3:22][Si:23]([CH3:26])([CH3:25])[C:24]#[C:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:2]=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#COC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
25 g (0.08 mol) Methyl 4-iodo-3-nitrobenzoate (compound IV), 20 ml (0.14 mol) triethylamine and 200 ml tetrahydrofuran were added into a reaction flask, protected by nitrogen gas, and stirred to dissolve, then 2.4 g (0.0034 mol) bis(triphenylphosphine)palladium dichloride, 0.65 g (0.0034 mol) cuprous iodide and 13.7 ml (0.096 mol) trimethylsilylethyne were added, the mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure to evaporated most of the tetrahydrofuran. After extracting with 300 ml ethyl acetate, the organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and separated by column chromatography to obtain methyl 4-(2-(trimethylsilyl)ethynyl-3-nitrobenzoate (Compound III), 15.1 g (0.055 mol), yield 66.9%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17].[CH3:20][N:21]1C(=O)CCC1>O>[C:20]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17])#[N:21]
Reactant: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Reactant: CN1CCCC1=O
Solvent: O
Product: Cc1c(NC(=O)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Temperature: 220 °C
Yield: 51.7 %

Procedure:
To a solution of N-(4-chloro-2-methyl-3-(trifluoromethyl)phenyl) pivalamide (3c) (0.4 g, 1.36 mmol) in NMP (5 mL) CuCN (0.3 g, 34.0 mmol) was added at room temperature under nitrogen atmosphere and heated to 220° C. for 36 h. The reaction mixture was slowly brought to room temperature, diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography to furnish the nitrile 3d (0.2 g, 52%) as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([S:9][CH2:10][CH2:11][N:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[O:15][CH2:14][CH2:13]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1.O>C(Cl)Cl>[C:27]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([S:9]([CH2:10][CH2:11][N:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[O:15][CH2:14][CH2:13]2)=[O:41])[CH3:8])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(SCCN1CCOc2c(OCC(=O)O)cccc21)(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CC(c1ccccc1)(c1ccccc1)S(=O)CCN1CCOc2c(OCC(=O)O)cccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
(4-(2-(1,1-diphenylethylthio)ethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid (51 mg) was dissolved in methylene chloride (5 ml), and the resultant solution was stirred at room temperature. m-CPBA (20 mg) was then added to the solution, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added to water (20 ml), and then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by Lober® column chromatography (DIOL, type A, developing solvent: n-hexane/ethyl acetate=1/2) to obtain the object compound (43 mg, yield 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:27]([O:26][C:25]([N:24]([CH2:23][C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:14])=[O:15])[CH:11]=1)[CH3:32])=[O:31])([CH3:28])([CH3:29])[CH3:30]
Reactant: COC(=O)CBr
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1h (100 mg, 0.22 mmol), methyl bromoacetate (40 mg, 0.26 mmol) and potassium carbonate (45 mg, 0.33 mmol) were added to 5 mL of acetonitrile, then the reaction solution was heated up to 50° C. and stirred for 16 h. The reaction solution was concentrated under reduced pressure. 50 mL of water were added, and the reaction solution was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product methyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 1i (110 mg, a yellow oil), which was used directly in the next step.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)C>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:25][CH2:24]1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(CC(=O)Nc2cccc(-c3cnc4ccccc4n3)c2)CC1
Yield: 34.6 %

Procedure:
A solution of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol) and N-methylpiperazine (79 μL, 0.706 mmol) in ethanol (5 mL) was heated at 100° C. for 18 hrs. The solvent was evaporated and the oily residue was submitted to preparative LCMS to afford 2-(4-methylpiperazin-1-yl)-N-[3-(quinoxalin-2-yl)phenyl]acetamide (42 mg, 34%). LCMS calculated for C21H23N5O (M+H): 362.19. found 362.16. 1H-NMR (DMSO-d6, 400 Mhz) δH: 9.90 (1H, br. s), 9.51 (1H, s), 8.54 (1H, m), 8.19-8.12 (2H, m), 8.08 (1H, d, J=7 Hz), 7.94-7.82 (3H, m), 7.55 (1H, m), 3.18 (2H, s), 2.60-2.53 (4H, br), 2.48-2.40 (4H, br), 2.20 (3H, s).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:18](=O)[CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][OH:23].CO.C([BH3-])#N.[Na+]>C(Cl)Cl>[OH:23][CH2:22][CH2:21][NH:20][CH:18]1[C:13]2[C:14]3[C:15](=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:16][CH2:17]1
Reactant: NCCO
Reactant: O=C1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCCNC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 13 h
Yield: 32 %

Procedure:
A portion (0.20 g) of the compound obtained in Example 41 and 2-aminoethanol (0.49 ml) were suspended in a mixed solvent of methanol (3 ml) and methylene chloride (2 ml) and to the suspension was added sodium cyanoborohydride (61 mg). The mixture was stirred for 13 hours at room temperature and heated to reflux for further 8 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with three portions of methylene chloride. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride/methanol=19:1) and further crystallized from ether to yield 75 mg (32%) of the titled compound as yellowish brown crystals.