Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH:15]([NH:17][CH2:18][C@@H:19]([C:21]2[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([NH:27][CH:28]=[O:29])[CH:26]=2)[OH:20])[CH3:16])=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C.I.[NH2:41][C:42]1[C:43]([C:50]([NH:52][C:53](=[NH:56])SC)=[O:51])=[N:44][C:45]([Cl:49])=[C:46]([NH2:48])[N:47]=1>C(O)C>[NH2:41][C:42]1[C:43]([C:50]([N:52]=[C:53]([NH2:56])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH:15]([NH:17][CH2:18][C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([NH:27][CH:28]=[O:29])[CH:26]=3)[OH:20])[CH3:16])=[CH:10][CH:11]=2)=[O:51])=[N:44][C:45]([Cl:49])=[C:46]([NH2:48])[N:47]=1
Reactant: CC(CCCc1ccc(CCCCN)cc1)NC[C@H](O)c1ccc(O)c(NC=O)c1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(CCCc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)NC[C@H](O)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A solution composed of compound 28 (0.10 g, 0.25 mmol), Hunig's base (0.21 mL, 1.23 mmol) and ethanol (5 mL) was heated at 70° C. for 30 min before 1-(3,5-diamino-6-chloropyrazine-2-carbony)-2-methylisothiourea hydriodide (0.11 g, 0.27 mmol) was added. The resulting solution was continuously stirred at that temperature for an additional 3 h before it was cooled to room temperature. The solvent was removed by evaporation. The resulting residue was subjected to column chromatography eluting with a mixture of methanol (0-28%), concentrated ammonium hydroxide (0-2.8%) and dichloromethane (100-69.2%) to afford 30 (87 mg, 56%) as a yellow solid: m.p. 120-121° C. (decomposed); [α]D25 −6.65° (c 0.20, methanol); 1H NMR (500 MHz, DMSO-d6) δ 1.08 (d, 3H), 1.32 (m, 2H), 1.48-1.72 (m, 6H), 2.55 (m, 4H), 2.64-2.92 (m, 3H), 3.16 (m, 2H), 4.56 (m, 1H), 6.76 (m, 1H), 6.82 (m, 1H), 6.92 (m, 1H), 7.10 (m, 4H), 8.07 (s, 1H), 8.28 (s, 1H), 8.51 (s, 1H), 9.30 (s, 1H), 9.59 (s 1H); m/z (ESI) 626 [C30H40ClN9O4+H]+.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]4[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OC2CCCCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OC4CCCCC4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-cyclohexyloxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.56 mmol) described in Manufacturing Example 79-1-4 and 3-ethynyl-pyridine-2,6-diamine (47.6 mg, 0.357 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (195 μL, 1.4 mmol). This reaction mixture was stirred for 4 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried with anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (83 mg, 41%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:29])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:30]S(C1C=CC(N2C=CC(O[C@H]3CC[C@H](C(OCC)=O)CC3)=CC2=O)=CC=1)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]3[CH2:19][CH2:20][C@H:21]([C:24]([O:26][CH:27]([CH3:30])[CH3:28])=[O:25])[CH2:22][CH2:23]3)=[CH:13][C:12]2=[O:29])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Product: CC(C)OC(=O)[C@H]1CC[C@@H](Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1

Procedure:
Example 65 was prepared according to procedures described in Example 66 substituting cis-ethyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)cyclohexanecarboxylate for trans-ethyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)cyclohexanecarboxylate. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.5 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 7.20 (d, J=7.5 Hz, 1H), 6.05 (d, J=7.5 Hz, 1H), 5.96 (s, 1H), 5.00 (sept, J=6.2 Hz, 1H), 4.44-4.48 (m, 1H), 3.08 (s, 3H), 2.36-2.41 (m, 1H), 1.99-2.08 (m, 2H), 1.83-1.95 (m, 2H), 1.63-1.79 (m, 4H), 1.21 (d, J=6.2 Hz, 6H). MS (ESI) 434 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][N:4]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>COCCOC.[I-].[Na+]>[I:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:8]=1
Reactant: BrCc1cc(I)ccn1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: Ic1ccnc(CN2CCOCC2)c1
Temperature: 90 °C
Yield: 61.7 %

Procedure:
2-(Bromomethyl)-4-iodopyridine (500 mg, 1.68 mmol) in 1,2-dimethoxyethane (15 ml) was treated with morpholine (1.00 g, 11.48 mmol) and sodium iodide (13 mg, 0.09 mmol) and the resulting solution was heated at 90° C. for 5 h. After cooled to room temperature, the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and concentrated to give 4-[(4-iodo-2-pyridinyl)methyl]morpholine as a brown solid (315 mg, 62% yield).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[K+]>O>[C:1]1([C:7]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 62.5 g. of ethyl 3-phenyl-3-(4-nitrophenyl)propenoate, 100 ml. of ethanol and 300 ml. of 1.5 N potassium hydroxide was heated on a steam bath for 1 hour. To the cooled reaction mixture was added 800 ml. of water and 500 ml. of ethyl acetate, and then the ethyl acetate layer was removed. The aqueous layer was acidified, and the solid which precipitated was collected by filtration. This solid was recrystallized from toluene and then from carbon tetrachloride to give 22 g. of the title compound, m.p. 188°-189° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22]C1CCCCO1)(=[O:3])[CH3:2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO.CCOC(C)=O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)OCCCCCCCCCCCCCCCCCO
Temperature: 55 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
THP ether 39 (1.207 g, 3.03 mmol) was dissolved in 95% EtOH (12 ml) and PPTS (76 mg, 0.3 mmol) was added. Reaction mixture was stirred at 55° C. for 4 h, cooled to room temperature and diluted with EtOAc. Mixture was washed with H2O three times, organic extract was dried over Na2SO4 and evaporated. Residue was chromatographed on silica gel to give 864 mg (91%) of 17-acetoxy-heptadecanol.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:5].CS(O[CH:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)(=O)=O.O>CN(C=O)C>[CH3:5][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]2)=[CH:9][C:8]=1[CH3:14])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Cc1cc(O)ccc1CN(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 1.0 g, 23 mmol) in dry DMF (25 mL) under nitrogen was cooled by an ice-bath. A solution of 20A (2.9 g, 18 mmol) in DMF (20 mL) was added drop-wise over 10 minutes. The mixture was stirred for one hour and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (5.3 g, 21 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (200 mL) was added and the mixture was extracted three times with EtOAc (100 mL). The combined organic phases were dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography on SiO2 using 5-75% EtOAc/heptane as eluent. The product was further purified using 0.5% NH3 in MeOH/DCM as eluent. There was obtained 3.1 g (55%) of 20B as a semi-solid. 1H NMR (600 MHz, CDCl3): δ 1.44 (s, 9H), 2.21 (s, 6H), 2.32 (s, 3H), 3.29 (s, 2H), 3.93-4.02 (m, 2H), 4.21-4.32 (m, 2H), 4.79-4.89 (m, 1H), 6.48 (d, 1H), 6.55 (s, 1H), 7.12 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH:20]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][CH2:26][CH2:25][CH2:24][O:23][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: CC(C)OCCCN
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCCCOC(C)C
Yield: 88 %

Procedure:
The compound prepared in Example 3 was reacted with 3-isopropoxy-propylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 88%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[OH-:11].[Cs+]>C(OCC)(=O)C.CCCCCCC>[N+:8]([C:4]1[CH:3]=[C:2]([OH:11])[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(O)c1
Yield: 78 %

Procedure:
Following general mode A, 1-bromo-3-nitrobenzene (202 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of a red solid with a yield of 78% (eluent: ethyl acetate/heptane 20:80).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:6][C:5]([CH3:27])=[CH:4][N:3]=1.C([N:35]1[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]1)(OC(C)(C)C)=O.[H-].[Na+]>CN(C=O)C>[CH3:27][C:5]1[CH:6]=[C:7]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:2]([O:41][CH:38]2[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cnc(F)c(-c2nccc3cc(S(=O)(=O)Nc4nccs4)ccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc(OC2CCNCC2)c(-c2nccc3cc(S(=O)(=O)Nc4nccs4)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vial charged with 1-(2-fluoro-5-methylpyridin-3-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Example 377) (50 mg, 0.125 mmol) was added 1-boc-4-hydroxypiperidine (27.6 mg, 0.137 mmol) and DMF (499 μl) and the resulting solution cooled in an ice water bath prior to the addition of NaH (60% in mineral oil) (12.48 mg, 0.312 mmol). The mixture was stirred overnight at room temperature (ice melt) affording conversion to desired product as the primary species. To the light brown solution was added IPA (0.5 ml) and AcOH (50 μl). The resulting mixture was dried under reduced pressure affording a yellow oil to which DCM (1 ml) and TFA (0.3 ml) was added. The resulting mixture was stirred at room temperature for 2 hrs affording no Boc cleavage according to LC-MS. Another 0.7 ml of TFA was added and stirring was continued at room temperature for 2 hr affording complete Boc cleavage. The mixture dried under reduced pressure, dissolved in DMSO (1 ml) and purified with RP-HPLC (Gilson) ramping ACN in H2O (5-95%, 0.1% TFA modifier) affording separation of impurities. The product containing eluents were dried under reduced pressure and free-based with a 5 g SCX-2 column washing with MeOH, then 2M NH3 in MeOH. The basic wash was dried under reduced pressure affording a light yellow film which was lyophilized from MeOH/H2O to provide 1-(5-methyl-2-(piperidin-4-yloxy)pyridin-3-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as an off-white powder (25 mg, 0.052 mmol, 41.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J=5.67 Hz, 1H), 8.43 (d, J=1.66 Hz, 1H), 8.16 (dd, J=0.78, 2.45 Hz, 1H), 8.04 (d, J=5.38 Hz, 1H), 7.88 (dd, J=1.71, 8.85 Hz, 1H), 7.66-7.74 (m, 2H), 7.02 (d, J=4.01 Hz, 1H), 6.59 (d, J=4.11 Hz, 1H), 5.27 (td, J=3.47, 6.94 Hz, 1H), 2.91 (br. s., 2H), 2.61-2.79 (m, 2H), 2.30 (s, 3H), 1.86-2.01 (m, 2H), 1.56 (br. s., 2H). m/z (ESI) 482.1 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[IH:11]>C(Cl)Cl>[I:11][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: I
Reactant: CSc1cc(Cl)nc(C)n1
Solvent: ClCCl
Product: CSc1cc(I)nc(C)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.4 %

Procedure:
A mixture of 4-chloro-2-methyl-6-(methylthio)pyrimidine (5.3 g, 30.3 mmol) and hydriodic acid (67% solution, 5.71 mL, 76 mmol, Alfea Aesar, Avocado, Lancaster) in DCM (20 mL) was stirred at room temperature for 20 h and filtered. The collected solid was washed with DCM and then suspended in saturated NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to give 4-iodo-2-methyl-6-(methylthio)pyrimidine (7.3 g, 27.4 mmol, 90% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H); 2.62 (s, 3H); 2.52 (s, 3H). m/z (ESI, +ve ion) 266 (M+H)+.
Reaction SMILES: Br.C[O:3][C:4]1[CH:5]=[C:6]([C:10]23[CH2:19][CH:14]([N:15]([CH3:18])[CH:16]2[CH3:17])[CH2:13][CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1>Br>[OH:3][C:4]1[CH:5]=[C:6]([C:10]23[CH2:19][CH:14]([N:15]([CH3:18])[CH:16]2[CH3:17])[CH2:13][CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C23CCCC(C2)N(C)C3C)c1
Agent: Br
Product: CC1N(C)C2CCCC1(c1cccc(O)c1)C2
Yield: 95.5 %

Procedure:
A mixture of 3.1 g of 1-(3-methoxyphenyl)-6,7-dimethyl- 6-azabicyclo[3,2,1]octane hydrobromide and 30 ml of 48% aqueous hydrobromic acid is refluxed for 1.5 hours. After the reaction, the mixture is concentrated under reduced pressure. Aqueous ammonia is added to the residue, and the aqueous mixture is extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. The residue thus obtained is recrystallized from ethylacetate. 2.1 g of 1-(3-hydroxyphenyl)-6,7-dimethyl-6-azabicyclo[3,2,1]octane is obtained.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19]S(C2C=CC=CC=2)(=O)=O)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH3:29])[CH:6]=1)#[N:4].CC1CCCO1.[F:36][C:37]([F:53])([F:52])[C:38]1[CH:39]=[C:40]([NH:44][C:45]2[CH2:50][CH2:49][CH2:48][C:47](=[O:51])[CH:46]=2)[CH:41]=[CH:42][CH:43]=1>O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19][C:46]2[C:47](=[O:51])[CH2:48][CH2:49][CH2:50][C:45]=2[NH:44][C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([C:37]([F:36])([F:53])[F:52])[CH:39]=2)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[C:7]([CH3:29])[CH:6]=1)#[N:4]
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Reactant: Cc1cc(C#N)ccc1N(CS(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: Cc1cc(C#N)ccc1N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 150 mg, 3.75 mmol) is added in portions to a mixture of tert-butyl (4-cyano-2-methylphenyl)(phenylsulfonyl)methylcarbamate (step 1, 1.88 g, 3.41 mmol) and 2-methyltetrahydrofuran (10 mL), and the mixture is stirred at room temperature for 30 min 3-(3-(Trifluoromethyl)phenylamino)cyclohex-2-enone (869 mg, 3.41 mmol) is added, and the mixture is stirred for 2 h. Water is added, and the mixture is extracted with dichloromethane. The phases are separated, and the organic layer is concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 1.57 g; ESI mass spectrum [M+H]+=500; Retention time HPLC: 0.79 min (X012_S01).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C[O:18][C:19](=[O:30])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][C:23]=1[CH3:29]>>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][S:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([OH:30])=[O:18])=[C:23]([CH3:29])[CH:24]=2)=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)COc1ccc(S)cc1C
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Product: Cc1cc(SCc2ccc(OCc3ccccc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 1-chloromethyl-4-benzyloxy-benzene and 2C. MS m/z 409 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[O:24]>C1COCC1>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:24])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
To a stirred solution of ethyl 4-aminophenylacetate (1.13 g, 6.31 mmol) and Et3 N (965 ml, 6.92 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (953 ml, 6.31 mmol) and the reaction mixture was stirred at room temperature for 2 days. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give ethyl 4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.93 g, 84%) as white needles. mp 137–139° C.; 1H-NMR (CDCl3) δ 1.25–1.29 (m, 3 H), 3.59 (s, 2 H), 4.15–4.20 (m, 2 H), 7.05 (br s, 1 H), 7.13–7.23 (m, 6 H), 7.47–7.51 (m, 1 H), 7.54–7.56 (m, 1 H), 8.01–8.03 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([NH2:16])[CH:6]=1)=[O:4].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:27](O)=[O:28])=[CH:21]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([NH:16][C:27]([C:22]2[NH:23][C:24]3[C:20]([CH:21]=2)=[CH:19][C:18]([Cl:17])=[CH:26][CH:25]=3)=[O:28])[CH:6]=1)=[O:4]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)c1cc(N)cc2c1OCCCO2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)c2cc3cc(Cl)ccc3[nH]2)cc2c1OCCCO2
Reaction time: 4 h
Yield: 22.6 %

Procedure:
8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (0.300 g), 5-Chloro-1H-Indole-2-carboxylic acid (0.263 g), BOP (0.594), TEA (0.377 mL) and DMF (3.0 mL) were mixed together and stirred for 4 hours. The reaction was diluted with water and the resulting filtrate filtered. The resulting solid was tritriated with EtOAc, rinished with the same and purified by flash chromatography (silica gel; 25% EtOAc/hexane) to yield 122 mg of the product. MS PDS: M+ 401/403
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2I)=[O:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=1)=[O:4]
Reactant: COC(=O)c1ncc2c(I)cccc2c1O
Reactant: COc1cccc(O)c1
Product: COC(=O)c1ncc2c(Oc3cccc(OC)c3)cccc2c1O

Procedure:
The title compound was synthesized from 4-hydroxy-8-iodo-isoquinoline-3-carboxylic acid methyl ester and 3-methoxy-phenol in analogy to example 19d; MS-(+)-ion: M+1=326.4.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:5]=2[N:4]=[CH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:46][C:47]1[CH:48]=[C:49]([NH:54][C:55](=[O:67])[C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([C:65]#[N:66])([CH3:64])[CH3:63])[CH:57]=2)[CH:50]=[CH:51][C:52]=1[CH3:53]>CN(C=O)C>[C:65]([C:62]([C:58]1[CH:57]=[C:56]([CH:61]=[CH:60][CH:59]=1)[C:55]([NH:54][C:49]1[CH:50]=[CH:51][C:52]([CH3:53])=[C:47]([NH:46][C:11]([C:9]2[S:10][C:5]3[N:4]=[CH:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)=[O:13])[CH:48]=1)=[O:67])([CH3:64])[CH3:63])#[N:66]
Reactant: O=C(O)c1cc2[nH]c(=O)cnc2s1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2[nH]c(=O)cnc2s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 0.3 %

Procedure:
A solution of 2-oxo-1,2-dihydrothieno[3,2-b]pyrazine-6-carboxylic acid 84 (27 mg, 0.138 mmol), TBTU (48.6 mg, 0.151 mmol) and DIPEA (0.068 mL, 0.413 mmol) in DMF (1 mL) was stirred for 15 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (45.4 mg, 0.138 mmol) in DMF (1 mL) was added and stirred overnight at 50° C. Quenched with water and extracted with EtOAc. Organic layer was washed with water, dried and evaporated. Purification by HPLC gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-oxo-1,2-dihydrothieno[2,3-b]pyrazine-6-carboxamide 85 (0.2 mg, 0.308%). (m/z)=472 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[C:9]([C:12]3[CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[S:15][CH:16]=3)=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[N:8]2[C:9]([C:12]3[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[S:15][CH:16]=3)=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=1
Reactant: COC(=O)c1cc(-c2cnc3cc(-c4ccccc4)cc(OC)n23)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(-c2ccccc2)cc2ncc(-c3csc(C(=O)O)c3)n12
Temperature: 70 °C

Procedure:
To a solution of methyl 4-(5-methoxy-7-phenylimidazo[1,2-a]pyridin-3-yl)thiophene-2-carboxylate (94 mg, 0.26 mmol) in methanol (10 ml) and water (0.5 ml) was added a 5M aqueous solution of sodium hydroxide (0.50 ml, 2.5 mmol). The reaction mixture was heated to 70° C. After 1 h the reaction mixture was cooled and quenched with a 1N solution of hydrochloric acid (2.5 ml, 2.5 mmol), and then partially concentrated to precipitate yellow solids. The solids were washed with water and dried under vacuum to give 4-(5-methoxy-7-phenylimidazo[1,2-a]pyridin-3-yl)thiophene-2-carboxylic acid. LRMS (ESI) calculated for C19H15N2O3S [M+H]+, 351.1 found 351.0.