Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].[CH:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](OC2C=CC=CC=2)=[N:14][C:15]#[N:16])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C>CC#N>[F:2][CH2:3][CH2:4][NH:5][C:13](=[N:14][C:15]#[N:16])[O:12][C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: NCCF
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#CN=C(NCCF)Oc1ccccc1
Reaction time: 14 h

Procedure:
Fluoroethyl amine hydrochloride (5.50 g, 90% purity, 49.75 mmol) was added to a solution of diphenyl cyanocarbonimidate (11.84 g, 49.70 mmol) in CH3CN, followed by addition of diisopropylethyl amine (17.30 mL, 99.32 mmol). After stirring for 14 hours, the reaction mixture was concentrated and the residue was taken up in EtOAc. The organic layer was washed sequentially with H2O (3×75 mL) and aq 2N KOH (3×100 mL), then concentrated to give a viscous oil, which was solidified upon standing at room temperature. Recrystallization from ether gave the desired 1-(2-fluoro-ethyl)-2-phenyl-3-cyanoisourea intermediate. A portion of this intermediate was mixed with an appropriate amine in CH3CN. The resulting reaction mixture was refluxed for 14 hours. After cooling to room temperature, the mixture was diluted with EtOAc and the resulting organic phase was washed with H2O (3×75 mL) and then concentrated. The residue was purified by column chromatography using hex:EtOAc (2:3) as eluant to give a semi-pure product. Recrystallization from EtOAc afforded the final pure cyanoguanidine.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH:39]2[CH2:38][CH2:37][N:36]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:41][CH2:40]2)=[O:11])=[CH:8][N:7]=1
Reactant: O=C(O)c1ccc(NC(=O)C(F)(F)F)nc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cn1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
0.1 g (0.00043 mol) of 6-trifluoroacetamido-nicotinic acid was dissolved in 10 ml of THF, treated with 0.073 g (0.00045 mol) of carbonyldiimidazole and stirred at 60° for 2 hrs. Then, 0.086 g (0.00045 mol) of 1-benzyl-4-hydroxypiperidine was added and the mixture was stirred at 60° overnight. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.097 g (72%) of 1-benzyl-piperidin-4-yl 6-amino-nicotinate was obtained as white crystals; m.p. 135°-136°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11]C)[C:5]([OH:7])=[O:6].Br.C(O)(=O)C>O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1F
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(O)c(F)c1
Yield: 85.7 %

Procedure:
98.8 g of 3-fluoro-4-methoxy benzoic acid was mixed with 215 ml of concentrated hydrogen bromide solution and 215 ml of acetic acid and heated under reflux for 34 hours with stirring. Thereafter, the reaction mixture was cooled with water, and the precipitated crystal was filtered to obtain a blackish brown crystal. This crystal was recrystallized with water to obtain 77.73 g (yield: 86%) of a black crystal. Moreover, the use of this crystal itself caused no problem at the subsequent step though it may be changed into white by further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH2:54][C:55](O)=[O:56])[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[CH3:53][O:52][C:50]1[CH:49]=[C:48]([CH2:54][C:55]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:56])[CH:47]=[C:46]([O:45][CH3:44])[CH:51]=1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc(OC)c1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3,5-dimethoxyphenylacetic acid (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford 2-(3,5-dimethoxy-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.8 g, 79%) as a white solid: mp 294-296° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.88 min. (98%); 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.94 (m, 1H), 3.45 (s, 2H), 3.71 (s, 6H), 4.70 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.8 Hz, 1H), 6.37 (t, J=2.2 Hz, 1H), 6.46 (d, J=2.2 Hz, 2H), 7.51-7.67 (m, 1H), 7.72-7.81 (m, 2H), 8.61 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.83, 42.51, 48.82, 55.05, 98.34, 107.08, 121.88, 127.12, 131.51, 133.17, 134.61, 138.20, 139.18, 160.28, 166.90, 167.42, 169.77, 170.34, 172.73; Anal. Calcd. for C24H23N3O7: C, 61.93; H, 4.98; N, 9.03. Found: C, 61.62; H, 4.61; N, 8.91.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH2:19][CH2:18]2>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:19][CH2:18]2
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Clc1ccc2c(c1)CCN2
Product: O=C(O)c1cccc(S(=O)(=O)N2CCc3cc(Cl)ccc32)c1

Procedure:
3-(chlorosulfonyl)benzoic acid (1.0 g, 4.53 mmol) was treated with 5-chloroindoline (2.08 g, 13.60 mmol) using method A to give 3-(5-chloroindolin-1-ylsulfonyl)benzoic acid as an off white solid. Yield: 720 mg (47%). 1H-NMR: 8.09 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.5 Hz, 2H), 7.48-7.43 (m, 1H), 7.27-7.23 (m, 2H), 3.97 (t, J=8.5 Hz, 2H) 2.91 (t, J=8.5 Hz, 2H).
Reaction SMILES: [N:1]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][N:35]([Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[C:32]3=[N:33][CH:34]=2)O1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.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>[N:1]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:29]4[CH:30]=[C:31]5[CH:37]=[CH:36][N:35]([Si:38]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[CH:39]([CH3:40])[CH3:41])[C:32]5=[N:33][CH:34]=4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Reactant: Ic1ccc2ncnc(N3CCc4ccccc43)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccc4ncnc(N5CCc6ccccc65)c4c3)cnc21
Yield: 73.4 %

Procedure:
0.20 g of 4-(2,3-dihydroindol-1-yl)-6-iodoquinazoline, 0.21 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine, 0.13 g of sodium hydrogencarbonate and 0.07 g of Pd(PPh3)2Cl2 in 5.00 ml of dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 5 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography; (gradient heptane: EA 5-100% in 16 min), giving 0.20 g of 4-(2,3-dihydroindol-1-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-quinazoline as white powder (yield 71%, content 99%); EI-MS (M+H+)=519.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH:9]=[O:10])=[N:7][CH:8]=1
Reactant: COc1cnc(CO)cc1[N+](=O)[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cnc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (5-methoxy-4-nitropyridin-2-yl)methanol (4 g, 0.021 mol) in DCM (30 mL), was added Dess-Martin Periodinane (18.43 g, 0.043 mol, Spectrochem, India) and reaction was stirred for 3 h at rt. The reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, sat'd NaHCO3 (20 mL) was added and the product was extracted with DCM (3×25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.95 (s, 1H), 9.02 (s, 1H), 8.36 (s, 1H), 4.19 (s, 3H). MS (ESI, positive ion) m/z: 182.9 (M+H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)s1
Product: O=C(Cl)c1ccc(Br)s1

Procedure:
Following the procedure of Example 32, 2.07 g (10.0 mmoles) of commercially available 5-bromo-2-thiophenecarboxylic acid was reacted with 10 ml of thionyl chloride to give 2.35 g of crude 5-bromo-2-thiophenecarbonyl chloride as a red oil. The total crude acid chloride was coupled to 1.76 g (8.33 mmoles) of 5-chloro-2-oxindole-1-carboxamide by the procedure in Example 32 using 3.05 g (25.0 mmoles) of 4-(N,N-dimethylamino)pyridine and 50 ml of N,N-dimethylformamide. Acidic workup gave a solid which was recrystallized to give 1.77 g (4.43 mmoles, 53% yield) of title compound as reddish-brown crystals, m.p. 228°-229° C. (tetrahydrofuran).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH2:31])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[CH3:2].[F:33][C:34]([F:48])([F:47])[C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:46])[CH2:42][C:43](=O)[CH3:44])=[CH:37][CH:36]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:31]/[C:43](/[CH3:44])=[CH:42]\[C:41](=[O:46])[C:38]1[CH:39]=[CH:40][C:35]([C:34]([F:33])([F:47])[F:48])=[CH:36][CH:37]=1)[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(N)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)N/C(C)=C\C(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 105 a], [rac]-2-amino-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester was reacted with 1-(4-trifluoromethyl-phenyl)-butane-1,3-dione in toluene in the presence of a catalytic amount of p-toluene sulfonic acid at reflux to yield [rac]-2-[1-methyl-3-oxo-3-(4-trifluoromethyl-phenyl)-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 105 b] to yield [rac]-2-[1-methyl-3-oxo-3-(4-trifluoromethyl-phenyl)-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid as light yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@@H:26](O)[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.C(N(S(F)(F)[F:38])CC)C>C(Cl)Cl.O>[CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@H:26]([F:38])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@@H](O)CC2)c(C(=O)O)s1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](F)CC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (102 mg, 0.23 mmol) in dry CH2Cl2 (2 mL) is added DAST (Diethylaminosulphurtrifluoride) (90 μL, 0.69 mmol), and the mixture is stirred for 4 h at room temperature. Then it is diluted with CH2Cl2, water is added to the mixture, and it is vigorously stirred for 20 min. Organic fraction is separated, dried over Na2SO4, concentrated, and the residue is purified by preparative HPLC to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[CH3:23]>N1C=CC=CC=1>[CH3:23][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[CH2:16][CH2:15][C:14]1[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=1[NH:12][C:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Product: CN1CCCCC1CCc1ccccc1NC(=O)C=Cc1ccccc1
Reaction time: 3 h
Yield: 70 %

Procedure:
Cinnamoyl chloride (6.0 g., 0.036 mole) is added to a solution of 2-(o-aminophenethyl)-1-methylpiperidine (7.8 g., 0.036 mole) in 100 ml. of pyridine in one portion with vigorous stirring. Stirring is continued for 3 hours and the pyridine solution is then concentrated in vacuo. The resulting residue is taken up to 150 ml. of water and made basic with 40% sodium hydroxide. The basified solution is extracted with several 200 ml. portions of ether, which are combined, washed with water, dried over magnesium sulfate and the ether solvent evaporated. The residue thus obtained crystallizes and is further purified by crystallizing from isopropyl ether providing 8.7 g. (70% yield) of analytically pure 2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide melting at 101.5°-103.5° C. (corr.).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:6][C:7]=1[NH:8]CC1C=CC(OC)=CC=1OC)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:7]1[S:6][C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)c1sc(NCc2ccc(OC)cc2OC)c(C#N)c1-c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
Ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-[(2,4-dimethoxybenzyl)amino]thiophene-2-carboxylate (4.70 g, 0.00956 mol) was dissolved in dichloromethane (100 mL). Trifluoroacetic acid (25 mL) was added and the solution was stirred at room temperature for 10 minutes. The reaction was concentrated in vacuo, diluted with ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (2.92 g, 90%) as a yellow solid. LCMS: (FA) ES+, 341. 1H NMR (400 MHz, d6-DMSO) δ: 8.17 (s, 2H) 7.75 (d, 1H, J=2.00 Hz), 7.52-7.48 (m, 1H), 7.39 (d, 1H, J=8.28 Hz), 4.05-3.92 (m, 2H), 1.02-0.96 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][O:14][CH3:15])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.C([Li])CCC.[CH:21](N1CCOCC1)=[O:22].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([CH2:12][CH2:13][O:14][CH3:15])[C:5]=1[O:10][CH3:11])[CH:21]=[O:22]
Reactant: COCCc1cc(Br)cc(OC)c1OC
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCc1cc(C=O)cc(OC)c1OC
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.3 g of 5-bromo-1,2-dimethoxy-3-(2-methoxy-ethyl)benzene in 20 ml of THF there was added dropwise 2 ml of n-butyllithium (2.66 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −70° C. for 30 minutes, 0.7 ml of N-formylmorpholine was added and the temperature was raised from −70° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (806 mg) as an oil.
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][N:31]=2)=[CH:41][CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Difluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 92%).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]CC)=O)(=O)[CH:2]([CH3:4])[CH3:3].[CH3:12][NH:13][NH2:14]>C(O)C>[OH:9][C:7]1[N:13]([CH3:12])[N:14]=[C:1]([CH:2]([CH3:4])[CH3:3])[CH:6]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: CCO
Product: CC(C)c1cc(O)n(C)n1
Yield: 88 %

Procedure:
To a solution of 30.0 grams of ethyl isobutyrylacetate in 130 ml of ethanol (anhydrous,5% methanol) at 10 C. was added dropwise over 30 minutes a solution of 8.7 grams of methyl hydrazine in 30 mls of ethanol. The reaction temperature did not exceed 20 C. After twenty minutes of additional stirring the cooling bath was removed and 2 ml of glacial acetic acid was added. After one hour of stirring at room temperature the reaction was then refluxed for four hours. After stirring overnight at room temperature the reaction was concentrated to yield a yellowish solid. This solid was stirred with 100 ml of hexanes for 30 minutes and the off-white solid was collected and rinsed with 75 ml of hexanes. The solid was dried in a vacuum oven at 45 C. overnight to yield 23.3 g of the desired product, mp 120-122 C.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[C:7]([O:13][CH2:14][CH2:15][O:16][C:17](ON1C(=O)CCC1=O)=[O:18])(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]>>[CH3:2][N:1]([C:17]([O:16][CH2:15][CH2:14][O:13][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:18])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CNCC(=O)O
Reactant: CCCCC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Product: CCCCC(=O)OCCOC(=O)N(C)CC(=O)O
Yield: 53.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.104 g, 1.1 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl pentanoate (0.268 g, 0.93 mmol) were reacted to provide 0.130 g (53.3% yield) of the title compound (43) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=6.79 (q, 1H), 4.12 (m, 2H), 3.0 (2s, 2H), 2.36 (m, 2H), 1.62 (q, 2H), 1.56 (2d, 3H), 1.39 (q, 2H), 0.97 (t, 3H). MS (ESI) m/z 284.09 (M+Na)+; 260.05 (M−H)−.
Reaction SMILES: Br[C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C.[N:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[N:40][CH:39]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:28][CH:25]1[CH2:26][CH2:27][N:23]([C:3]2[C:2]([C:42]3[CH:43]=[N:38][CH:39]=[N:40][CH:41]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:24]1
Reactant: OC1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(-c2cncnc2)c1
Temperature: 25 °C

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 60 mg, 0.152 mmol), (Rac.)-pyrrolidin-3-ol (15.86 mg, 0.182 mmol), and DIPEA (53.0 μL, 0.303 mmol) in iPrOH (250 μL) were added to a MW vial and subjected to MW irradiation at 110° C. for 20 min. The RM was then transferred into a MV vial containing pyrimidin-5-ylboronic acid (56.4 mg, 0.455 mmol), Pd(PPh3)2Cl2 (10.65 mg, 0.015 mmol), Na2CO3 (80 mg, 0.758 mmol) and treated with a mixture of DME (600 μL)-water (200 μL). The vial was sealed, evacuated/purged with argon and the RM was subjected to MW irradiation at 80° C. for 2 h. The RM was cooled to RT, diluted with THF (1.5 mL), treated with Si-Thiol (Silicycle, 59.7 mg, 0.076 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 13, 30% for 0.2 min then 30% to 60% in 12 min) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.01 min, m/z=446.0 [M+H]+, m/z=444.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.79 (m, 1H) 1.79-1.90 (m, 1H) 2.88 (d, J=11.0 Hz, 1H) 3.18-3.27 (m, 2H) 3.38-3.43 (m, 1H) 4.17-4.25 (m, 1H) 4.79-5.01 (m, 1H) 7.35 (d, J=8.3 Hz, 2H) 7.85 (d, J=4.9 Hz, 2H) 8.10 (d, J=2.4 Hz, 1H) 8.79 (d, J=2.4 Hz, 1H) 8.89 (s, 2H) 9.19 (s, 1H) 10.18 (s, 1H).