Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:11]([C:7]2[CH:6]=[C:5]([CH2:4][CH2:3][C:1]#[N:2])[CH:10]=[CH:9][N:8]=2)=[N:12]1
Reactant: COC(=O)c1ccccc1S
Reactant: N#CCCc1ccnc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#CCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 50 %

Procedure:
4-(2-Cyanoethyl)-2-pyridinecarbonitrile (0.70 g, 4.5 mmol) and methyl thiosalicylate (1.1 g, 6.2 mmol) were dissolved in toluene (3.5 ml), and triethylamine (1.2 ml, 8.9 mmol) was added thereto. The reaction mixture was refluxed for 8 hrs and kept at room temperature. The precipitated crystals were collected by filtration and washed with toluene. The obtained crystals were recrystallized from tetrahydrofuran-ethanol to give the titled compound (0.66 g, 51%) as white crystals
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=4[N:14](C(C)=C)[C:13]3=[O:25])[CH:10]=1)[N:7]([CH3:26])[C:6]([CH3:27])=[C:5]2[CH3:28].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=4[NH:14][C:13]3=[O:25])[CH:10]=1)[N:7]([CH3:26])[C:6]([CH3:27])=[C:5]2[CH3:28]
Reactant: C=C(C)n1c(=O)n(Cc2cc(Cl)cc3c(C)c(C)n(C)c23)c2ccc(C)cc21
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)[nH]c(=O)n2Cc1cc(Cl)cc2c(C)c(C)n(C)c12
Temperature: 60 °C
Yield: 75.4 %

Procedure:
To a solution of 1-(5-Chloro-1,2,3-trimethyl-1H-indol-7-ylmethyl)-3-isopropenyl-5-methyl-1,3-dihydro-benzimidazol-2-one (60 mg, 0.15 mmol) in a mixture of MeOH (3 mL) and water (3 mL), was added 1N HCl (2 mL). The reaction mixture was heated to 60° C. for 2 h. When the reaction was completed, the mixture was extracted with CH2Cl2 (×2). The organic phase was dried over Na2SO4 and concentrated to afford 40 mg of the desired product. The resulting residue was used for the next reaction without 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.[F:44][C:45]([F:61])([F:60])[C:46]1[CH:47]=[C:48]([CH2:56][C:57](O)=[O:58])[CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[F:44][C:45]([F:60])([F:61])[C:46]1[CH:47]=[C:48]([CH2:56][C:57]([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:58])[CH:49]=[C:50]([C:52]([F:53])([F:54])[F:55])[CH:51]=1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 50.4 %

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-di-(trifluoromethyl)-phenylacetic acid (0.7 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The reaction mixture was stirred at room temperature overnight and was 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-bis-trifluoromethyl-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.6 g, 54%) as a white solid: mp 202-204° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=13.69 min. (97%); 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.92 (m, 1H), 3.82 (s, 2H), 4.75 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.67-7.83 (m, 3H), 8.00 (s, 3H), 8.82 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.93, 30.89, 37.91, 40.88, 48.83, 117.94, 120.21 (120.26, 120.31), 121.98, 117.94 (121.55, 125.17, 128.75), 127.19, 130.14, 129.28 (129.71, 130.57), 131.54, 133.27, 134.60, 138.86, 139.45, 166.87, 167.39, 169.43, 169.76, 172.71; Anal. Calcd. for C24H17N3O5F6: C, 53.24; H, 3.16; N, 7.76; F, 21.05. Found: C, 53.16; H, 2.99; N, 7.73; F, 21.14.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][CH:12](O)[CH3:13].OS(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:8][CH3:9])=[C:6]([CH:12]([CH3:13])[CH3:11])[CH:7]=1
Reactant: CC(C)O
Reactant: COc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: COc1c(F)cc(Br)cc1C(C)C
Temperature: 80 °C
Yield: 38.4 %

Procedure:
To a mixture of 4-bromo-2-fluoroanisole (2.0 g, 9.70 mmol) and 2-propanol (1.2 g, 19.4 mmol) at room temperature was added 80% H2SO4 (10.0 mL). The reaction mixture was heated at 80° C. for 12 h, cooled to room temperature, quenched with ice (50 g) and extracted with ether (20 mL×2). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexanes to afford 4-bromo-6-fluoro-2-iso-propylanisole (0.92 g, 38%): 1H NMR (300 MHz, CD3OD): δ 7.36 (d, J=10.5 Hz, 1H), 7.22 (d, J=10.5 Hz, 1H), 3.91 (s, 3H), 3.24 (m, 1H), 1.26 (d, J=6.6 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (5:95); Rf=0.50.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][CH:25]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[N:22][C:21]([NH:24][CH:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)=[CH:20][CH:19]=2)=[CH:3][C:2]([C:42]2[CH:43]=[C:38]([Cl:37])[C:39]([OH:54])=[C:40]([Cl:53])[CH:41]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(NC2CCNC2)nc1)C1CC1
Yield: 44.7 %

Procedure:
Following general procedure D, tert-butyl 3-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-ylamino)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (43 mg, 45% over 2 steps) as a yellow-orange solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.26-8.07 (m, 3H), 8.00 (d, J=8.9 Hz, 1H), 7.57 (dd, J=8.9, 2.7 Hz, 1H), 7.34 (s, 2H), 6.85-6.77 (m, 1H), 4.65-4.56 (m, 1H), 3.66-3.49 (m, 2H), 3.44-3.30 (m, 2H), 2.86 (br s, 1H), 2.47-2.36 (m, 1H), 2.18-2.07 (m, 1H), 1.27-1.15 (m, 4H). ESI MS m/z 534 [C28H25Cl2N5O2+H]+; HPLC>99.0% (AUC), tR=10.64 min.
Reaction SMILES: CC(C)([O-])C.[K+].C[O:8][CH2:9][CH2:10][O:11]C.Cl[C:14]1[N:19]=[C:18]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:17]=[C:16]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[C:15]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH2:41]C>C(O)CO>[OH:8][CH2:9][CH2:10][O:11][C:14]1[N:19]=[C:18]([C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[N:17]=[C:16]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[C:15]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]
Reactant: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(Cl)c1Oc1ccccc1OCC
Reactant: COCCOC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: OCCO
Product: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Temperature: 85 °C

Procedure:
To a solution of potassium tert.-butoxide (366.5 mg) in ethylene glycol (5 ml) was added 1,2-dimethoxy ethane (5 ml) and n-propanesulfonic acid [6-chloro-5-(2-ethoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]amide (420 mg). The reaction mixture was heated to 85° C. for 7 days, concentrated in vacuo, poured onto water, acidified by 2N HCl and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The precipitated product was washed with diethylether, filtered and dried at HV to give n-propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (401 mg). LC-MS: tR: 3.67, [M+H]+: 462.26.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][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][CH3:18].[NH3:21].C(O)(=O)CCCCCCCCCCCCCCCCC.O>O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][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][CH3:18].[NH4+:21]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: N
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Product: [NH4+]

Procedure:
To 100 parts of water, 60 parts of stearic acid was added, and the stearic acid was completely melted by heating to 72° C. i.e. the melting point of the stearic acid, with stirring. In this state, stearic acid is present as oil droplets in water. Then, a mixture comprising 73.9 parts of 10% aqueous ammonia and 100 parts of water, was dropwise added to the above-mentioned molten stearic acid/water mixture, with stirring, to obtain an aqueous dispersion of ammonium stearate having a solid content of 20%.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[CH3:11][C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1.[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1>>[C:21]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][CH:1]=[C:16]2[C:17](=[O:18])[O:19][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:15])[CH:22]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(OCC)OCC
Product: CC1(C)OC(=O)C(=CNc2cccc(-c3ccccc3)c2)C(=O)O1
Yield: 95.5 %

Procedure:
Triethyl orthoformate (148 g, 1.00 mol), Meldrum's acid (137 g, 0.95 mol), and biphenyl-3-ylamine (155 g, 0.916 mol) were combined and treated according to the general procedure described in Part A of Example 1 to obtain 283 g of 5-(biphenyl-3-ylaminomethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2ccc(O)cc2)ccc1=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1nc(-c2ccc(OCCCCl)cc2)ccc1=O

Procedure:
Phenol from step 3 (500 mg, 2.3 mmol), 3-bromo-1-chloropropane (720 mg, 4.6 mmol) and K2CO3 (950 mg) in CH3CN (25 mL) was stirred at reflux 20 h. The reaction was filtered and concentrated. The resulting oil was dissolved in Et2O, and washed with water, NaCl solution, dried (MgSO4) and concentrated. The product was triturated with Et2O-hexanes to yield 580 mg (91%) mp 186-187° C. 1H NMR (DMSO-d6) δ 2.2 (t, 2H), 3.7 (s, 3H), 3.8 (t, 2H), 4.15 (t, 2H), 7.0-7.1 (m, 3H), 7.8 (d, 2H), 8.0 (d, 1H). MS m/z=279 (M+H).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([O:11][CH3:12])=[N:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:12][O:11][C:5]1[C:6]2[N:7]([CH:8]=[N:9][N:10]=2)[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[CH:3][N:4]=1
Reactant: COc1ncc(Br)n2cnnc12
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cccs2)n2cnnc12
Temperature: 100 °C
Yield: 97.9 %

Procedure:
A 50 mL round bottom flask was charged with 5-bromo-8-methoxy-[1,2,4]triazolo[4,3-a]pyrazine (0.25 g, 1.1 mmol), thiophen-2-ylboronic acid (280 mg, 2.2 mmol), Pd(PPh3)4 (190 mg, 0.16 mmol), Cs2CO3 (530 mg, 1.6 mmol), 1,4-dioxane (11 mL) and water (4 mL). The resulting mixture was heated under N2 at 100° C. overnight. Work-up: the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL) and the filtrate was extracted with more EtOAc (10 mL×3). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a 1:50 methanol/dichloromethane, to afford 0.25 g (99%) of the product as a yellow solid. MS m/z: 233 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.CS(ON1C2C=CC=CC=2N=N1)(=O)=O.[CH2:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH2:45])[CH3:38]>O1CCCC1>[CH2:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH:45][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[CH3:38]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Reactant: CCN1CCCC1CN
Agent: CS(=O)(=O)On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
2-Methoxy-5-sulfamoylbenzoic acid (2.3 g) and triethylamine (1.4 ml) are dissolved in anhydrous tetrahydrofuran (20 ml), and therto is added 1-methanesulfonyloxy-1,2,3-benzotriazole (2.2 g). After stirring at room temperature for 20 minutes, to the mixture is added 1-ethyl-2-aminomethylpyrrolidine (1.3 g) to precipitate oily products with exotherm. The mixture is stirred for 1 hour and then the solvent is distilled off. The resulting oily residue is dissolved in 1 N hydrochloric acid and the solution is washed twice with ethyl acetate. The aqueous layer is distilled under a reduced pressure to remove the remaining ethyl acetate and made alkaline with aqueous ammonia. The resulting precipitates are separated by filtration, washed with diluted aqueous ammonia and dried to give 1-ethyl-2-(2-methoxy-5-sulfamoylbenzamidomethyl)pyrrolidine (2.2 g), melting point: 175°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[C:5](\[NH2:16])/[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[CH3:25][C:24]([NH:16]/[C:5](/[CH2:6][C:7]1[C:8]([F:15])=[CH:9][C:10]([F:14])=[C:11]([F:13])[CH:12]=1)=[CH:4]\[C:3]([O:2][CH3:1])=[O:17])=[O:26]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)/C=C(\N)Cc1cc(F)c(F)cc1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)/C=C(/Cc1cc(F)c(F)cc1F)NC(C)=O
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A solution of (Z)-methyl-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate (4.90 g, 20 mmol) of Example 2, pyridine (4.8 ml) and acetic anhydride (4.80 g, mmol) in THF (30 ml) was heated to reflux for 16 h. The reaction mixture was stirred at room temperature, quenched with 1N HCl, and extracted with ethyl acetate (3×20 ml). The combined organic phase was washed with saturated sodium bicarbonate, then brine, then dried over sodium sulfate. Concentration was followed by purification by flash chromatography to afford 4.03 g of product (70.3%). 1H NMR (300 MHz, CDCl3) 11.14 (s, 1H) 7.10-7.00 (m, 1H), 6.96-6.87 (m, 1H), 4.81 (s, 1H), 4.14 (s, 2H), 3.70 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: C([NH:4][NH:5][C:6]([N:8]1[N:12]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[S:10][C:9]1([CH2:27][O:28][CH2:29][O:30][CH3:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])(=O)C.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)Cl.Cl[CH:47](Cl)[CH3:48]>>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C:11]1[S:10][C:9]([CH2:27][O:28][CH2:29][O:30][CH3:31])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:8]([C:6]2[O:7][C:47]([CH3:48])=[N:4][N:5]=2)[N:12]=1
Reactant: CC(Cl)Cl
Reactant: COCOCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)NNC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nnc(C)o1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a mixture of N′-acetyl-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbohydrazide (0.221 g, 0.491 mmol) and DIEA (0.634 g, 4.91 mmol) in dichloroethane (10 mL) was added POCl3 (0.376 g, 2.45 mmol). After stirring for 30 minutes, the mixture was partitioned between dichloromethane (10 mL) and saturated NaHCO3 (5 mL). The organic layer was extracted with dichloromethane (10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and chromatographed (20:1 to 10:1 hexanes/ethyl acetate) to provide the final product (0.080 g, 38%). MS ESI (+) m/z 433 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.68 (m, 1H), 7.54 (d, 2H, J=7 Hz), 7.35 (m, 3H), 7.10 (m, 2H), 4.90 (d, 1H, J=11 Hz), 4.74 (m, 2H), 4.52 (d, 1H, J=11 Hz), 3.37 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:8]([C:7]1[CH:6]=[C:5]([O:10][CH3:11])[N:4]=[CH:3][C:2]=1[O:1][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:9]
Reactant: COc1cc(C=O)c(O)cn1
Reactant: COC(=O)c1cncc(CCl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncc(COc2cnc(OC)cc2C=O)c1
Temperature: 60 °C
Yield: 50.6 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (352 mg, 2.29 mmol, 1 eq.), methyl 5-(chloromethyl)nicotinate hydrochloride (506 mg, 2.29 mmol, 1 eq.), and K2CO3 (1.26 g, 9.16 mmol, 4 eq.) in DMF (8.0 mL) was heated at 60° C. for 3 h. The mixture was cooled and added into water (50 mL) dropwise. The precipitate was filtered, washed with water, and dried to give methyl 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate (350 mg, 85%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 9.26 (d, J=2.0 Hz, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.42 (t, J=2.1 Hz, 1H), 8.09 (s, 1H), 7.15 (s, 1H), 5.29 (s, 2H), 4.01 (s, 3H), 3.95 (s, 3H). LRMS (M+H+) m/z 303.1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]([N:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][C:28]3[C:29](=[C:31]([C:35](O)=[O:36])[CH:32]=[CH:33][CH:34]=3)[N:30]=2)=[CH:22][CH:21]=1)[CH3:18])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH4+:38].[OH-].O>ClCCl>[C:35]([C:31]1[C:29]2[N:30]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([CH2:19][N:17]([CH3:18])[C:15](=[O:16])[O:14][CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:21][CH:22]=3)[O:27][C:28]=2[CH:34]=[CH:33][CH:32]=1)(=[O:36])[NH2:38]
Reactant: [NH4+]
Reactant: CN(Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1)C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN(Cc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1)C(=O)OCc1ccccc1
Temperature: 50 °C

Procedure:
Oxalyl chloride (218 mg, 1.72 mmol) is slowly added to a solution of 2-(4-(((benzyloxycarbonyl)(methyl)-amino)methyl)phenyl)benzo[d]oxazole-4-carboxylic acid (0.65 g, 1.57 mmol) in dichloromethane (10 mL) with stirring. The reaction mixture is warmed to 50° C. for 4 h and then cooled to 25° C. The solution is condensed in vacuum and then slowly added to 28% NH4OH (6 mL). The mixture is warmed to 50° C. and stirred for another 2 h. Water (50 mL) is added to the reaction mixture and the slurry is cooled to 25° C. The product is filtered and the cake is washed with water, dried to afford benzyl 4-(4-carbamoylbenzo[d]oxazol-2-yl)benzyl(methyl)carbamate solid. MS (ESI) m/e 416 [M+H]+.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:8]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:27]=[C:28]([SH:32])[CH:29]=[CH:30][CH:31]=1>>[CH3:21][C:20]1([CH3:22])[N:16]([CH2:15][CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:5]3[S:6][C:2]([S:32][C:28]4[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][CH:29]=4)=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)[C:17](=[O:24])[NH:18][C:19]1=[O:23]
Reactant: Cc1cccc(S)c1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(I)s2)n1
Product: Cc1cccc(Sc2ccc(-c3ccnc(NCCN4C(=O)NC(=O)C4(C)C)n3)s2)c1

Procedure:
The title compound was prepared from 1-{2-[4-(5-iodothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethyl-imidazolidine-2,4-dione and 3-methylthiophenol in a manner analogous to Example 259. MS (M+H)+ 454.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>C(O)C.O>[F:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]([C:8]3([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:17])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:28]=[N:27][CH:26]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: NC1=NC(c2ccncc2)(c2cccc(-c3cncc(F)c3)c2)c2ccccc21
Yield: 53.9 %

Procedure:
A mixture of 1-(3-bromophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine (Scheme #9, C) (0.073 g, 0.20 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.067 g, 0.30 mmol), potassium carbonate (0.055 g, 0.40 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (0.020 g, 0.025 mmol), dimethoxyethane (2 mL), water (1 mL) and ethanol (0.3 mL) under an argon atmosphere was irradiated in a microwave at 100° C. for 15 min. The reaction mixture was filtered and partitioned between water and ethyl acetate, the organic phase was concentrated and the residue was purified by preparative HPLC, which gave the title compound (0.041 g, 54%). 1H NMR (DMSO-d6) δ 8.67-8.63 (m, 1 H), 8.57 (d, J=2.78 Hz, 1 H), 8.49-8.42 (m, 2 H), 7.99-7.90 (m, 2 H), 7.85-7.79 (m, 1 H), 7.67-7.62 (m, 2 H), 7.55-7.41 (m, 4 H), 7.37-7.28 (m, 2 H), 6.95 (br s, 2 H), 1.91 (s, 2.2 H); MS (ESI) m/z 381 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:11](O)[CH2:12][CH2:13][CH3:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[SH:16][CH2:17][C:18]([OH:20])=[O:19].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH:11]([S:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH3:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=C(O)CS
Reactant: CCCC(O)c1cc2c(cc1C)OCO2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCC(SCC(=O)O)c1cc2c(cc1C)OCO2
Yield: 54 %

Procedure:
A solution of 5.6 g of (6-methyl-1,3-benzodioxol-5-yl)butan-1-ol, 4.8 g of mercaptoacetic acid and a catalytic amount of D-10-camphorsulfonic acid in 60 ml of benzene was heated under reflux for 3 hours, followed by the addition of ethyl acetate. The obtained mixture was washed with water and extracted with a 1N aqueous solution of sodium hydroxide. The aqueous layer was washed with ethyl acetate, acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and distilled to remove the solvent. The obtained residue was chromatographed over silica gel column and eluted with chloroform to obtain a colorless crystal. This crystal was recrystallized from isopropyl ether/hexane to obtain 4.1 g of the title compound as a colorless prismatic crystal.