Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=O.[F:8][C:9]([F:15])([F:14])[C:10]([NH:12][NH2:13])=[O:11]>C1C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[C:10]([NH:12][NH:13][C:3](=[O:5])[C:2]([F:7])([F:6])[F:1])=[O:11]
Reactant: O=C(O)C(F)(F)F
Reactant: NNC(=O)C(F)(F)F
Solvent: c1ccccc1
Product: O=C(NNC(=O)C(F)(F)F)C(F)(F)F
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (7.6 mL, 0.1 mol) was added to a stirred solution of trifluoroacethydrazide (12.8 g, 0.1 mol) in benzene (100 mL) and the mixture was heated under reflux for 2 h. A Dean and Stark trap was fitted, and reflux was continued for 3 h. Reflux was continued in the absence of the Dean and Stark trap (3 h) and then with the trap refitted (20 h). The resulting white solid was collected by filtration, dried in vacuum and identified as 1,2-bis(trifluoroacetyl)hydrazine (16.5 g, 73%). M.p. 173-175° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:25])[CH:4]([N:12]1[C:18](=[O:19])[CH:17]([NH2:20])[CH2:16][C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=2[CH2:13]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:26][CH:27]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])[C:28](O)=[O:29]>>[CH3:1][NH:2][C:3](=[O:25])[CH:4]([N:12]1[C:18](=[O:19])[CH:17]([NH:20][C:28](=[O:29])[CH:27]([Br:26])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[C:39](=[O:40])[C:38]3=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]3[C:36]2=[O:45])[CH2:16][C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=2[CH2:13]1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNC(=O)C(Cc1ccccc1)N1Cc2ccccc2CC(N)C1=O
Reactant: O=C(O)C(Br)CCCCN1C(=O)c2ccccc2C1=O
Product: CNC(=O)C(Cc1ccccc1)N1Cc2ccccc2CC(NC(=O)C(Br)CCCCN2C(=O)c3ccccc3C2=O)C1=O

Procedure:
Prepare by the method of Example 3.1 using 2-(4-amino-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionic acid, N-methyl amide and 2-bromo-6-phthalimidohexanoic acid to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([C:11](=[O:14])[CH2:12]Br)[N:6]2[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[N:46]1([CH2:52][CH2:53][CH2:54][OH:55])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CS(C)=O>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([C:11](=[O:14])[CH2:12][O:55][CH2:54][CH2:53][CH2:52][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: OCCCN1CCOCC1
Reactant: Nc1ncnn2c(C(=O)CBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1ncnn2c(C(=O)COCCCN3CCOCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Temperature: 40 °C
Reaction time: 17 h
Yield: 16.6 %

Procedure:
To a stirred solution of Example 257 (200 mg, 0.351 mmol) in DMSO (1 mL), was added diisopropylethylamine (435 μL, 2.64 mmol) and 3-morpholin-4-ylpropan-1-ol (364 μL, 2.64 mmol) at rt. The reaction was allowed to stir at 40° C. for 17 hr. The mixture was allowed to cool and purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 37 mg (17%) of the desired product. 1H-NMR (DMSO-d6) δ 9.62 (br s, 1H), 9.47 (br s, 1H), 8.65 (dd, J=2.4, 7.2 Hz, 1H), 8.23 (t, J=8.4 Hz, 1H), 7.92 (s, 1H), 7.54-7.47 (m, 1H), 7.42-7.38 (m, 1H), 7.31 (dd, J=2.1, 12.3 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 6.88 (s, 1H), 4.24 (d, J=11.7 Hz, 2H), 4.05-3.96 (m, 4H), 3.86-3.77 (m, 4H), 3.43 (t, J=5.7 Hz, 2H), 3.24-3.20 (m, 2H), 1.91-1.85 (m, 2H); MS [M+H]+=634.2; LCMS RT=2.75 min.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1.[N:18]([O-])=O.[Na+].[ClH:22]>O>[ClH:22].[NH:3]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:6][CH:5]=1)[NH2:18]
Reactant: Nc1ccc(S(=O)(=O)O)c2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1ccc(S(=O)(=O)O)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4 g of NaOH are added to a suspension of 22.33 g of 4-amino-1-naphthalenesulphonic acid in 125 ml of water. The mixture is cooled to 0° C. and 2 ml of concentrated NaOH are added, followed by 7.5 g of sodium nitrite and 125 g of ice to maintain the temperature at 0° C. The suspension thereby obtained is poured into 75 ml of concentrated HCl cooled beforehand to 0° C., and left stirring for 2 hours 15 minutes at this temperature. The reaction mixture is added slowly to a solution, cooled beforehand to -10° C., of 55 g of stannous chloride dihydrate in 50 ml of concentrated HCl and 25 ml of water. After one night, the expected product is obtained by filtration, rinsing with 1N HCl and with water, m=23.96 g.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:12]([CH:11]([C:1]([OH:3])([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH3:14]
Reactant: CCCCC(=O)OCC
Reactant: CC(=O)c1ccccc1
Product: CCCC(C(=O)OCC)C(C)(O)c1ccccc1

Procedure:
A 10 milligram sample of the prepared hydroxy-ester is pyrolyzed is an open tube at 250° C. for 5 minutes. Examinationof the pyrolyzate by G.C., L.C. and T.L.C. indicates >90% decomposition to form a 1:1 mixture of acetophenone and ethyl valerate.
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6](=[O:22])[CH2:7][C:8]1[NH:9][C:10](=[S:21])[C:11]([F:20])=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:13]=1)C>C1COCC1>[F:20][C:11]1[C:10](=[S:21])[NH:9][C:8]([CH2:7][C:6]([O-:22])=[O:5])=[N:13][C:12]=1[N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1.[Na+:2]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)c(F)c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=S)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.85 ml of 2N sodium hydroxide is added to a solution of 255 mg of (5-fluoro-4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetic acid ethyl ester in 2 ml of THF. The reaction medium is stirred at ambient temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is oven-dried under vacuum in the presence of P2O5, so as to give 0.32 g of sodium (5-fluoro-4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate which is used as it is in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[CH2:14]1[C@@H:18](C(O)=O)[NH:17][CH2:16][C@@H:15]1[OH:22]>CS(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[N:17]3[CH2:16][C@H:15]([OH:22])[CH2:14][C@H:18]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Cl)c2C(=O)N2C[C@H](O)C[C@@H]12

Procedure:
37.0 g (187.3 mmol) of 6-chloroisatoic acid anhydride and 24.6 g (187.3 mmol) of L-4-hydroxyproline in 180 ml of dimethyl sulphoxide is heated to 100° for 2 hours, evaporated to dryness in a high vacuum and the residue obtained is heated to 130° for 2 hours. By recrystallization from ethanol there is obtained (2R,11aS)-6-chloro-1,2,3,11a-tetrahydro-2-hydroxy-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 284°-287°.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH3:28])[CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:47]([CH3:51])[C:48]([NH2:50])=[O:49]>CN(C=O)C>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH3:28])[CH:22]4[CH2:23][CH2:24][N:25]([CH:47]([CH3:51])[C:48]([NH2:50])=[O:49])[CH2:26][CH2:27]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CCNCC1
Reactant: CC(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(N)=O)N1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
To a solution of 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(methyl-piperidin-4-yl-amino)-thiazol-4-one (Example 17) (90 mg, 0.15 mmol) in DMF (2 mL) was added potassium carbonate (43 mg, 0.31 mmol) followed by 2-Bromo-propionamide (29 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 4 hours and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (60 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([C:7]1[C:8](=[O:15])[NH:9][C:10]([CH2:13][CH3:14])=[CH:11][CH:12]=1)=[O:6].C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClC(Cl)C.CN(C)C1C=CN=CC=1>[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([O:15][C:8]2[C:7]([C:5](=[O:6])[C:4]3[CH:16]=[CH:17][CH:18]=[C:2]([Cl:1])[CH:3]=3)=[CH:12][CH:11]=[C:10]([CH2:13][CH3:14])[N:9]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1ccc(C(=O)c2cccc(Cl)c2)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1ccc(C(=O)c2cccc(Cl)c2)c(OS(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
3-(3-Chlorobenzoyl)-6-ethyl-2-pyridone (95.8 g, 366 mmol) was dissolved in 1,000 ml of dichloroethane, 56.4 ml (403 mmol) of triethylamine, 4.52 g (366 mmol) of 4-dimethylaminopyridine and 76.7 g (403 mmol) of p-toluenesulfonyl chloride were added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was washed with water, 1 N hydrochloric acid-brine and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration and then the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was recrystallized from ethyl acetate-hexane to give 139.90 g of 3-(3-chlorobenzoyl)-6-ethyl-2-pyridyl p-toluenesulfonate in the form of crystals. The yield was 91.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]([NH2:36])([CH3:35])[CH3:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH:33]([CH3:35])[CH3:34])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.017 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.017 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 2 hours with a stream of nitrogen bubbling through it. A solution of isopropylamine (2.06 g, 0.035 mole) in tetrahydrofuran was added dropwise and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated and the solid residue was triturated with water. The solid was collected and dried under high vacuum overnight. The solid was recrystallized from isopropyl alcohol with cooling in the freezer, collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 4.0 g (70%), mp 248°-9° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([C:11](=[O:19])[CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:6]2[N:5]=[CH:4][N:3]=1.CN(C=O)C.[CH2:26]([N:33]1[CH:41]=[C:40]2[C:35]([CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:39]2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>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>[NH2:1][C:2]1[C:7]2=[C:8]([C:37]3[CH:38]=[CH:39][C:40]4[C:35]([CH:36]=3)=[N:34][N:33]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:41]=4)[CH:9]=[C:10]([C:11](=[O:19])[CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnn2c(C(=O)CN3CCOCC3)cc(Br)c12
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nc1ncnn2c(C(=O)CN3CCOCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 100 °C
Yield: 15.8 %

Procedure:
To a stirred solution of 1-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-morpholin-4-ylethanone (90 mg, 0.27 mmol) and tetrakis(triphenylphosphine)palladium(0) (61 mg, 0.05 mmol), in degassed 1,4-dioxane (1.0 mL) and DMF (2.0 mL) was added 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (97 mg, 0.29 mmol), K2CO3 (80 mg, 0.58 mmol), and H2O (0.3 mL). The mixture was degassed and heated (100° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous K2CO3 solution (25 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 20 mg (16%) of the desired product. 1H-NMR (DMSO-d6) 8.57 (s, 1H), 8.13 (s, 1H), 7.82 (d, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.36-7.28 (m, 5H), 7.14 (d, 1H), 5.65 (s, 2H), 3.93 (s, 2H), 3.58-3.56 (m, 4H), 2.56-2.53 (m, 4H); LC-MS [M+H]+=468, RT=2.27 min.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16]CS([O-])(=O)=O)[N:15]=2)=[CH:5][CH:4]=1.[N:24]1([CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH:28]=[CH:27][N:26]=[N:25]1.C1COCC1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][CH2:31][CH2:30][CH2:29][N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)=[CH:34][CH:35]=3)[N:15]=2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: O=S(=O)([O-])CCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methylmethanesulfonate (500 mg, 1.44 mmol), 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (344 mg, 1.58 mmol) and tetra(n-butyl) ammonium bromide (45 mg, 0.14 mmol) were added to THF (5 ml), and 1N-aqueous sodium hydroxide solution (3.0 mL, 3.00 mmol) was added. The mixture was stirred at room temperature for 5 hours. 10% Brine (10 ml) was added and the mixture was extracted with ethyl acetate (10 ml). The organic layer was washed with 10% brine (10 ml). The aqueous layers were combined and extracted with ethyl acetate (10 ml). The organic layers were combined and concentrated. Ethanol (15 ml) was added to the residue and the mixture was refluxed under heating for dissolution. After allowing to cool to room temperature and stirring, the mixture was stirred for 1 hour under ice-cooling. The precipitated crystals were collected by filtration, washed with cold-ethanol (2 ml) and dried under reduced pressure to give 1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole (556 mg, 1.19 mmol, yield 81%).
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C:17]2(O)[CH2:21][CH2:20][CH2:19][CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.N1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@:7]([C:17]2[CH2:21][CH2:20][CH2:19][CH:18]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)(C2(O)CCCC2)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[C@H]1OC(=O)[C@](C2=CCCC2)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Intermediate (1b) (650 mg, 2.1 mmol) was dissolved in 6.8 mL anhydrous THF and the solution was cooled to 0° C. Thionyl chloride (436 μL, 6 mmol) was added dropwise, followed by the addition of pyridine (777 μL, 9.6 mmol). The mixture was stirred at 0° C. for 1 hour. Saturated aqueous ammonium chloride (14 mL) was added and the mixture was stirred for 5 minutes while warming to room temperature. The layers were separated, and the aqueous layer was washed (2×100 mL EtOAc.). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to yield intermediate (1c) as a light yellow oil (540 mg), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C@@H:11]([CH3:25])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[C:20]=2[CH:22]=O)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[CH2:38]([O:37][C:35]([C:34]1[O:24][C:19]2=[CH:18][CH:17]=[C:16]3[C:21]([N:13]([CH2:12][C@@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:26])[CH3:25])[N:14]=[CH:15]3)=[C:20]2[CH:22]=1)=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: C[C@@H](Cn1ncc2ccc(O)c(C=O)c21)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ncc2ccc3oc(C(=O)OCc4ccccc4)cc3c21)NC(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 71.1 %

Procedure:
To a stirred solution of the product from Step C, Example 1 (0.12 g, 0.32 mmol) in DMF (10 mL) was added potassium carbonate (0.15 g, 1.05 mmol) followed by benzyl 2-bromoacetate (0.08 g, 0.48 mmol) at room temperature and the mixture was heated at 70° C. for 20 h. A saturated aqueous solution of ammonium chloride (20 mL) was added followed by ethyl acetate (50 mL). The organic layer was separated and the aqueous was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried and evaporated to a residue, which was purified by chromatography (silica, 50% ethyl acetate in hexane) to give a solid (0.11 g, 71%): mp 140-141° C.; MS (ES) m/z 484 (M+).
Reaction SMILES: CN(C)[CH:3]=[O:4].C.ClCCl.P(Cl)(Cl)(Cl)=O.[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:19]=1[CH3:28]>ClCCl>[CH3:15][O:16][C:17](=[O:29])[C:18]1[C:19]([CH3:28])=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([O:24][CH3:25])[C:23]=1[CH:3]=[O:4]
Reactant: COC(=O)c1cc(OC)cc(OC)c1C
Reactant: CN(C)C=O
Agent: C
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1c(C)c(OC)cc(OC)c1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 340 ml of N,N-dimethylformamide in 11 of dichloromethane methane were added slowly 404 ml of phosphoryl chloride. The solution was stirred for 1.5 h at room temperature, and then, a solution of 618 g of 3,5-dimethoxy-2-methylbenzoic acid methyl ester in 200 ml of dichloromethane was added within 10 min. The mixture was heated for 72 h at reflux temperature. After cooling, the mixture was slowly poured into 3 l of ice-water and subsequently extracted with 3.6 1 of dichloromethane. The organic layer was washed with 2 l of saturated sodium carbonate solution and twice with 2 l of water. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The solid residue was triturated in 3 l of ethyl acetate at 60° C., and after cooling, 1.5 l of hexane were added. The solid was isolated by filtration to yield 646 g of 2-formyl-3,5-dimethoxy-6-methylbenzoic acid methyl ester, m.p. 164°-165° C.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]2[CH:26]=O.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]2[CH2:26][NH:6][CH3:5]
Reactant: COc1ccc2c(c1)c(C=O)cn2C
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2ccc(OC)cc12
Yield: 98 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 5-methoxy-1-methyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.85 g, 98%) was obtained as a light yellow oil: MS (ES) m/e 205.2 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1[CH:12]=[CH:11][C:10]([CH2:13][SH:14])=[CH:9][CH:8]=1.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1F)=[O:17].[Cl-].[NH4+]>O1CCCC1>[CH2:13]([S:14][C:23]1[CH:22]=[C:21]([F:24])[CH:20]=[CH:19][C:18]=1[C:16](=[O:17])[CH3:15])[C:10]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(F)cc1SCc1ccccc1
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
Potassium tert-butoxide (7.3 g, 65.1 mmol) was dissolved in tetrahydrofuran (250 mL) and benzylthiol (7.52 mL, 64.1 mmol) in tetrahydrofuran (40 mL) was added via syringe over 10 minutes. The thick suspension was stirred for 15 minutes before adding 2,4-difluoroacetophenone (10 g, 64.1 mmol). The reaction was stirred for 1 hour to give a deep red solution. Saturated aqueous ammonium chloride was added and the products extracted into ethyl acetate (×2). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was triturated with methanol to give 1-[2-(benzylthio)-4-fluorophenyl]ethanone (10.13 g, 61%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[Li]CCCC.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][CH3:24]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[C:18]1([S:23][CH2:24][CH2:9][C:7](=[O:8])[CH2:6][C:5]([O:4][CH3:3])=[O:10])[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=1
Reactant: CSc1ccccc1Cl
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CC(=O)CCSc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 22.7 %

Procedure:
To a suspension of NaH (60%) (815 mg, 20.39 mmol) in THF-HMPA (20 ml, 5 ml) was added methylacetoacetate (2.0 g, 18.5 mmol) in THF (5 ml) at 0° C. The mixture was stirred for 10 min. at 0° C. under nitrogen atmosphere. BuLi (12.3 ml, 20.39 mmol) was dropwise added and the red mixture was stirred for 15 min. at 0° C. Then a solution of chlorothioanisole (2.7 ml, 20.39 mmol) in THF (5 ml) was added to the mixture at 0° C. The mixture was stirred for 1 h at -5° C. The mixture was quenched with H2O, then extracted with AcOEt (100 ml×2). AcOEt layer was washed with H2O (10 ml×2) and brine (10 ml), then dried over MgSO4 and evaporated. The residue was purified by a silica gel column chromatography (150 g, hexane :AcOEt=6:1) to give a colorless oil (1.0 g, 22.7%).