Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8](=[O:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C)C=O>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:8](=[O:23])[CH:7]([CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:24])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(=O)CCc1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Yield: 59.1 %

Procedure:
A solution of 5-biphenyl-4-yl-3-oxo-pentanoic acid tert-butyl ester (13.7 g, 42.4 mmol) in dimethylformamide (10 mL) was added dropwise over 20 min to a stirred suspension of sodium hydride (60% mineral oil suspension; 1.78 g, 44.4 mmol) in dimethylformamide (10 mL) at 0° C. under nitrogen. After stirring for 20 min (2-bromoethoxy)-t-butyldimethylsilane (10.0 g, 46.4 mmol) was added dropwise over 20 min at 0° C. then the reaction heated to 70° C. for 2.5 h. On cooling to room temperature the reaction was quenched by careful addition of water (5 mL) then the volatiles evaporated. The residue was partitioned between saturated aqueous ammonium chloride solution (200 mL) and dichloromethane (200 mL) and the phases separated. The aqueous phase was washed with dichloromethane (3×200 mL) then the organic phases combined, washed with brine (200 mL), dried (sodium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (10% diethyl ether: cyclohexane) to give the title compound (12.1 g, 59%) as colourless oil which was a mixture of diastereomers. LC/MS: 4.70 min; z/e 483, calcd (M+1) 483. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.50 (2H), 7.40 (2H), 7.35 (1H), 7.25 (2H), 3.60 (2H), 2.95 (3H), 2.20 (1H minor) 2.0 (1H major), 1.55 (1H), 1.45 (11H), 0.85 (9H), 0.5 (6H).
Reaction SMILES: C1(O[C:8](=[O:19])[C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[C:11]([CH3:17])[C:10]=2[OH:18])C=CC=CC=1.[CH2:20]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:33]([N:32]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8](=[O:19])[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[C:11]([CH3:17])[C:10]=1[OH:18])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: Cc1cc(C)c(C(=O)Oc2ccccc2)c(O)c1C
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Product: CCCCCCCCCCCCN(CCCCCCCCCCCC)C(=O)c1c(C)cc(C)c(C)c1O
Temperature: 120 °C
Yield: 91 %

Procedure:
In a 250 ml flask fitted with a mechanical stirrer and a reflux condenser, were placed 30.7 g (0.12 mole) of the 2-hydroxy-3,4,6-trimethylbenzoic acid phenyl ester prepared in step (2) and 42.36 g (0.12 mole) of didodecylamine. This mixture was heated in a nitrogen atmosphere at 120° C. for 12 hours. The phenol formed was distilled off under vacuum (7 g were thus collected). After cooling, the crystallization of the desired product was started by scraping.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([C:11]1[N:12]=[C:13]([C:16]2[CH:25]=[C:24]([O:26][CH:27]3[CH2:45][CH:44]4[N:29]([C:30](=[O:65])[N:31](CC5C=CC(OC)=CC=5)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH:38][CH:39]5[C:41]([C:47]([NH:49][S:50]([CH:53]6[CH2:55][CH2:54]6)(=[O:52])=[O:51])=[O:48])([NH:42][C:43]4=[O:46])[CH2:40]5)[CH2:28]3)[C:23]3[C:18](=[C:19]([CH3:68])[C:20]([O:66][CH3:67])=[CH:21][CH:22]=3)[N:17]=2)[S:14][CH:15]=1)([CH3:10])[CH3:9].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:8]([C:11]1[N:12]=[C:13]([C:16]2[CH:25]=[C:24]([O:26][CH:27]3[CH2:45][CH:44]4[N:29]([C:30](=[O:65])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH:38][CH:39]5[C:41]([C:47]([NH:49][S:50]([CH:53]6[CH2:55][CH2:54]6)(=[O:52])=[O:51])=[O:48])([NH:42][C:43]4=[O:46])[CH2:40]5)[CH2:28]3)[C:23]3[C:18](=[C:19]([CH3:68])[C:20]([O:66][CH3:67])=[CH:21][CH:22]=3)[N:17]=2)[S:14][CH:15]=1)([CH3:10])[CH3:9]
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4cc(-c5nc(C(C)C)cs5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCNC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
TFA (10 mL) was added to a solution of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxy-8-methylquinolin-4-yloxy]-2,15-dioxo-14-(4-methoxybenzyl)-3,14,16-triazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide (90) in DCM (20 mL). After 30 min at room temperature, water (20 mL) was added to the reaction mixture and the pH was adjusted to 3-4 with NaHCO3. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (gradient MeOH/CH2Cl2, 0:1 to 1:99, then AcOEt/CH2Cl2 1:1) to afford 313 mg (73%) of the desired title product 91 as a yellowish solid: m/z=751 (M+H)+. 1H-NMR (CDCl3): 0.88-1.64 (m, 16H), 1.96 (m, 2H), 2.52 (m, 1H), 2.68 (m s, 5H), 2.79-2.92 (m, 3H), 3.18 (m, 1H), 3.63-3.69 (m, 2H), 3.86 (m, 1H), 3.97 (s, 3H), 4.34 (m, 1H), 4.59 (m, 1H), 5.08 (m, 1H), 5.40 (m, 1H), 5.80 (m, 1H), 6.73 (s, 1H), 7.03 (s, 1H), 7.21 (d, J=8.9 Hz, 1H), 7.26 (br s, 1H), 7.47 (s, 1H), 7.92 (d, J=8.9 Hz, 1H), 10.20 (br s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]([CH3:40])([CH3:39])[CH:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][CH2:24][CH3:25])[CH:18]=[C:17]2[CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=1[O:37][CH3:38])O)([OH:10])=[O:9].C([SiH](CC)CC)C.O>C(Cl)(Cl)(Cl)Cl>[C:8]([C:11]([CH3:39])([CH3:40])[CH2:12][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][CH2:24][CH3:25])[CH:18]=[C:17]2[CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=1[O:37][CH3:38])([OH:10])=[O:9]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C(O)C(C)(C)C(=O)O)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(C)(C)C(=O)O)ccc21
Reaction time: 0.58 h
Yield: 56 %

Procedure:
Trifluoroacetic acid (1.25 g) was added slowly to a stirred solution of methyl 4-[5-(2-carboxy-1 hydroxy-2-methylpropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate 0.5 g) and triethylsilane (0.128 g) in carbon tetrachloride (7 ml) under an atmosphere of nitrogen. After 35 min, the mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed (water (4 times), brine), dried (MgSO4) and evaporated to give a dark oil. The product was purified by flash chromatography, eluting with 90:10:2 toluene:ethyl acetate:acetic acid, to give methyl 4-[5-(2-carboxy-2-methylpropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate as an oil (0.27 g, 56%): partial NMR (250 MHz, DMSO-d6): 0.82(t, 3H, CH2CH3), 1.02(s, 6H, C(CH3)2), 1.68(m, 2H, CH2CH3), 291(s, 2H, C(CH3)2CH2), 3.82(s, 3H, OCH3), 3.89(s, 3H, OCH3), 4.01(m, 4H, NCH2, ArCH2Ar'), 12.15(br s, about 1H, COOH).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([O:29][CH3:30])[CH:23]=1)[CH3:20].[CH3:31][C:32]1[N:33]=[CH:34][C:35]([NH:38][C:39](N)=[O:40])=[N:36][CH:37]=1>>[CH3:20][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:39]([NH:38][C:35]2[CH:34]=[N:33][C:32]([CH3:31])=[CH:37][N:36]=2)=[O:40])=[C:24]([O:29][CH3:30])[CH:23]=1)[CH3:18]
Reactant: Cc1cnc(NC(N)=O)cn1
Reactant: COc1cc(CN(C)C)ccc1N
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: COc1cc(CN(C)C)ccc1NC(=O)Nc1cnc(C)cn1

Procedure:
According to the diphenylphosphoryl azide method described above for compound 336, 4-dimethylaminomethyl-2-methoxy-phenylamine was converted to the (5-methyl-pyrazin-2-yl)-urea. The crude product was purified by preparative TLC, eluting with 5% MeOH in CH2Cl2. 1H NMR (400 MHz, d6-DMSO): δ11.21 (s, 1H), 8.95 (s, 1H), 8.39 (s, 1H), 8.21 (d, J=7.83 Hz, 1H), 8.04 (s, 1H), 7.01 (s, 1H), 6.89 (d, J=7.83 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 2H), 2.26 (s, 3H), 2.24 (s, 6H). MS APCI-Pos, M+1=316.0.
Reaction SMILES: [H-].[Na+].CS([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)(=O)=O.[OH2:21]>CN(C)C=O>[CH3:17][C:18]1[CH:19]=[C:20]([O:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[CH:11]=[CH:12][C:13]=1[C:14](=[O:21])[CH3:15]
Reactant: CS(=O)(=O)OCCOc1ccc2ccccc2c1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 4-hydroxy-2-methylacetophonone (2 g) in dimethylformamide (30 mL) under argon was treated with 55% sodium hydride (0.58 g), stirred for 30 minutes and treated with 2-(2-naphthalenyloxy)ethyl methanesulfonate (3.65 g). The mixture was heated at 60° C. for 2 hours, cooled, diluted with water and filtered. The damp solids were mixed with water and excess sodium hydroxide solution, the product was extracted twice with dichloromethane, and the organic layers were washed with water. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give crude material which was crystallized from dichloromethane-diethyl ether to provide 3.5 g of 1-[2-methyl-4-[2-(2-naphthalenyloxy)ethoxy]phenyl]ethanone as a colorless solid, mp 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]1([C:15]([F:18])([F:17])[F:16])[CH2:14][O:13]1.[C:32](=O)([O-])[O-:33].[Cs+].[Cs+].O>CO>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]([OH:13])([CH2:14][O:33][CH3:32])[C:15]([F:17])([F:16])[F:18]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(Nc2cc(F)cc3[nH]c(=O)ccc23)C2(C(F)(F)F)CO2)c(Cl)c1F
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COCC(O)(C(Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(OC)c(F)c1Cl)C(F)(F)F
Yield: 42.9 %

Procedure:
2.14 g (4.64 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-on obtained in example 3 are stirred with 2.57 g (7.9 mmol) Caesium carbonate in 37 ml methanol. After 3 days water is added and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent flash chromatography on silica gel (methanol in dichloromethan 0 to 5%) yields 0.98 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C[Si]([C:24]#[N:25])(C)C>C(O)(=O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:13]2([C:24]#[N:25])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:12][CH:11]=1)[CH3:10]
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NC2(C#N)CCCCC2)cc1
Reaction time: 0.25 h

Procedure:
2 g (12.1 mmol, 1 eq.) of ethyl 4-aminobenzoate (Starting material 1) are added to a solution of 1.25 g (12.1 mmol, 1 eq.) of cyclohexanone (Starting material 2) in 20 ml of acetic acid at 0° C. The solution is stirred for 15 minutes, and 1.6 ml (12 mmol, 1 eq.) of trimethylsilyl cyanide are added. The reaction medium is stirred for 5 hours at room temperature. It is then poured gently into ice-cold ammonium hydroxide solution and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The residue is precipitated from dichloromethane and heptane. The product 4-(1-cyano-cyclohexylamino)benzoic acid ethyl ester is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[CH:3]=1.[O:13]1[CH2:15][C@H:14]1[CH2:16]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH2:16][C@@H:14]2[CH2:15][O:13]2)[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(=O)Nc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(F)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of N-(4-fluoro-2-hydroxyphenyl)acetamide (1.69 g, 10.0 mmol), (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (2.59 g, 10.0 mmol) and Cs2CO3 (4.87 g, 15.0 mmol) in DMF (15 mL) was stirred at room temperature for 2 h. The reaction mixture was partitioned between ethylacetate and H2O. The organic layer was dried over Na2SO4 filtered and concentrated. The residue was purified by silica gel flash chromatography to give the subtitled compound (1.35 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:17][C:18]([CH3:20])=[CH2:19])=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7]([CH:13]=[O:14])[C:6]([CH3:16])([CH3:15])[CH2:5]2.C(=O)([O-])[O-].[Ca+2].[I:26](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[I:26][CH2:19][C:18]1([CH3:20])[O:1][C:2]2[C:3](=[C:4]3[C:8](=[C:9]([CH3:12])[C:10]=2[CH3:11])[N:7]([CH:13]=[O:14])[C:6]([CH3:15])([CH3:16])[CH2:5]3)[CH2:17]1
Reactant: O=I(=O)Cl
Reactant: C=C(C)Cc1c(O)c(C)c(C)c2c1CC(C)(C)N2C=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C)c2c(c3c1OC(C)(CI)C3)CC(C)(C)N2C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
To a solution of 2,3-dihydro-5-hydroxy-2,2,6,7-tetramethyl-4-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (1.60 g, 5.85 mmol) in dichloromethane (15 mL) and methanol (5 mL) were added calcium carbonate (0.76 g, 7.6 mmol) and benzyltrimethylammonium dichloroiodate (2.24 g, 6.44 mmol), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered and concentrated under reduced pressure. To the residue was added a 5% aqueous sodium hydrogen sulfite solution (15 mL), and the mixture was extracted with ethyl acetate two times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane-ethyl acetate 10:1) to obtain 1.93 g of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:20][C:19]([OH:30])=[N:18]2)=[CH:13][CH:12]=1.Cl[CH2:32][C:33]1[N:37]=[CH:36][O:35][N:34]=1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:20][C:19]([O:30][CH2:32][C:33]3[N:37]=[CH:36][O:35][N:34]=3)=[N:18]2)=[CH:15][CH:16]=1
Reactant: ClCc1ncon1
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(OCc3ncon3)nn2-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 43.1 %

Procedure:
Potassium carbonate (279 mg, 2.02 mmol) and potassium iodide (335 mg, 2.02 mmol) was added to a solution of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (200 mg, 0.673 mmol) in dimethylformamide (2 mL). After 5 minutes stirring, 3-(chloromethyl)-1,2,4-oxadiazole (239 mg, 2.02 mmol) was added to the mixture and the mixture was heated at 100° C. for 1 hour. After cooling, ethyl acetate and water were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by preparative-TLC (toluene-ethyl acetate 4:1). The desired product was triturated with isopropylether, isolated by filtration, and dried in vacuo to give 3-({[1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-yl]oxy}methyl)-1,2,4-oxadiazole (110 mg, 43.1% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([OH:11])=[CH:9][N:8]([CH3:12])[C:7]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>O.C(Cl)Cl>[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([C:9]1[N:8]([CH3:12])[C:7]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10]=1[OH:11])=[O:24]
Reactant: O=C(Cl)c1ccccc1CCl
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(O)cn1C
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1c(C(=O)OCC)c(O)c(C(=O)c2ccccc2CCl)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Ethyl 3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate (510 mg, 2.0 mmol) is mixed with o-(chloromethyl)benzoyl chloride (565 μl, 4.0 mmol) under nitrogen, and 2.0 ml anhydrous trifluoromethanesulfonic acid is added. The reaction mixture is stirred at room temperature for one hour followed by dilution with methylene chloride (50 ml), and then water (30 ml). Solid sodium bicarbonate is slowly added until the acid is neutralized. The organic layer is separated and the aqueous layer is washed with methylene chloride (50 ml). The combined organic layers are washed with water (20 ml) and saturated brine (50 ml). Subsequently, the washed layers are dried with sodium sulfate and the solvent is removed in vacuo to give a red solid which is recrystallized from ethanol to give 525 mg (64.5%) of ethyl 5-[o-(chloromethyl)benzoyl]-3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=2)[C:9]([CH3:21])([CH3:20])[CH2:8]1)=[O:5].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[C:9]([CH3:21])([CH3:20])[CH2:8]1)=[O:5]
Reactant: COC(=O)c1ccc2c(c1)C(NC(=O)c1ccccc1Cl)CC2(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(NC(=O)c2ccccc2Cl)c2cc(C(=O)O)ccc21
Reaction time: 4 h
Yield: 98 %

Procedure:
Methyl 3-(2-chlorobenzamido)-1,1-dimethyl-2,3-dihydro-1H-indene-5-carboxylate (B-39) (120 mg, 0.34 mmol, 1 eq.) was dissolved in a mixture of solvents THF:MeOH:H2O (5:3:1, 5 ml) and LiOH (70 mg, 1.67 mmol, 5 eq.) was added portionwise at 0° C. The reaction mixture was stirred for 4 h and then the solvent was evaporated under reduced pressure. Water (4 ml) was added to the reaction to get a clear solution and it was then acidified with citric acid. This was followed by extraction with EtOAc (2×50 ml). The organic part was washed with brine (20 ml), dried over Na2SO4, filtered and evaporated under reduced pressure to yield the crude product which was purified by column chromatography (silica gel, 5% MeOH/MC) to yield the desired product as a white solid. Yield: 98% (115 mg, 0.34 mmol).
Reaction SMILES: [C:1]1(C)[C:2]([C:7](N)=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:11]([NH:14][C:15]1[C:16]([C:21]([OH:23])=O)=[N:17][CH:18]=[CH:19][N:20]=1)(=O)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:43](C(OCC)=O)=NC(OCC)=O>CN(C)C1C=CN=CC=1.O1CCOCC1>[CH3:12][C:11]1[N:43]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:7])[C:21](=[O:23])[C:16]2[C:15](=[N:20][CH:19]=[CH:18][N:17]=2)[N:14]=1
Reactant: Cc1ccccc1C(N)=O
Reactant: CC(=O)Nc1nccnc1C(=O)O
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: CN(C)c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1ccccc1-n1c(C)nc2nccnc2c1=O
Temperature: 25 °C

Procedure:
To a mixture of 3-acetamidopyrazine-2-carboxylic acid o-toluamide (1.0 g, 3.70 mmol), triphenylphosphine (2.91 g, 11.1 mmol), and 4-dimethylaminopyridine (0.045 g, about 10 mol %) in dioxane (45 mL) was added diethyl azodicarboxylate (1.75 mL, 11.1 mmol) dropwise via syringe. The reaction was refluxed overnight, cooled to ambient temperature and concentrated. The residue was partitioned between methylene chloride and water. The phases were separated and the organic layer was washed with brine, dried and concentrated. The residue was flash chromatographed on silica gel (2.25×4 inches, packed in hexane) with elution proceeding as follows: 20%-80% ethyl acetate/hexane, forerun; 85% ethyl acetate/hexane (1000 mL), 0.71 g (76%) of 2-methyl-3-(2-methyl-phenyl)-3H-pteridin-4-one which was suitable for use without further purification. A sample was recrystallized from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][CH2:12][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][O:15][CH3:16].CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:9]=[C:8]([NH:11][CH2:12][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:14][O:15][CH3:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)cc1Br
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H](CNc1ccc(C#N)c(Br)c1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 78.1 %

Procedure:
To a solution of 2-bromo-4-fluorobenzonitrile (0.2 g, 1 mmol) in DMSO (3 mL) was added (R)-tert-butyl 1-amino-3-methoxypropan-2-ylcarbamate (0.22 g, 1.08 mmol) and DIPEA (0.267 mL, 1.5 mmol). The mixture was heated at 100° C. for 15 h, and was diluted with EtOAc and washed with 1N HCl and Sat. NaHCO3. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 1-(3-bromo-4-cyanophenylamino)-3-methoxypropan-2-ylcarbamate (0.3 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:8]=1[C:22]#[N:23])(=O)=O.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC.CCOC(C)=O>COCCOC.[Cl-].[Na+].O.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:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[C:8]([CH:9]=1)[C:22]#[N:23]
Reactant: N#Cc1cc(-c2nc3ccccc3o2)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2nc3ccccc3o2)ccc1-c1ccccn1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The degassed solution of 4-(1,3-benzoxazol-2-yl)-2-cyanophenyl trifluoromethanesulfonate (300 mg, 1.2 mmol) in DME (5 mL) was added 2-tri-n-butylstannylpyridine (273 mg, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.1 mmol). The reaction was stirred at 90° C. overnight and cooled to rt. EtOAc (100 mL) was added, as well as brine (50 mL). The organic layer was washed with brine (2×20 mL), dried (MgSO4), and the crude material was purified on flash column (silica gel, hexanes:EtOAc 3:1) to afford desired 5-(1,3-benzoxazol-2-yl)-2-pyridin-2-yl benzonitrile as pinkish solid. 1H NMR (CD3OD, 300 MHz), δ 8.85 (d 1H), 8.72 (d, 1H), 8.59 (m, 1H), 8.08 (d, 1H), 7.91 (d, 2H), 7.85 (m, 1H), 7.65 (m, 1H), 7.45 (m, 3H). MS (ESI) 298 (M+H)+.