Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=3[O:31][CH2:32][CH:33]([F:35])[F:34])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[F:35][CH:33]([F:34])[CH2:32][O:31][C:18]1[C:19]([C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:36])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C=C(C)c1cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3OCC(F)F)cccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=CC(=O)O)c1cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3OCC(F)F)cccc2s1
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 0.450 mmol of 3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, and the crude acid was recrystallized from acetonitrile to afford 192 mg (0.378 mmol, yield: 58%) of 3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}-but-2-enoic acid was isolated as a white solid. 1H NMR (CDCl3), δ: 7.81 (dd, J=7.3, 1.5 Hz, 1H), 7.45 (m, 4H), 7.21 (d, J=2.4 Hz, 1H), 6.33 (s, 1H), 5.19 (dt, J=55.5, 4.3 Hz, 1H), 3.51 (m, 2H), 2.59 (s, 3H), 1.48 (s, 9H), 1.35 (s, 9H).
Reaction SMILES: N[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[C:18]([F:21])[CH:17]=[C:16]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.N([O-])=[O:29].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH:25]1([NH:24][C:22]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][OH:29])=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[C:18]([F:21])[CH:17]=2)=[O:23])[CH2:26][CH2:27]1
Reactant: O=N[O-]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CO)o2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide (Example 45) (96 mg) in acetic acid/water (1:1 v/v, 7 ml) was cooled to 0° C. Sodium nitrite (206 mg) was added and the solution stirred for 30 minutes at 0° C. and then for a further 16 hours at room temperature. Concentrated sodium hydroxide solution (10 ml) was added to the reaction and the mixture extracted with ether (3×40 ml) and then chloroform (40 ml). The organic phases were combined, dried and reduced to dryness under vacuum. The residue was dissolved in 5% potassium hydroxide in methanol and stirred at room temperature for 90 minutes. The methanol was removed in vacuo, the residue partitioned between ethyl acetate/chloroform (1:1)/water and the organic phase dried and reduced to dryness under vacuum. This material was purified by chromatography on a bond-elut (silica, 2 g), eluting with an ethyl acetate/cyclohexane gradient to give after evaporation of the solvent N-cyclopropyl-5-fluoro-4′-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [C:1]1([S:7]([O:10][CH2:11][C:12]([N:14]2[CH2:18][C@@H:17]([F:19])[CH2:16][C@H:15]2[C:20]([NH2:22])=O)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C>[C:1]1([S:7]([O:10][CH2:11][C:12]([N:14]2[CH2:18][C@@H:17]([F:19])[CH2:16][C@H:15]2[C:20]#[N:22])=[O:13])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
(2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolid ine-2-carboxamide (516 mg) was dissolved in acetonitrile (10 mL) and triethylamine (0.52 mL) was added to the solution. While this mixture was cooled in an ice bath, trifluoroacetic anhydride (0.27 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure. Water (5 mL) was added to the residue and the resulting crystal was collected by filtration. The filtered solid was washed with water and was dried under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carbonitrile as a white crystal (339 mg, 70% yield).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[F:39][C:40]1[CH:41]=[CH:42][C:43]([C:49]([F:52])([F:51])[F:50])=[C:44](B(O)O)[CH:45]=1>>[NH2:30][C:29]1[S:28][C:27]([C:44]2[CH:45]=[C:40]([F:39])[CH:41]=[CH:42][C:43]=2[C:49]([F:50])([F:51])[F:52])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: OB(O)c1cc(F)ccc1C(F)(F)F
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3cc(F)ccc3C(F)(F)F)sc2N)c1N1CCC(CN)CC1
Yield: 55 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 5-fluoro-2-(trifluoromethyl)phenylboronic acid gave 279 as a brown solid (54 mg, 55% over two steps). 1H NMR (400 MHz, d4-MeOD) 7.94 (dd, J=8.9, 5.4 Hz, 1H), 7.60-7.50 (m, 2H), 7.40 (td, J=8.3, 2.6 Hz, 1H), 3.73 (s, 3H), 3.21-3.09 (m, 4H), 2.63 (d, J=6.6 Hz, 2H), 1.84 (d, J=12.5 Hz, 2H), 1.57-1.48 (m, 1H), 1.38 (qd, J=11.8, 4.7 Hz, 2H). LCMS (ES+) m/z 498 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][O:11][CH3:12])[CH:4]=1.[Li]CCCC.[I:18]I>O1CCCC1>[I:18][C:4]1[C:5]([O:9][CH2:10][O:11][CH3:12])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COCOc1cccc(OC)c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cccc(OC)c1I
Temperature: -70 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a solution of 1-(methyloxy)-3-{[(methyloxy)methyl]oxy}benzene (Intermediate 45, 10 g, 59.5 mmol) in tetrahydrofurane (100 ml, SCRC) precooled to −78° C. was added dropwise BuLi (2.5 M in THF, 28.5 ml, 71.3 mmol, SCRC), maintaining the inner temperature lower than −70° C. After the addition was complete, the mixture was stirred at −70° C. for 2 hours and a solution of iodine (15.09 g, 59.5 mmol, SCRC) in THF (50 ml, SCRC) was added dropwise. The resulting mixture was stirred for 2 hours at room temperature and quenched with a saturated aqueous solution of ammonium chloride (100 ml). The mixture was extracted with ethyl acetate (3 times 300 ml, SCRC) and the combined organic layers were dried, evaporated and purified by silica gel chromatography with as eluents EtOAc:PE (1/100) to afford the title compound (16.2 g) as a yellow liquid.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[CH3:11][C:12]([CH3:14])=[O:13].C[O-].[Na+]>C1COCC1>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:3](=[O:4])[CH2:11][C:12](=[O:13])[CH3:14])[CH:6]=1
Reactant: COC(=O)c1cccnc1
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.4 %

Procedure:
To a solution of methylpyridine-3-carboxylate (20.0 g, 146 mmol) in THF (200 mL) was added acetone (50 mL, 681.0 mmol). Sodium methoxide (32.7 mL of 25% w/w, 146.0 mmol) was added dropwsie at rt under N2. The mixture was stirred at rt for 72 hours, quenched with sat. NH4Cl, acidifed with 1 N HCl to pH-5. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (0-10% EtOAc-Hex) to provide 1-(3-pyridyl)butane-1,3-dione (7 g) as a light yellow crystalline solid. 1H NMR (400 MHz, CDCl3) δ 15.98 (s, 1H), 9.19-8.99 (m, 1H), 8.74 (dd, J=4.8, 1.7 Hz, 1H), 8.34-8.04 (m, 1H), 7.41 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 6.20 (s, 1H), 2.24 (s, 3H). ESI-MS m/z calc. 163.06, found 164.3 (M+1)+; Retention time: 0.32 minutes (3 min run).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:47]([Si:51]([CH3:54])([CH3:53])Cl)([CH3:50])([CH3:49])[CH3:48].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.C1COCC1.O.CCCCCC.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:51]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:54])[CH3:53])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@H](C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
Analogously to Example 1j), 2.44 g (3.90 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(p-benzyloxyphenylmethyl)-hexanoic acid in 14 ml of DMF are silylated with 2.70 g (17.6 mmol) of tert-butyldimethylchlorosilane and 2.18 g (32 mmol) of imidazole. Hydrolysis of the silyl ester function with 3.2 g of potassium carbonate in 90 ml of methanol/THF/water 3:1:1 and column chromatography (SiO2, hexane/ethyl acetate 2:1→1:1) of the crude product yields the title compound: TLC Rf (A)=0.53; FAB-MS (M+H)+ =740.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24](F)=[CH:23][C:22]=1[F:31]>>[C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:24]2[CH:23]=[C:22]([F:31])[C:21]([F:20])=[CH:26][C:25]=2[N+:27]([O-:29])=[O:28])[CH:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1cc(F)c(F)cc1[N+](=O)[O-]
Yield: 16.7 %

Procedure:
By the same procedure described for example 2 method 2B, from 1.5 g of racemic 4-carbobenzyloxypiperazine-2-carboxylic acid and 1,2,4-trifluoro-5-nitro-benzene, there was obtained 0.4 g (16.7%) of title compound as an orange-red residue.
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7]([CH3:8])=[CH:6][CH:5]=1)[CH3:3].Cl[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=1[N+:27]([O-:29])=[O:28].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:23]([O:22][C:20]([C:19]1[CH:25]=[CH:26][C:16]([CH:8]=[C:7]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([CH2:2][CH3:3])[CH:5]=[CH:6]2)=[C:17]([N+:27]([O-:29])=[O:28])[CH:18]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC[n+]1ccc(C)c2ccccc21
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(C=C2C=CN(CC)c3ccccc32)c([N+](=O)[O-])c1

Procedure:
1-Ethyllepidinium iodide (5.8 g., 19.4 mmole) and ethyl 4-chloro-3-nitrobenzoate (4.6 g., 20 mmole) are stirred together in acetonitrile (50 ml.). Diisopropylethylamine (5.2 g., 40 mmole) is added and the mixture refluxed on a steam bath for 6 hours. The mixture is dissolved in 500 ml. ether and extracted five times with 200 ml. portions of water. The ether extract is dried over anhydrous magnesium sulfate. The dried ether solution is evaporated to dryness and then taken up on 25 ml. ether and chilled overnight. The precipitated dye is filtered off, washed with ether and petroleum ether, and dried. The yield is 2.8 g. (40%) with a m.p. of about 100° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:28](Br)[C:29]1[C:30]([CH3:35])=[CH:31][CH:32]=[CH:33][CH:34]=1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C(#N)C.C(O)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4[CH2:35][C:30]5[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1C(Br)Br
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: Fc1ccc2c(C3CCN(CCCN4Cc5ccccc5C4)CC3)noc2c1

Procedure:
A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CS(C)=O>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@H:17]([C:18](=[O:19])[NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3,N-diphenyl-propionamide in DMSO to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O)[CH2:2][CH:3]=[CH2:4].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO>[CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[N:17][OH:18])[CH2:2][CH:3]=[CH2:4]
Reactant: NO
Reactant: C=CCCC1C(=O)CCc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCCC1C(=NO)CCc2ccccc21

Procedure:
A mixture of 5.43 g of 1-(but-3-ene-yl)-2-tetralone, 54 ml of methanol, 2.06 g of hydroxylamine hydrochloride, and 2.41 g of sodium acetate was stirred and heated at reflux for 20 minutes. The reaction mixture was concentrated in vacuo to a small volume and the residue partitioned between ether and water. The ether layer was washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated to an oil, 5.78 g.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:33])([CH3:32])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:8][CH:7]=[C:6](/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:5]=2.[H][H]>CCO.[Pd]>[OH:1][C:2]1[C:3]([CH3:33])([CH3:32])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:8][CH:7]=[C:6]([CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:5]=2
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(/C=C/c3ccccc3)ccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(CCc3ccccc3)ccc2C1=O

Procedure:
(E)-tert-butyl 2-(2-hydroxy-1,1-dimethyl-4-oxo-7-styryl-1,4-dihydronaphthalene-3-carboxamido)acetate (150 mg, 335 μmol, Example 108) was dissolved in EtOH (3352 μL). Palladium (10% on carbon, 35.7 mg, 335 μmol) was added, and the reaction mixture was placed under one atmosphere of hydrogen with a balloon for 2 hours. The reaction mixture was filtered through a pad of Celite, washed with DCM, and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1c(Cl)cnn(Cc2ccccc2)c1=O
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(-c2ccc(Cl)cc2)cnn(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 82.4 %

Procedure:
To a stirred solution of 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (20.0 g, 79.8 mmol) in toluene (500 mL) was added Pd(PPh3)4 (5.5 g, 4.76 mmol) under an atmosphere of argon. 4-Chlorophenylboronic acid (18.7 g, 119.6 mmol) was added subsequently. Under vigorous stirring, Na2CO3 (33.8 g, 318.9 mmol) pre-dissolved in water (90 mL) was added to the suspension. A stream of argon was bubbled through this suspension for 10 min. After this time, the flask was placed in an oil bath preheated at 120° C. The reaction was refluxed for 3 h. After this time, the reaction was cooled to RT The reaction mixture was then poured into water (200 mL). The layers were separated and the aqueous mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (2×200 mL) followed by saturated aqueous NaCl (2×100 mL). The organic layer was then concentrated under reduced pressure to obtain crude product. This crude product was purified by silica gel column chromatography eluting with 8% EtOAc/hexanes to give the title compound, 2-benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one, (21.5 g, 82%) as a white solid. HPLC: 3.79 min; M+H=327. 1H NMR (CDCl3, 500 MHz): δ 7.76 (1H, s), 7.48 (2H, d, J=10.0 Hz), 7.40-7.45 (4H, m), 7.28-7.36 (3H, m), 5.35 (2H, s), 4.10 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][Si:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC(=O)c1ccc(O)cc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 20 g of 4-hydroxybenzoic acid and 10 g of imidazole in 100 ml of dry dimethylformamide at 0° C. was added 40 g of t-butylchlorodiphenylsilane. The mixture was stirred at 0° C. for 30 minutes, then at 20° C. for 18 hours, and then partitioned between diethyl ether and water. The organic layer was washed with water, with 10% aqueous potassium hydrogen carbonate, with water and with brine, and then dried over magnesium sulphate. Evaporation in vacuo of the solvent afforded 47.5 g of the title compound as a crystalline white powder.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.Cl.[CH3:27][C:28]1[CH:32]=[C:31]([NH2:33])[S:30][N:29]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)([O-])C.[Na+]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:33][C:31]3[S:30][N:29]=[C:28]([CH3:27])[CH:32]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cc1cc(N)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)sn1
Temperature: 140 °C
Yield: 19.8 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 mol), 3-methylisothiazol-5-amine hydrochloride (79.3 mg, 526 mol), BINAP (10.9 mg, 17.5 mol), palladium (II) acetate (19.7 mg, 87.7 mol) and sodium tert-butoxide (101 mg, 1.05 mmol, Eq: 3) in DMF (1.2 mL) and toluene (600 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 50-100% ethyl acetate in hexanes) gave N-tert-butyl-2-(3-methylisothiazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (32 mg, 69.5 mol, 20%) as a yellow solid. (EI/CI) m/z: 461.3 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].CN(C=O)C.Cl[C:20]1[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=2)=[CH:4][C:3]=1[O:9][C:10]([F:12])([F:11])[F:13]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: Oc1ccc(Br)c(OC(F)(F)F)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Oc2ccc(Br)c(OC(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3-[(trifluoromethyl)oxy]phenol (257 mg, 1.0 mmol) in dry DMF (4 mL) potassium carbonate (276 mg, 2 mmol) and then 2-chloro-5-nitropyrimidine (319 mg, 2.0 mmol) were added and the reaction mixture was stirred for 2 hours at r.t. The reaction was quenched with water (1 mL), diluted with brine (5 mL) and extracted with ethyl acetate (2×15 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give crude 2-({4-bromo-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-nitropyrimidine. This crude was dissolved in THF/water (2:1) (6 mL) and Iron (279 mg, 5 mmol) and NH4Cl (267.5 mg, 5 mmol) were added and the reaction mixture was stirred overnight at r.t. The solid was filtered off and the solution was diluted with an aqueous saturated solution of NaHCO3 (5 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 25 g) eluting from 75:25 to 40:60 cyclohexane/ethyl acetate to afford the title compound (280 mg) as light yellow solid.