Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl[Si](C)(C)C.[C:7]([O:26]C)(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[OH:26][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7](=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC
Agent: C[Si](C)(C)Cl
Agent: [Na]
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Temperature: 40 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a 500 mL round bottom flask, purged with nitrogen, was added anhydrous toluene (70 mL) followed by finely sliced pieces of sodium metal (425 g, 185 mmol). chlorotrimethylsilane (17 mL, 136.1 mmol) was added slowly and the reaction was heated to 40° C. To this solution was added methyl linoleate (10 g, 32.4 mmol) drop wise over 45 minutes. The solution was brought to reflux for 2 hours where upon the sodium changed from a large mass to small 1-2 mm beads (reaction turned purple after ˜1.5 hours). The reaction was cooled to room temperature and slowly quenched with methanol (25 mL) at 0° C. over 30 minutes. Once the unreacted sodium metal had dissolved, the reaction mixture was filtered through celite with ether rinses (400 mL). The filtrate (˜400-500 mL) was stirred vigorously with saturated ammonium chloride (300 mL) for 16 hours. Upon completion, the ether/toluene layer was separated and washed with brine (1×100 mL). The organic layer was dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The yellow oil was purified by column chromatography (gradient: 100% Hexanes to 5% EtOAc in hexanes) to afford the title compound as a pale yellow oil (4.8 g, 56%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@H:10]([CH2:11]2)[C@H:9]1[C:14](=[O:27])[NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[CH2:17][OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28]COC(C)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@H:10]([CH2:11]2)[C@H:9]1[C:14](=[O:27])[NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[CH2:17][O:18][CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@H]2[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Product: COC[C@@H](NC(=O)[C@@H]1[C@@H]2C[C@@H]2CN1C(=O)OC(C)(C)C)c1cccc(Cl)c1F

Procedure:
was prepared according to Scheme B9 (Step B) from (1R,2S,5S)-2-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. TLC, Rf (EtOAc): 0.45; MS (UPLC/MS): 413.3/415.3 [M+H]+, 457.3 [M+HCOO]−; tR (HPLC conditions a): 3.64 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][CH:12]=[CH:11][CH2:10]1.C([O-])(O)=O.[Na+]>Cl.CO.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([NH2:15])[CH2:13][CH:12]=[CH:11][CH2:10]1
Reactant: O=[N+]([O-])[C@@H]1CC=CC[C@H]1c1ccc(F)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N[C@@H]1CC=CC[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of Example 3A (100 mg, 0.039 mmol) in 2 mL of 1:1 aqueous concentrated HCl in methanol at 0° C., Zn dust (32 mg, 0.5 mmol) was added in several portions. The solution was allowed to warm to room temperature over three hours, after which the solution was carefully basified with saturated NaHCO3. The mixture was extracted with ethyl acetate, concentrated, taken up in dichloromethane, and filtered through Celite. Concentration of the filtrate gave the title compound. 1H NMR (300 MHz, C5D5N) δ ppm 7.33-7.35 (m, 1H), 7.22-7.28 (m, 1H), 7.06-7.10 (m, 1H), 5.68-5.77 (m, 2H), 3.22-3.37 (m, 2H), 2.43-2.48 (m, 1H), 2.29-2.36 (m, 1H), 2.06-2.14 (m, 2H). MS (ESI+) m/z 227 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]=[C:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([NH:18][C:19](=[O:37])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:22][CH:21]=3)[C:12]=2[O:11][C:10]([C:38]2[N:39]=[N:40][N:41](O)[N:42]=2)=[CH:9]1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[Ti]>[CH:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]([C:19]([NH:18][C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8](=[O:7])[CH:9]=[C:10]([C:38]5[N:42]=[N:41][NH:40][N:39]=5)[O:11][C:12]=34)=[O:37])=[CH:21][CH:22]=2)=[CH:32][CH:33]=1
Reactant: O=C(Nc1cccc2c(=O)cc(-c3nnn(O)n3)oc12)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti]
Agent: [Al+3]
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c(=O)cc(-c3nn[nH]n3)oc12)c1ccc(OCCCCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a suspension of titanium tetrachloride (0.49 ml, 1.8 mole equivalents) in tetrahydrofuran (2.5 ml) was added lithium aluminium hydride (123 mg, 1.3 mole equivalents) to produce a black suspension of titanium (0) which was stirred for 15 minutes. 4-Oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(2-hydroxytetrazol-5-yl)-4H-1-benzopyran (1.24, 1 mole equivalent) was added, together with additional tetrahydrofuran (5 ml). The mixture was stirred for 60 minutes at room temperature and then heated at reflux for 90 minutes to give pranlukast in 71% solution yield.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[O:4][N:3]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[O:4][N:3]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccccc1-c1cc(O)no1
Reactant: CC(C)(C)OC(=O)NCCO
Product: Cc1ccccc1-c1cc(OCCNC(=O)OC(C)(C)C)no1
Yield: 85.3 %

Procedure:
3-Hydroxy-5-(2-methylphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.2 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.31 g, 86%) as a colorless powder.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([NH:8][NH:9][C:10]([S-:12])=[S:11])=O)(=[O:3])[CH3:2].[K+]>S(=O)(=O)(O)O>[C:1]([NH:4][CH2:5][C:6]1[S:11][C:10]([SH:12])=[N:9][N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)NNC(=S)[S-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)NCc1nnc(S)s1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
Potassium 3-(N-acetylglycyl)dithiocarbazate (102.3 g) was added bit by bit to concd. sulfuric acid (1 liter) at 0° to 5° C and the mixture was stirred for an hour at the same temperature. The reaction mixture was added dropwise on crushed ice (c.a. 10 kg) under stirring. Precipitating crystals were collected by filtration to give 5-acetamidomethyl-1,3,4-thiadiazole-2-thiol (54.5 g). m.p. 200° to 203° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[C:16]1([CH3:23])[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][CH:17]=1.N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2](/[N:1]=[C:18]2\[CH:17]=[C:16]([CH3:23])[C:21](=[O:22])[CH:20]=[CH:19]\2)[C:3](=[O:15])[N:4]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccccc1O
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC1=C/C(=N\c2c(C)n(C)n(-c3ccccc3)c2=O)C=CC1=O

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of o-cresol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[F:18])=[C:5]([CH3:7])[N:6]=1.[C:19](#[N:21])[CH3:20]>>[F:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[C:4]1[O:3][C:2]([NH:21][C:19]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:20]=2[CH2:5][CH:4]([OH:3])[CH2:8][CH2:9]3)=[N:6][C:5]=1[CH3:7]
Reactant: CC#N
Reactant: Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1F
Product: Cc1nc(Nc2cccc3c2CC(O)CC3)oc1-c1ccc(C(F)(F)F)cc1F
Yield: 14 %

Procedure:
A mixture of Example 5D (1.32 g, 4.72 mmol) and Example 1A (1.31 g, 4.72 mmol) in acetonitrile (16 mL) was heated at 150° C. in a microwave reactor for 20 minutes. The solution was cooled and concentrated, and the crude material was chromatographed on silica gel (1 to 20% methanol-CH2Cl2 eluant). The resulting crude product was further purified by trituration with 1:1 hexane-ether, which yielded 0.278 g (14% yield) of the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.64-7.76 (m, 3H), 7.51 (m, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.87 (m, 1H), 4.79 (d, J=4.0 Hz, 1H), 3.91 (m, 1H), 2.67-2.98 (m, 3H), 2.52 (m, 1H), 2.18 (s, 3H), 1.86 (m, 1H), 1.61 (m, 1H). MS (ESI+) m/z 407 (M+H)+, 429 (M+Na)+. Anal Calcd for C21H18F4N2O2: C, 62.07; H, 4.46; N, 6.89. Found: C, 61.90; H, 4.37; N, 6.85.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3.Br[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:32]3[C:37]([C:38]=2[CH:39]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20]([C:35]5[CH:34]=[CH:33][C:32]6[N:31]([C:40]7[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=7)[C:30]7[C:38]([C:37]=6[CH:36]=5)=[CH:39][CH:27]=[CH:28][CH:29]=7)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: CC1(C)c2cnccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)c2cnccc2-n2c3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3c3cccc1c32

Procedure:
36 g (110 mmol) of 8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene-3-boronic acid, 35 g (110 mmol) of 3-bromo-9-phenyl-9H-carbazole and 9.7 g (92 mmol) of sodium carbonate are suspended in 350 ml of toluene, 350 ml of dioxane and 500 ml of water. 913 mg (3.0 mmol) of tri-o-tolylphosphine and 112 mg (0.5 mmol) of palladium(II) acetate are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water each time and subsequently evaporated to dryness. The residue is recrystallised from toluene and from CH2Cl2/isopropanol and finally sublimed in a high vacuum. Yield: 50 g (99 mmol), 89% of theory, purity according to HPLC 99.9%.
Reaction SMILES: [F:1]C1C=C2C(N=C(O)C3N2C(C(F)(F)F)=NN=3)=CC=1.P(Cl)(Cl)(Cl)=O.C(N(CCC)CCC)CC.[Cl:35][C:36]1[C:37]2[N:38]([C:47]([C:50]([F:53])([F:52])[F:51])=[N:48][N:49]=2)[C:39]2[C:44]([N:45]=1)=[CH:43][CH:42]=[C:41](F)[CH:40]=2>>[Cl:35][C:36]1[C:37]2[N:38]([C:47]([C:50]([F:53])([F:52])[F:51])=[N:48][N:49]=2)[C:39]2[C:44]([N:45]=1)=[CH:43][C:42]([F:1])=[CH:41][CH:40]=2
Reactant: Oc1nc2ccc(F)cc2n2c(C(F)(F)F)nnc12
Reactant: Fc1ccc2nc(Cl)c3nnc(C(F)(F)F)n3c2c1
Agent: CCCN(CCC)CCC
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc2c(c1)nc(Cl)c1nnc(C(F)(F)F)n12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame-dried 250 ml. three-necked reaction flask under a dry nitrogen atmosphere, there were placed 12.5 g. (0.046 mole) of 8-fluoro-4-hydroxy-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline and 85 ml. of phosphorus oxychloride together with 17.5 ml. of tri-n-propylamine. The reaction mixture was then refluxed overnight for approximately 16 hours and finally cooled to room temperature (~20° C.) prior to being slowly poured over 1000 ml. of ice/water with the aid of mechanical stirring. The resulting aqueous mixture was next stirred for an additional period of 30 minutes at room temperature, followed by extraction with three-300 ml. portions of chloroform. The combined chloroform layers were then successively washed with saturated aqueous sodium bicarbonate solution, water and saturated brine and finally dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was finally obtained a yellow solid product which consisted of 10.47 g. (79%) of pure 4-chloro-8-fluoro-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 135°-138° C. Mass Spectrum: m/e, 292/290 (P+).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([C@@H:9]([N:41]=[N+:42]=[N-:43])[CH2:10][C@@H:11]([CH:38]([CH3:40])[CH3:39])[CH:12]([OH:37])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:15]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:14]=2)[O:6][C:5]1=[O:44])([CH3:3])[CH3:2].[C:45](OC(=O)C)(=[O:47])[CH3:46]>N1C=CC=CC=1>[CH:1]([C@@H:4]1[CH2:8][C@@H:7]([C@@H:9]([N:41]=[N+:42]=[N-:43])[CH2:10][C@@H:11]([CH:38]([CH3:39])[CH3:40])[CH:12]([O:37][C:45](=[O:47])[CH3:46])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:15]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:14]=2)[O:6][C:5]1=[O:44])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: COCCCOc1cc(C(O)[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OCCCOCc1ccccc1
Solvent: c1ccncc1
Product: COCCCOc1cc(C(OC(C)=O)[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OCCCOCc1ccccc1

Procedure:
A solution of 144 mg of 3(S)-isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-hydroxy-4-[4-(3-benzyloxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one in 1.8 ml of acetic anhydride and 0.057 ml of pyridine is stirred for 30 hours at room temperature and is then concentrated to dryness by evaporation at room temperature and under reduced pressure. The residue is partitioned between dichloromethane (3×) and water/saturated sodium chloride solution (3×). The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (hexane/ethyl acetate=4:1), yielding the title compound: Rf (hexane/ethyl acetate=2:1)=0.38 and 0.33; HPLC Rt =21.76 and 21.82 minutes (diastereoisomeric mixture); FAB-MS M+ =653, (M+Na)+ =676.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]1=[NH:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: BrCc1ccccc1
Product: N=c1n(Cc2ccccc2)c2ccccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 2-aminobenzimidazole and benzyl bromide by Procedure A. The title product was isolated by filtration and washed with acetonitrile and water to give the title compound as the hydrobromide salt (solid, mp>300° C.). MS(ES+) m/z 314 ([M+1]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7](=[C:8]([OH:17])[C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:16]2[C:7](=[C:8]([O:17][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(O)c3ccccc3nc12
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1c2ccccc2nc2c(OC)cccc12
Temperature: 120 °C
Yield: 31.8 %

Procedure:
4-methoxyacridin-9-ol (2.0 g, 8.88 mmol), 1-bromooctane (2.17 g, 11.24 mmol), and potassium carbonate (7.91 g, 57.2 mmol) was mixed in N,N-dimethylformamide and heated at 120° C. for 8 h and the potassium carbonate was filtered off. The reaction mixture was quenched with water and extracted two times with ether and the combined organic phases was then washed once with 1M HCl, two times with water, and evaporated to obtain a yellow solid. The solid was recrystallised in methanol to give 4-methoxy-9-(octyloxy)acridine (0.95 g, 2.82 mmol) as yellow crystals. 1H-NMR (CDCl3, 5): 0.881 (t, 3H), 1.2-1.4 (m, 10H), 1.924 (m, 2H), 3.985 (s, 3H), 4.507 (t, 2H), 7.2-7.3 (m, 3H), 7.621 (d, 1H), 7.707 (m, 1H), 8.181 (m, 1H), 8.498 (m, 1H) MS MALDI-TOF (m/z): 337.146
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[CH2:13]1[O:15][C@H:14]1[C:16]([F:19])([F:18])[F:17]>C1COCC1.O>[F:17][C:16]([F:19])([F:18])[C@H:14]([OH:15])[CH2:13][O:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: COc1ccc(CO)cc1
Reactant: FC(F)(F)[C@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COC[C@@H](O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (390 mg, 8.9 mmol, 55% in mineral oil) in THF (10 mL) at 0° C. was added 4-methoxybenzylalcohol (1.27 g, 8.92 mmol) in THF (5 mL). After 1 h stirring at 0° C. R-(+)-3,3,3-trifluoro-1,2-epoxypropane (500 mg, 4.46 mmol) was added to a 20 mL microwave vial via syringe. The closed vial was heated at 100° C. for 18 h. The reaction mixture was diluted with water and extracted twice with Et2O. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated. Chromatography over silica (cyclohexane-EtOAc 95:5 to cyclohexane-EtOAc 75:25) afforded the title compound: ESIMS [M+NH4]+=268; 1H NMR (360 MHz, CDCl3): δ 7.29 (d, 2H), 6.94 (d, 2H), 4.56 (s, 2H), 4.15 (m, 1H), 3.87 (s, 3H), 3.74 (dd, 1H), 3.66 (dd, 1H), 2.88 (d, 1H).
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:4])[NH2:3].C(N(CC)CC)C.[C:20]([C:23]1[C:24](=[O:34])[O:25][C:26]([OH:33])=[C:27]([C:30](=O)[CH3:31])[C:28]=1[OH:29])(=[O:22])[CH3:21]>CO>[C:20]([C:23]1[C:24](=[O:34])[O:25][C:26](=[O:33])[C:27](=[C:30]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([O:5][C:2](=[O:4])[NH2:3])=[CH:7][CH:8]=2)[CH3:31])[C:28]=1[OH:29])(=[O:22])[CH3:21]
Reactant: NC(=O)Oc1ccc(N)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(OC(N)=O)cc2)C(=O)OC1=O

Procedure:
A solution of 1.88 g. (0.01 m.) of p-carbamoyloxyaniline hydrochloride and 1.0 g. (0.01 m.) of triethylamine in 50 ml. of methanol is added to a hot solution of 2.21 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of methanol. The resulting mixture is refluxed for two hours, cooled and the filtered solid recrystallized to give 5-acetyl-3-[1-(p-carbamoyloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 213°-215° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([C:12]#[N:13])(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N12CCCN=C1CCCCC2>ClCCl.O1CCCC1.[Al+3].[Cl-].[Cl-].[Cl-]>[CH3:1][C:2]1[N:3]=[N:4][C:5]([C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: Cc1cccnn1
Reactant: C[Si](C)(C)C#N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(C#N)nn1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To a stirring solution of 3-methylpyridazine (11 g, 118 mmol) in dichloromethane (200 mL) was added AlCl3 (0.05 g) followed by trimethylsilylcyanide (21 g, 211 mmol). After 20 min, a solution of p-toluenesulfonyl chloride (38 g, 201 mmol) in dichloromethane (50 mL) was added via addition funnel and the solution continued to stir overnight. The next morning, the solvent was removed in vacuo and the residue was suspended in ethanol with stirring for 15 min and then filtered to give a white solid. The solid was dissolved in tetrahydrofuran (200 mL) and to this stirring solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (16 mL, 105 mmol). After 1 h, the solvent was removed in vacuo and the residue was partitioned between hexanes and saturated aqueous NH4Cl. The phases were separated and the aqueous phase was basified with solid Na2CO3, then extracted three times with ethyl acetate. The combined ethyl acetate phases were dried (MgSO4), filtered and concentrated in vacuo to give 9 g (64%) of white solid.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][C:4](=O)[CH2:3]1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:9]#[N:10])=[C:4]1[CH2:3][C@@H:2]([CH3:1])[C@H:6]([CH3:7])[CH2:5]1)[CH3:16]
Reactant: C[C@@H]1CC(=O)C[C@H]1C
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1C[C@@H](C)[C@H](C)C1
Yield: 93 %

Procedure:
Trans-3,4-dimethyl cyclopentanone (2.91 g, 25.94 mmol), ethyl cyanoacetate (2.93 g, 25.93 mmol), ammonium acetate (0.20 g, 2.60 mmol), and acetic acid (0.31 g, 5.17 mmol) were heated together in refluxing toluene under a Dean-Stark trap for 24 hours. After cooling and filtration through kieselguhr, evaporation gave the required product as an off-white solid (5.0 g, 93%).
Reaction SMILES: [C:1]1(=O)[N:5]([CH2:6]/[CH:7]=C/CBr)[C:4](=O)[C:3]2=[CH:12][CH:13]=CC=[C:2]12.C([NH:19]CC)C.[F-].[K+].[ClH:24]>C(#N)C.C(O)(=O)C>[ClH:24].[ClH:24].[CH2:1]([N:5]([CH2:6][CH3:7])[CH2:4]/[CH:3]=[CH:12]/[CH2:13][NH2:19])[CH3:2]
Reactant: CCNCC
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/CBr
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCN(CC)C/C=C/CN
Yield: 41 %

Procedure:
(E)-1-Phthalimido-4-bromobut-2-ene (4.2 g, 15 mmol), diethylamine (1.1 g, 15 mmol) and KF supported on Celite (7.5 g) were stirred together in acetonitrile (75 ml) at 40° C. for 18 h. The solution was filtered, and the filtrate was concentrated in vacuo to afford an oil, which was dissolved in glacial acetic acid (30 ml) and conc. HCl (30 ml). The mixture was heated at reflux for 30 h. The solution was cooled, filtered and the solvents were removed in vacuo to afford (E)-N,N-diethyl-1,4-diaminobut-2-ene dihydrochloride as an oil (1.32 g, 41%). δH (90 MHz, D2O) 1.19 (6H, m) 3.24 (4H, q), 4.05 (4H, m) and 5.96 (2H, m).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[C:32]([Cl:39])[CH:31]=1)([OH:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.C1([Pd+]C2CCCCC2)CCCCC1.C(O)C>[Cl:39][C:32]1[CH:31]=[C:30]([C:27]([OH:29])=[O:28])[CH:35]=[CH:34][C:33]=1[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[N:12]([C:13]3[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:19])[N:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Reactant: CC(C)(O)c1cc(COc2ccc(Br)cc2)n(-c2c(Cl)cccc2Cl)n1
Agent: C1CCC([Pd+]C2CCCCC2)CC1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CC(C)c1cc(COc2ccc(-c3ccc(C(=O)O)cc3Cl)cc2)n(-c2c(Cl)cccc2Cl)n1
Temperature: 80 °C

Procedure:
Into a 8 mL flask was added 256 mg (0.56 mmol) of 2-[5-(4-bromo-phenoxymethyl)-1 (2,6-dichloro-phenyl)-1H-pyrazol-3-yl]-propan-2-ol, 134 mg (0.67 mmol) of (4-carboxy-2-chlorophenyl)boronic acid, 200 mg of potassium carbonate (1.68 mmol), 10 mg (0.017 mmol) of dicyclohexyl palladium acetate and 2 mL of ethanol. The reaction mixture was heated to 80° C. for 4 h. After cooling, the crude reaction mixture was filtered through a pad of celite, concentrated in vacuo, and purified on a reverse phase HPLC-MS to afford 2-chloro-4′-[2-(2,6-dichloro-phenyl)-5-isopropyl-2H-pyrazol-3-ylmethoxy]-biphenyl-4-carboxylic acid as an off white solid (34 mg, 11%); 1H NMR (400 MHz, CDCl3): δ 8.16 (m, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.45 (d, J=7.83 Hz, 2H) 7.35 (m, 4H), 6.88 (d, J=8.84 Hz, 2H), 6.54 (s, 1H), 4.92 (s, 2H), 1.66 (s 6H), MS (ES): 531 [M+H]+.