Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[CH:11][C:10]=2[C:18]([OH:20])=O)=[C:4]([F:21])[CH:3]=1.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:18]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:15]=[N:16][CH:17]=2)[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:21])=[O:20])=[CH2:23]
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a solution of 5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2.0 g, 5.7 mmol) and O-(2-vinyloxyethyl)-hydroxylamine (0.71 g, 6.8 mmol) in DMF (44 mL) was added EDCI hydrochloride (1.42 g, 7.41 mmol), HOBt (1.0 g, 7.41 mmol) and DIPEA (0.97 mL, 5.69 mmol). The reaction mixture was stirred at room temperature for 3 hours before being concentrated in vacuo. The resultant residue was dissolved in 1:1 diethylether:ethyl acetate (30 mL) and aqueous saturated sodium hydrogen carbonate solution (30 mL) was added. The resultant mixture was sonicated until a precipitate formed. The precipitate was collected by filtration and washed with 1:1 diethylether:ethyl acetate to yield the title compound as a tan solid (1.33 g, 53%). LCMS (Method B): RT=2.78 min, M+H+=435/437.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[N:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:27]1[CH:26]=[C:25]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[O:14][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:11][N:12]=3)=[CH:16][CH:17]=2)[CH:30]=[N:29][CH:28]=1
Reactant: Brc1cncnc1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
4-(5-{[3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (160.6 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilysilyl)amide (149.6 mg, 0.75 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (119.2 mg, 0.75 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 200° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca, 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (87.0 mg). Yield 43.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=2)[O:36]1>>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:45][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)CCC(c1ccc(Cl)cc1Cl)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccc(Cl)cc2Cl)O3)nc1

Procedure:
2-[2-(2,4-dichlorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 530 mg of 2-(2,4-dichlorophenyl)chroman-6-ol. The product was purified on preparative TLC-plate covered with silica gel using heptane-ethyl acetate (3:1) as an eluant. 1H NMR (400 MHz, CDCl3) δ: 9.06 (d, 1H, J 2.7 Hz), 8.47 (dd, 1H, J 9.0, 2.7 Hz), 7.56 (d, 1H, J 8.4 Hz), 7.41 (d, 1H, J 2.0 Hz), 7.33 (dd, 1H, J 8.4, 2.0 Hz) 7.02 (d, 1H, J 9.0 Hz), 6.99-6.92 (m, 3H), 5.39 (dd, 1H, J 10.4, 2.2 Hz), 3.06 (ddd, 1H, J −16.9, 11.9, 6.0 Hz), 2.83 (ddd, 1H, J −16.9, 5.3, 2.7 Hz), 2.34 (m, 1H), 1.89 (m, 1H).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N#N.C([C@@]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO[C:32]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C@@H](O)C1)(=O)C(C)C>>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([C:32]([O:7][CH2:6][C@H:5]2[O:8][C@@H:1]([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[CH2:2][C@@H:3]2[OH:4])([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:46][CH:45]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@](C(=O)C(C)C)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: N#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
This compound was prepared from thymidine by the same procedure used for the preparation of N2 -isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyguanosine.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:5](=[O:6])[CH2:4][CH:3]1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:11])[C:5](=[O:6])[CH2:4][CH:3]1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C1CC(=O)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C(=O)CC1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of methyl 2,2-dimethyl-3-oxocyclobutanecarboxylate (5.0 g, 32.1 mmol) in MeOH (37.5 mL) was added an aqueous solution of sodium hydroxide (4.48 N, 18.5 mL, 84 mmol). The resulting mixture was stirred at 50° C. for 2 h. After completion, the excess MeOH was removed under reduced pressure and the mixture was extracted with diethyl ether (15 mL). The aqueous solution was neutralized with hydrochloric acid (4 N, 30 mL) and the mixture was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford the title product (3.9 g, 27.5 mmol, 86% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 12.4 (br, 1H), 3.31-3.23 (m, 1H), 3.17-3.08 (m, 1H), 2.97-2.91 (m, 1H), 1.22 (s, 3H), 1.04 (s, 3H).
Reaction SMILES: [Li]CCCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.C(OC([N:22]1[CH2:27][CH2:26][C:25]2([CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[CH2:24][CH2:23]1)=O)(C)(C)C>C(OCC)C>[S:6]1[C:7]([C:30]2[CH2:31][CH2:32][C:25]3([CH2:26][CH2:27][NH:22][CH2:23][CH2:24]3)[CH2:28][CH:29]=2)=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: c1ccc2sccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: C1=C(c2cc3ccccc3s2)CCC2(C1)CCNCC2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Was prepared according to method A with the following variation: n-BuLi (1.6 M in hexanes (4 mL, 6.4 mmol)) was added drop-wise to a solution of benzothiophene (778 mg, 5.80 mL) in diethyl ether (10 mL). The reaction was warmed to reflux for 1 h and then cooled to −78° C. 9-Oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (500 mg, 1.87 mmol) in diethyl ether was added drop-wise and the mixture was stirred at −78° C. for 2 h. Mp. 107.3-110.2° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:5][N:4]=1.I[Si](C)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[N:4][CH:5]=1
Reactant: COc1ccc(-c2ccccc2-c2ccccc2C)cn1
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1-c1ccccc1-c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 64.7 %

Procedure:
To a solution of 2-methoxy-5-(2′-methylbiphenyl-2-yl)pyridine (2.20 g) in DCM (50 mL) was added iodo(trimethyl) silane (5.0 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 4 days. To the reaction mixture was added brine (50 mL). The mixture was extracted with EtOAc and the organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:chloroform=3:7) to afford 5-(2′-methylbiphenyl-2-yl)pyridin-2-ol (1.35 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].S(Cl)(O[CH2:54][Cl:55])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C.ClCCl.C1COCC1>[NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:11]2[N:15]=[C:14]([O:16][CH2:54][Cl:55])[N:13]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[N:12]=2)[C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)OCCl
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nc(OCCl)n(-c3ncccn3)n2)c1
Temperature: -10 °C
Yield: 34.9 %

Procedure:
To a mixture of dichloromethane (20 mL), THF (20 mL), and water (20 mL), N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 1a, 901 mg), sodium hydrogen carbonate (632 mg), and tetrabutylammonium hydrogen sulfate (102 mg) were sequentially added. After cooling the resulting mixture to −10° C., a mixture of chloromethyl chlorosulfate (373 mg) and dichloromethane (5 mL) was added dropwise thereto with stirring, and the resulting mixture was stirred overnight at room temperature. Dichloromethane (10 mL), THF (10 mL), and water (10 mL) were added to the mixture, and the resulting mixture was cooled again to −10° C., after which a mixture of chloromethyl chlorosulfate (373 mg) and dichloromethane (5 mL) was added dropwise thereto with stirring, and the resulting mixture was stirred overnight at room temperature. Ethyl acetate (300 mL) and water (100 mL) were added to the mixture, and the resulting mixture was shaken, after which the organic layer was collected. Ethyl acetate (80 mL) and THF (20 mL) were added to the aqueous layer, and the resulting mixture was shaken again, after which the organic layer was collected. The combined organic layers were dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (340 mg).
Reaction SMILES: [ClH:1].[C:2]([O:5][C:6]1[C:11]2[O:12][C:13]3[C:18]([C:19]4([CH2:24][CH2:23][N:22](CC5C=CC=CC=5)[CH2:21][CH2:20]4)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:4])[CH3:3]>C(O)C.[Pd]>[ClH:1].[C:2]([O:5][C:6]1[C:11]2[O:12][C:13]3[C:18]([C:19]4([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1cccc2c1Oc1ccccc1C21CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)Oc1cccc2c1Oc1ccccc1C21CCNCC1

Procedure:
A solution of 4-acetoxy-1'-benzylxanthene-9-spiro-4'-piperidine hydrochloride (13.5 g.) in ethanol (200 ml.) is hydrogenated using 5% w/w palladium-on-carbon catalyst, at 1 atmosphere and 25° C. The catalyst is filtered off and the solvent evaporated to dryness. The residue is crystallised from ethanol-ether to give 4-acetoxyxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 162°-165° C.
Reaction SMILES: C(OC([C:6](=[C:11]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][C:8]([OH:10])=[O:9])=O)C.Br>C(O)(=O)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(CC(=O)O)=C(c1ccccc1)c1ccc(F)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)CC=C(c1ccccc1)c1ccc(F)cc1
Yield: 47 %

Procedure:
3-Ethoxycarbonyl-4-(4-fluorophenyl)-4-phenylbut-3-enoic acid (47 g., 0.143 mole) was added to a mixture of glacial acetic acid (1000 ml.) and 48% aqueous hydrobromic acid (500 ml.), and the resulting mixture stirred at reflux for 16 hours. The reaction mixture was then concentrated under vacuum and the concentrate extracted with ether (3×500 ml.). The combined ether extract was extracted with 4% aqueous ammonium hydroxide (5×200 ml.). The combined aqueous extract was acidified with 6N hydrochloric acid to a pH of 6.5 and extracted again with ether (3×250 ml.). The combined ether extract was dried (MgSO4), filtered and evaporated under vacuum to an oil, which solidified on standing. Trituration with hexane gave 15 g. of the named product (47% yield, m.p. 98°-100° C., elemental analysis calculated: 74.99% C.; 5.11% H; 7.41% F; found: 74.69% C; 5.40% H; 7.17% F).
Reaction SMILES: [Cl-].C[SiH](C)C.[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[CH2:9]Br.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:16][C:17]1[CH:22]=[C:21]([CH2:9][C:8]2[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:7]=2[Cl:6])[N:20]=[CH:19][N:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Fc1cccc(Cl)c1CBr
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(Cl)c1Cc1cc(Cl)ncn1
Reaction time: 0.33 h
Yield: 30.4 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 2.2 g of 2-chloro-6-fluorobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution J). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution J was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.77 g of 4-chloro-6-(2-chloro-6-fluorobenzyl)pyrimidine.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=1[C:15]#[C:16][CH2:17][O:18][CH3:19].CO>[Pd]>[CH3:1][O:2][N:3]([CH3:21])[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=1[CH2:15][CH2:16][CH2:17][O:18][CH3:19]
Reactant: COCC#Cc1nc(C(F)(F)F)ccc1C(=O)N(C)OC
Agent: [Pd]
Solvent: CO
Product: COCCCc1nc(C(F)(F)F)ccc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a suspension of N-methoxy-2-(3-methoxy-prop-1-ynyl)-N-methyl-6-trifluoromethyl-nicotinamide (247 mg, 0.817 mmol) in 5% Pd/C (50 mg) was added CH3OH (6 ml). The mixture was purged three times with hydrogen gas (50 psi) and shaken for 2 hours at room temperature. The reaction mixture was filtered over a pad of Celite and concentrated under reduced pressure. The crude residue was chromatographed to yield the N-methoxy-2-(3-methoxy-propyl)-N-methyl-6-trifluoromethyl-nicotinamide (160 mg, 64%).
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@:5]([CH3:38])([C:14](=[O:37])[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=2)=O)[CH2:4][O:3]1.Cl.[NH2:41]O.C(O)(C(F)(F)F)=O.C(Cl)Cl>N1C=CC=CC=1>[NH2:6][C@@:5]([C:14]1[O:37][N:41]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=2)[CH:15]=1)([CH3:38])[CH2:4][OH:3]
Reactant: CCCCCCCCOc1ccc(C(=O)CC(=O)[C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2cc([C@@](C)(N)CO)on2)cc1C(F)(F)F

Procedure:
The solution of (S)-tert-butyl 2,2,4-trimethyl-4-(3-(4-(octyloxy)-3-(trifluoromethyl)-phenyl)-3-oxo-propanoyl)oxazolidine-3-carboxylate (27 mg, 0.05 mmol, 1.0 equiv) and hydroxylamine hydrochloride (6.6 mg, 0.10 mmol, 2.0 equiv) in pyridine (0.5 mL) was stirred at 60° C. for 2 days. The reaction was condensed and the residue was treated with 20% TFA-DCM for 30 min. After removal of excess amount of TFA and DCM, the crude product was purified by prep. HPLC and afforded the title compound as mono-TFA salt (6.0 mg). MS (ESI, M+H+)=415.0; 1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 8.04 (d, 1H, J=9.6 Hz), 7.31 (d, 1H, J=9.6 Hz), 7.03 (s, 1H), 4.16 (t, 2H, J=6.0 Hz), 4.01, 3.83 (AB, 2H, J=12.0 Hz), 1.87-1.80 (m, 2H), 1.75 (s, 3H), 1.56-1.47 (m, 2H), 1.40-1.32 (m, 8H), 0.91 (t, 3H, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Cu]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1ccc(Br)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 210 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromoanisole (35 ml, 0.28 mol), 4-chlorophenol (43 g, 0.33 mol), anhydrous K2CO3 (13 g, 0.09 mol) and copper bronze (0.38 g, 5.98 mmol) were stirred under a nitrogen atmosphere at 210° C. for 2 hours. After cooling to room temperature, the mixture was dissolved in methylene chloride, extracted two times with 1 N NaOH, dried (MgSO4) and the solvent removed under reduced pressure to give a brown liquid. Excess 4-bromoanisole was removed by distillation under reduced pressure (60°-73° C., 1 mm) and the residual crystalline solid was purified by HPLC (hexane-methylene chloride). 4-Methoxy-4'-chlorodiphenyl ether was isolated as a white crystalline solid (28.84 g, 44%), mp 49°-51° C.
Reaction SMILES: CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Cl:49][C:50]1[CH:51]=[C:52]([C:57]2([C:62]([F:65])([F:64])[F:63])[CH2:61][CH2:60][NH:59][CH2:58]2)[CH:53]=[C:54]([Cl:56])[CH:55]=1.[Cl:66][C:67]1[CH:84]=[C:83](I)[CH:82]=[CH:81][C:68]=1[CH2:69][N:70]1C(=O)C2C(=CC=CC=2)C1=O.NN>C1(C)C=CC=CC=1.C(OC)(C)(C)C.CO.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:66][C:67]1[CH:84]=[C:83]([N:59]2[CH2:60][CH2:61][C:57]([C:52]3[CH:51]=[C:50]([Cl:49])[CH:55]=[C:54]([Cl:56])[CH:53]=3)([C:62]([F:65])([F:64])[F:63])[CH2:58]2)[CH:82]=[CH:81][C:68]=1[CH2:69][NH2:70]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: COC(C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 20.1 %

Procedure:
Sodium tert-butoxide (0.2 g), Tris(dibenzylidene acetone) dipalladium(0) (chloroform adduct) (0.03 g) and xantphos (0.05 g) was added to the solution of 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (0.4 g) and 2-(2-chloro-4-iodobenzyl)-1H-isoindole-1,3-(2H)-dione (0.69 g) in toluene under argon atmosphere, and the mixture was heated with stirring at 80° C. for 3 hours. The reaction solution was diluted with t-butylmethylether and then washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under the reduced pressure to yield the crude product. The product was dissolved in methanol, to which was then added aqueous hydrazine (0.03 g), followed by the mixture heated to reflux for 12 hours. The reaction solution was diluted with t-butylmethylether and then washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 1-{2-chloro-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]phenyl}methanamine (0.12 g). 1H-NMR (CDCl3) δ: 2.47-2.54 (1H, m), 2.78-2.85 (1H, m), 3.46-3.49 (2H, m), 3.69-4.01 (4H, m), 6.47-6.50 (1H, m), 6.73-6.76 (1H, m), 7.25-7.35 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13](/[CH:15]=[N:16]/[OH:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].ClN1C(=O)CCC1=O.[CH2:26]=[C:27]1[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH2:26][C:27]3([CH2:30][CH2:29][CH2:28]3)[O:17][N:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(/C=N/O)c1
Reactant: C=C1CCC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C2=NOC3(CCC3)C2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
To a solution of tert-butyl 3-bromo-5-[(E)-(hydroxyimino)methyl]benzoate (5.26 g, 17.5 mmol) in N,N-dimethylformamide (80 mL)) was added N-chlorosuccinimide (2.57 g, 19.3 mmol). The reaction mixture was heated to 50° C. After 1 h, the reaction was cooled to ambient temperature and methylenecyclobutane (6.49 mL, 70.1 mmol) was added. Triethylamine (12.2 mL, 88.0 mol) was added. The mixture was stirred at ambient temperature. After 10 min, saturated aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (2×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→90% hexanes/ethyl acetate) gave the title compound (2.86 g). MS 366 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=O)[CH2:13][C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:6][CH:7]=1
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
To a THF (5 ml) solution of 6-(4-chlorophenyl)-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (20.0 mg, 0.06 mmol) was added BH3 THF complex (1 mL, 1M in THF) slowly. The resulting solution was stirred at room temperature for 2 h, concentrated. The residue was purified by Prep-TLC (pure EA) to give 6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as an off-white solid (3.0 mg, 16%).