Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[O:11]1[CH2:16][CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC>[O:11]1[CH2:12][CH:13]=[C:14]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=2[OH:10])[CH2:15][CH2:16]1
Reactant: Cc1cc(C)c(O)c(Br)c1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(O)c(C2=CCOCC2)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
2-Bromo-4,6-dimethylphenol (430 mg, 2.14 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (494 mg, 2.35 mmol), Pd(dbpf)Cl2 (69.7 mg, 0.11 mmol) and sodium carbonate (680 mg, 6.45 mmol) were dissolved in dimethoxyethane:water=3 mL:1 mL, followed by stirring in microwave at 120° C. for 30 minutes. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and purified by column chromatography (silica gel; hexane/ethyl acetate, 9/1) to obtain 2-(3,6-dihydro-2H-pyran-4-yl)-4,6-dimethylphenol (160 mg, 37%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCO.[ClH:30]>[Fe].O>[ClH:30].[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([S:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([OH:1])[CH:7]=3)=[CH:14][CH:13]=2)=[O:26])=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(Sc2ccnc(O)c2)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)Nc2ccc(Sc3ccnc(O)c3)cc2)cc1
Reaction time: 8 h

Procedure:
Nitro compound 14 (0.48 g, 1.18 mmol) was suspended in 2:1 EtOH:H2O (100 mL) and the resulting suspension brought to reflux. To this mixture was sequentially added Fe dust (0.30 g, 9.59 mmol) and c.HCl (2 mL), and the resulting suspension refluxed for 15 min. TLC and LCMS analysis at this time showed that the reaction was incomplete, thus further quantities of Fe dust (0.80 g, 14.29 mmol) and c.HCl (10 mL) were added, and the mixture refluxed for a further 50 min. After this time, the reaction was complete, and thus the reaction mixture was filtered hot through a pad of Celite, and solvent was removed under reduced pressure. The residue was dried via two MeOH-azeotrope cycles, and then re-dissolved in MeOH and stirred overnight with Celite and activated charcoal. The resulting slurry was filtered through a pad of Celite, and solvent was removed under reduced pressure. The residue was re-dissolved in MeOH and adsorbed onto a quantity of silica gel, and the resulting silica adsorbate was purified by column chromatography on silica gel, eluting with 1%→20% MeOH:CH2Cl2 (with 0.5% aq.NH3), to afford crude 15. This material was purified further by re-precipitation from MeOH:methanolic HCl:EtOAc, to afford amine 15 as an amorphous cream solid (15 mg, 3%—presumably much material lost by adsorption to activated charcoal; latter was extracted several times, to little avail); 1H NMR [(CD3)2SO]: δ 11.40 (v v br s, 1H, quinolinyl-N+—H), 10.08 (s, 1H, ArH), 7.94 (ddd, J=9.40, 4.51, 2.59 Hz, 2H, ArH), 7.78 (d, J=8.67 Hz, 2H, ArH), 7.52 (ddd, J=9.40, 4.49, 2.61 Hz, 2H, ArH), 7.27 (d, J=6.95 Hz, 1H, ArH), 6.71 (d, J=8.52 Hz, 2H, ArH), 5.96 (dd, J=6.96, 1.93 Hz, 1H, ArH) [ArOH & ArNH2 not visible]; LCMS (APCl+): 338 (100%), 423 (60%), 169 (40%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].[OH2:18]>CC(C)=O>[C:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)([OH:18])=[O:2]
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Reactant: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(-c2ccc(-c3cccs3)s2)s1
Temperature: 15 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
0.27 g of 5-formyl-2,2':5',2"-terthiophene was dissolved in 50 ml of acetone and the temperature thereof was maintained at 15° C. CrO3 /H2O/H2SO4 solution (0.9 g/12 ml/0.2 ml) was dropped in slowly and stirred for 4 hours at 40° C. Then 50 ml of water was dropped in slowly, and the solution was filtered, washed with water, dried and a yellowish solid was thus obtained. After washed with chloroform, 150 mg of product was obtained and the melting point thereof was 239°-240° C. (yield: 51%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][C:10]=2[CH3:17])[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][N:27]=1>>[Cl:25][C:26]1[N:27]=[CH:28][C:29]([S:32]([N:15]([CH3:16])[C:12]2[CH:13]=[CH:14][C:9]([CH2:8][N:6]3[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:2]([CH3:1])[CH2:7]3)=[C:10]([CH3:17])[CH:11]=2)(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Product: Cc1cc(N(C)S(=O)(=O)c2ccc(Cl)nc2)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reaction time: 8 h

Procedure:
The title compound was prepared from D8 and 2-chloropyridine-5-sulfonyl chloride using a method similar to that described for D15 except that the reaction time was overnight. The work-up involved concentration of the reaction mixture and purification by elution through an SCX cartridge (MeOH then 0.2M NH3 in MeOH), followed by column chromatography eluting with 0-20% EtOAc/petroleum ether. δH (CDCl3, 400 MHz) 8.55 (1H, dd), 7.76 (1H, dd), 7.42 (1H, d), 7.21 (1H, d), 6.96 (1H, d), 6.80 (1H, dd), 6.86 (1H, dd), 4.20 (1H, br.s), 3.79 (1H, m), 3.38 (2H, AB), 3.20 (3H, s), 3.05 (1H, m), 2.69 (1H, m), 2.56 (1H, m), 2.32 (3H, s), 2.19 (1H, m), 1.99 (1H, m), 1.46 (9H, s), 1.21 (3H, d). MS (ES+): MH+ 509/511.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[CH3:19][N+:20]([CH3:24])=[C:21](Cl)[Cl:22].[Cl-]>ClCCCl>[Cl:22][C:21]([N:20]([CH3:24])[CH3:19])=[N:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: C[N+](C)=C(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2N)cc1
Agent: [Cl-]
Solvent: ClCCCl
Product: CN(C)C(Cl)=Nc1c(C#N)cnn1-c1ccc(S(C)(=O)=O)cc1
Yield: 80.9 %

Procedure:
A solution of 5-amino-1-(4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile (1.2 g, 4.57 mmol) and phosgeniminium chloride (0.900 g, 7.08 mmol) in dry 1,2-dichloroethane was refluxed for 4 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (30 to 50% ethyl acetate/hexanes) to yield 1-chloro-N′-[4-cyano-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-N,N-dimethyl-formamidine (1.3 g, 80%) as a yellowish solid. Exact mass calculated for C14H14ClN5O2S 351.06, found 352.20 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=O)[CH2:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(NC(C)C)(C)C.[C:41]([O:44][CH2:45][CH3:46])(=[O:43])[CH3:42]>C1COCC1.O.C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:13][O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[C:19](=[O:21])[CH2:42][C:41]([O:44][CH2:45][CH3:46])=[O:43])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(C)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-O-(tert-butyl)-L-serine (25.0 g) in dry THF (100 mL) was added 1,1′-carbonylbis-1H-imidazole (16.5 g) at 0° C. by small portions, and the mixture was stirred at room temperature overnight (solution 1). To a solution of diisopropylamine (25.7 g) in dry THF (330 mL) was added dropwise a 1.6 mol/L n-butyllithium-hexane solution (158.7 mL) under an argon atmosphere at −78° C. The mixture was stirred at −78° C. for 30 min, and a solution of ethyl acetate (24.8 mL) in dry THF (100 mL) was added dropwise. After the completion of the dropwise addition, the mixture was stirred for 30 min, and solution 1 was added dropwise. The mixture was stirred at −78° C. for 1 hr, and acetic acid (25 mL) was added to the reaction mixture. After warming to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=50:1→1:1) to give the title compound as a colorless oil (yield: 19.2 g, 62%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9](C(=O)C)[N:8]=1>>[CH3:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:14]=2)[NH:9][N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)n1nc(C)c2ccccc21
Product: Cc1n[nH]c2ccc(S(=O)(=O)Cl)cc12
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To chlorosulfonic acid (0.38 ml, 5.7 mmol) under a blanket of argon in an ice bath was added 1-(3-methyl-indazol-1-yl)-ethanone (200 mg, 1.1 mmol). The reaction was allowed to warm to RT and then was heated at 70° C. for 45 min. The reaction was cooled to rt, slowly quenched over ice and extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated in vacuo to a tan solid (160 mg, 0.7 mmol, 61% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH2:20][CH2:21][CH2:22]Cl)(=[O:19])=[O:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[H-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:22][CH2:21][CH2:20][S:17]3(=[O:19])=[O:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(NS(=O)(=O)CCCCl)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(N3CCCS3(=O)=O)c2c1C
Temperature: 25 °C
Yield: 64 %

Procedure:
To 4-(3-chloro-propane-1-sulfonylamino)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (246 mg, 0.68 mmol, 1 eq.) in THF (10 mL) cooled to <0° C. was added sodium hydride (60%, 30 mg, 0.75 mmol, 1.1 eq.). The reaction was allowed to slowly warm to room temperature, then transferred to a pressure tube and heated at 74° C. for 16 hours. After work-up and flash column chromatography, 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained. Yield: 64%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.5 (m, 2 H) 2.7 (s, 3 H) 3.5 (m, 2 H) 3.7 (dd, J=6.8 Hz, 2 H) 4.4 (q, J=7.1 Hz, 2 H) 7.4 (dd, J=7.8, 0.8 Hz, 1 H) 7.6 (m, 1 H) 7.7 (dd, J=8.3, 0.8 Hz, 1 H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:13])[S:11][CH:12]=1)=[O:7])C>C(O)C>[Cl:13][C:10]1[S:11][CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=1
Reactant: CCOC(=O)c1csc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
A mixture of NaOH (1.9 g, 47.5 mmol) and ethyl-2-chloro-4-thiazolecarboxylate (7.6 g, 40 mmol) in 100 mL absolute ethanol was stirred at RT for 4 h. After that, ethanol was removed in vacuo and the residue was dissolved in water. The aq layer was washed with ether and then acidified with conc HCl. The solid was filtered and air dried to give 4 g of 2-chloro-4-thiazolecarboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O)#[N:2].Cl.[NH2:14][OH:15]>C(O)C>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[N:14][OH:15])#[N:2]
Reactant: N#Cc1cccc2c1CCC2=O
Reactant: NO
Agent: Cl
Solvent: CCO
Product: N#Cc1cccc2c1CCC2=NO
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 157 mg (1.0 mmol) of 4-cyano-2,3-dihydro-1H-inden-1-one [Coll. Czechoslov. Chem. Commun. 43, 3227 (1978)] and 139 mg (2.0 mmol) of hydroxylamine hydrochloride in 4 ml of ethanol is stirred at 80° C. for 1.5 hours and cooled in an ice-water bath. The product that has crystallized out is filtered off with suction, washed with cold ethanol and diethyl ether and dried. In that manner there is obtained the intermediate 4-cyano-2,3-dihydro-1H-inden-1-one oxime, which melts at 200°-202° C. with decomposition; 1H-NMR (DMSO): δ=11.22 (s, 1H); 7.84 (d, 1H); 7.81 (d, 1H); 7.45 (t, 1H); 3.15 (t, 2H); 2.84 (t, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH2:22])[N:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C(C(O)=O)=NC=C(C#N)C=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:24])[F:25])[O:10][CH2:11][C@@:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH2:22])[N:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(N)ccc2F)CO[C@@]1(C)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#Cc1cnc(C(=O)O)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@@](C)(c2nc(N)ccc2F)CO[C@@]1(C)C(F)(F)F
Yield: 76 %

Procedure:
A mixture of [(2R,5R)-5-(6-amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (406 mg, 0.999 mmol), 3-chloro-5-cyanopicolinic acid (201 mg, 1.099 mmol), HOAt (245 mg, 1.798 mmol) and EDC hydrochloride (287 mg, 1.499 mmol) was stirred in DMF (10.2 ml) at rt for 44 hours. The reaction mixture was diluted with toluene and washed with sat. aq. sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and evaporated. The crude product (595 mg) was chromatographed over silicagel (toluene: ethyl acetate 9:1) to yield the title compound: 455 mg (76% yield).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=S)[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20][NH2:21]>C(O)CCC>[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20][NH:21][C:10]1[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[NH:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[N:9]=1
Reactant: COC(CN)OC
Reactant: S=C1Nc2ccccc2Nc2ccccc21
Solvent: CCCCO
Product: COC(CNC1=Nc2ccccc2Nc2ccccc21)OC
Temperature: 25 °C

Procedure:
5,10-Dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione (33.75 g., 150 mmol.) is suspended in 450 ml. of n-butyl alcohol and treated with 47.25 g. (450 mmol.) of commerical aminoacetaldehyde dimethyl acetal. The reagents are heated for 5.5 hours during which time the solution turns brown. The solution is cooled to room temperature and the solvent is removed in vacuo. The residue is dissolved in 600 ml. of hot ethyl acetate, filtered, concentrated to 400 ml. and cooled to give 36.0 g. (81%) of [(5H-dibenzo[b,e][1,4]diazepin-11-yl)amio]acetaldehyde dimethyl acetal of melting point 181°-182.5° C. A second crop (2.55 g., 5.7%) of melting point 181.5°-184° C. is also collected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]([NH:14][NH2:15])=[O:13])=[N:7]1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:13][C:27]([C:26]3[CH:30]=[CH:31][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=3)=[N:15][N:14]=2)=[N:7]1
Reactant: Cc1nc(C(=O)NN)nn1Cc1cccc(Br)c1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2nnc(-c3ccc(C(C)(C)C)cc3)o2)nn1Cc1cccc(Br)c1
Temperature: 100 °C
Yield: 32.4 %

Procedure:
To a solution of 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carbohydrazide (2.22 g, 7.16 mmol) dissolved in POCl3 (6 mL) was added 4-(tert-butyl)benzoic acid (1.27 g, 7.16 mmol). The reaction was heated to 100° C. for 2.5 h. The solvent was removed under reduced pressure and the crude material was taken up in EtOAc. The organic layer was then washed with NaHCO3 (3×40 mL) and brine (1×40 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and purified on a Biotage pre-packed silica gel column with a gradient of 12% to 100% EtOAc:Hexanes to afford 2-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazole (1.05 g, 32%). MS (ES+) C22H22BrN5O requires: 451, 453 found: 452, 454 [M+H]+(1:1).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]1[C:16]([C:17]2=[CH:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][CH2:23]2)=[C:15]([N+:25]([O-:27])=[O:26])[CH:14]=[N:13]1.[C:28]1([Se:34]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH3:11][N:12]1[C:16]([C:17]2=[CH:18][C:19](=[O:24])[CH:20]([Se:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:21][CH2:22][CH2:23]2)=[C:15]([N+:25]([O-:27])=[O:26])[CH:14]=[N:13]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1=CC(=O)CCCC1
Reactant: Br[Se]c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1=CC(=O)C([Se]c2ccccc2)CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of LiHMDS (1 M in THF, 1.28 mL, 1.28 mmol) at −78° C. was added (E)-3-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohept-2-enone (150 mg, 0.64 mmol) and the mixture was stirred at −78° C. for 1 hr. A solution of phenylselenium bromide (453 mg, 1.92 mmol) in THF (0.5 mL) was added and the reaction mixture was warmed to 0° C. and stirred for 45 min before being quenched with a saturated aqueous solution of ammonium chloride (2 mL). The mixture was extracted with EtOAc (3×5 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give (E)-3-(1-methyl-4-nitro-1H-pyrazol-5-yl)-7-(phenylselanyl)cyclohept-2-enone as an oil. This oil was dissolved in DCM (3 mL) and pyridine (0.1 mL, 1.28 mmol) was added, followed by hydrogen peroxide (30% wt in water, 0.37 mL, 3.34 mmol). The reaction mixture was stirred at room temperature for 18 hr. 1 M HCl (10 mL) was added and the mixture was extracted with DCM (2×5 mL). The combined organic layers were washed with 1 M HCl (5 mL), water (5 mL) and brine (5 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (2E,6Z)-3-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohepta-2,6-dienone as a yellow oil (26 mg, 17% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 6.88-6.82 (m, 1H), 6.26-6.23 (dd, J=12.0, 1.6 Hz, 1H), 6.19 (d, J=2.0 Hz, 1H), 3.87 (s, 3H), 2.82-2.73 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:21]=1[NH2:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.O1CCOCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])([C:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[O:17])[CH:21]([CH:23]=1)[NH2:22]
Reactant: O=C(O)Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: COc1ccc(Cl)cc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC1(C(=O)Cc2ccc(-c3ccc(O)cc3)cc2)C=CC(Cl)=CC1N
Yield: 70 %

Procedure:
A solution of 10 gm (44 millimols) of 4-hydroxy-4'-biphenyl-acetic acid (see W. H. Linnell and H. J. Smith, J. Chem. Soc. 1959,557) in a mixture of 33 ml of tetrahydrofuran and 162 ml of absolute dioxane were added at 0° C to a solution of 4.63 gm (29.4 millimols) of 2-methoxy-5-chloroaniline (m.p. 83°-85° C) in 40 ml of absolute dioxane, and the mixed solution was subsequently admixed with a solution of 9.1 gm (44 millimols) of N,N'-dicyclohexyl-carbodiimide in 20 ml of dioxane. After 20 hours of reaction time at 0° C, the dicyclohexylurea was filtered off and the solvent was distilled off. The residue was dissolved in 700 ml of chloroform, the solution was washed several times with 2N hydrochloric acid and water, dried over sodium sulfate, and the organic phase was evaporated in vacuo. The light brown, viscous crude product was purified on a silicagel column with toluene/acetic acid (4:1 ) as the eluant. Yield: 70% of theory; m.p. 165°-168° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=1.[NH3:25]>CN(C=O)C>[F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=1
Reactant: CCOC(=O)CCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyrate (0.25 g.), DMF (2 ml.), saturated ethanolic ammonia (5 ml.) and yellow mercuric oxide (0.2 g.) was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated to dryness and the residue recrystallised from EtOAc to give ethyl 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyrate, m.p. 120°-122°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:21]([CH3:23])[CH3:22]>CN1C(=O)N(C)CCC1>[CH:21]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)([CH3:23])[CH3:22]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)c1ccc2ccn(C(C)C)c2c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 1H-indole-6-carboxylate (5.00 g, 28.5 mmol) and cesium carbonate (18.6 g, 57.1 mmol) in DMPU (50 mL) was added 2-iodopropane (3.71 mL, 37.1 mmol). After stirring at 80° C. for 4 h, the solution was cooled to rt, poured onto ether, washed with H2O (three times) and brine, dried with Na2SO4, and concentrated. The crude compound was chromatographed to give the desired product. LCMS (M+1)=218.1
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][C@@H:10]([C:14]1[O:18][N:17]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]=1[CH3:24])[C@@H:11]([OH:13])[CH3:12].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[Si:5]([O:13][C@@H:11]([CH3:12])[C@H:10]([C:14]1[O:18][N:17]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]=1[CH3:24])[OH:9])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1noc([C@H](O)[C@H](C)O)c1C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1noc([C@H](O)[C@H](C)O[Si](C)(C)C(C)(C)C)c1C
Temperature: 25 °C

Procedure:
tertbutyldimethylsilyl chloride (6.3 g, 41.5 mmol) was added portionwise to ethyl 5-((1R,2S)-1,2-dihydroxypropyl)-4-methylisoxazole-3-carboxylate (Intermediate B)(8.65 g, 37.7 mmol), 4-dimethylaminopyridine (1.38 g, 11.32 mmol) and triethylamine (5.80 mL,) in DMF (100 mL) at 0° C. and the reaction was allowed to warm to room temperature. After 18 h the reaction was partitioned between EtOAc and brine, washed with saturated aqueous ammonium chloride, brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 15% EtOAc in iso-hexane afforded the title compound;