Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:11][C:12]([CH3:14])=[O:13].O>O1CCCC1>[Cl:10][C:2]1([O:13][C:12]1([CH3:14])[CH3:11])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cl)OC1(C)C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 70.8 g of potassium tert.-butylate in 500 ml of tetrahydrofuran was added over 30 minutes under an inert atmosphere to 111 g of tert.-butyl dichloroacetate and 35.5 g of acetone at 0°C and after letting the mixture return to room temperature, the mixture was stirred for 1 hour and poured into iced water. The mixture was extracted with petroleum ether and the extract was washed twice with water and dried over sodium sulfate. 40 g of alumina were added thereto and after stirring, the mixture was filtered to remove mineral products. The solvent was removed from the filtrate by distillation under reduced pressure to obtain 116.5 g of tert.-butyl 2-chloro-2,3-epoxy-3-methyl-butanoate in the form of a colorless liquid soluble in the usual organic solvents and insoluble in water.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28](O)=[O:29].CCN=C=NCCCN(C)C>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.ClCCl>[CH2:16]([O:15][C@H:3]1[C@@H:2]([NH:1][C:28]([C:24]2[NH:23][CH:27]=[CH:26][N:25]=2)=[O:29])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](OCc2ccccc2)C1
Reactant: O=C(O)c1ncc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ncc[nH]2)[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
tert-Butyl cis(±)-4-amino-3-(benzyloxy)piperidine-1-carboxylate obtained in Example (90d) (0.92 g, 3.0 mmol) was dissolved in DMA (10 mL). 1H-Imidazol-2-ylcarboxylic acid (0.19 g, 1.70 mmol), WSC (0.82 g, 0.43 mmol) and DMAP (60 mg, 0.49 mmol) were added, and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with dichloromethane, washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1, 1/1, 1/3) to obtain 0.31 g of the title compound as a colorless solid (46%).
Reaction SMILES: C1C2C=CS(=O)(=O)C=2C=C([N+]([O-])=O)C=1.CC(C)(C)COC([SiH3])N1C([C:29]2[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:32]3[CH:42]=[CH:43][CH:44]=[CH:45][C:31]=3[N:30]=2)C2C(=CC=CC=2)N1.[N+:49]([C:52]1[CH:60]=[C:59]2[C:55]([C:56]([Sn](C)(C)C)=[N:57][N:58]2[CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])=[CH:54][CH:53]=1)([O-:51])=[O:50].IN1C2C=CC=CC=2N(COCC[Si](C)(C)C)C1>[Cu]I.C1COCC1>[N+:49]([C:52]1[CH:60]=[C:59]2[C:55]([C:56]([C:29]3[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:41])[CH3:39])[C:32]4[CH:42]=[CH:43][CH:44]=[CH:45][C:31]=4[N:30]=3)=[N:57][N:58]2[CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])=[CH:54][CH:53]=1)([O-:51])=[O:50]
Reactant: CC(C)(C)COC([SiH3])N1Nc2ccccc2C1c1nc2ccccc2n1COCC[Si](C)(C)C
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2ccc([N+](=O)[O-])cc21
Agent: [Cu]I
Agent: C[Si](C)(C)CCOCN1CN(I)c2ccccc21
Agent: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)C=C2
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc([N+](=O)[O-])cc21
Yield: 82 %

Procedure:
Preparation of 6-nitro-1-[2-(trimethyl-silanyl-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]1-H-benzoimidazol-2-yl}-1-H-indazole: 6-Nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-1-H-indazole (7.50 g, 16.4 mmol), 3-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzimidazole (6.50 g, 17.4 mmol), and copper(I) iodide (313 mg, 1.64 mmol) were combined with dry THF (150 mL) in a flask purged with argon. Tetrakis(triphenylphosphine)palladium(0) was added, and the reaction stirred at reflux under argon for 23 h. The reaction was cooled and adsorbed directly onto silica gel (˜16 g). Purification by silica gel chromatography (4% to 15% ethyl acetate/hexanes) gave 7.28 g (82%) of 6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.91 (d, 1H, J=9.0 Hz), 8.59 (d, 1H, J=1.8 Hz), 8.22 (dd, 1H, J=8.7, 1.8 Hz), 7.92-7.89 (m, 1H), 7.66-7.62 (m, 1H), 7.40-7.36 (m, 2H), 6.24 (s, 2H), 5.90 (s, 2H), 3.68-3.59 (m, 4H), 0.94 (t, 2H, J=8.1 Hz), 0.86 (t, 2H, J=8.1 Hz), −0.04 (s, 9H), −0.15 (s, 9H). Anal. (C26H37N5O4Si2) C, H, N. Calculated: C, 57.85; H, 6.91; N, 12.97. Found: C, 57.60; H, 6.81; N, 12.82.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([O:12][C@@H:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[O:11])=[CH:5][CH:4]=1.Cl[CH2:30][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[O:32]>C(OCC)(=O)C>[CH:10]([O-:12])=[O:11].[CH:10]([O-:12])=[O:11].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][CH:9]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]([O:12][C@@H:13]2[CH:18]3[CH2:17][CH2:16][N+:15]([CH2:30][C:31](=[O:32])[C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)([CH2:20][CH2:19]3)[CH2:14]2)=[O:11])=[CH:27][CH:28]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][CH:9]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]([O:12][C@@H:13]2[CH:18]3[CH2:17][CH2:16][N+:15]([CH2:30][C:31]([C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)=[O:32])([CH2:20][CH2:19]3)[CH2:14]2)=[O:11])=[CH:27][CH:28]=1
Reactant: O=C(CCl)c1cccs1
Reactant: COc1ccc(CNC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(C(=O)O[C@H]2C[N+]3(CC(=O)c4cccs4)CCC2CC3)c2ccccc2)cc1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(4-methoxybenzylamino)-2-phenylacetate (C79) (78 mg, 0.21 mmol) in ethyl acetate (2.05 mL), is added 2-chloro-1-(thiophen-2-yl)ethanone (36.2 mg, 0.23 mmol). The colorless solution is stirred at RT overnight. The residue is first purified by flash chromatography (DCM/MeOH=90/10 to 85/15) and then by preparative LC/MS. MeOH is evaporated from the fractions collected and then the aqueous solution is freeze-dried overnight to obtain the title compound as a pale pink oil (44 mg, 36% yield, formate formate anion, mixture of diastereoisomers).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]#[N:25]>C(O)C.N1CCCCC1>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[CH:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=1)[C:24]#[N:25]
Reactant: N#CCc1ccccn1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1cc(C=C(C#N)c2ccccn2)cc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2.0 g (9.17 mmole) 3,5-di-tertbutylbenzaldehyde in 75 ml absolute ethanol are added 1.19 g (10.1 mmole) 2-pyridylacetonitrile and 12 drops piperidine. The reaction flask is equipped with a condenser and a drying tube (using anhydrous CaSO4), and the reaction is stirred and heated. After refluxing for 8 hours, the reaction is allowed to cool to room temperature and stirred overnight for 16 hours. The solvent is removed by rotary evaporation, and the residue purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate, 98:2. The colorless solid is washed with cold ether-hexane to give 2-(2-pyridyl)-3-(3,5-di-tert-butylphenyl)-2-propenenitrile, m.p. 90°-93° C.
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[C:6]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:20]([O:22]CC)=O.[ClH:25].[NH2:26][C:27]([NH2:29])=[NH:28].[CH3:30][O-].[Na+]>CO>[ClH:25].[CH3:30][NH:28][C:27]([NH2:29])=[N:26][C:20]([C:3]1[NH:2][C:10]2[C:5]([CH:4]=1)=[C:6]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH:7]=[CH:8][CH:9]=2)=[O:22]
Reactant: CCOC(=O)c1cc2c(CNC(=O)OC(C)(C)C)cccc2n1C
Reactant: C[O-]
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2c(CNC(=O)OC(C)(C)C)cccc2[nH]1

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 1.40 g (4.21 mmol) of ethyl 1-methyl-4-tert-butyloxycarbonylaminomethyl-2-indolecarboxylate, 4.02 g (42.1 mmol) of guanidine hydrochloride and 60 ml of a methanol solution of 2.27 g (42.1 mmol) of sodium methoxide. 1-Methyl-4-tert-butyloxycarbonylaminomethyl-2-indoloylguanidine hydrochloride was obtained in an amount of 1.50 g. After the compound was dissolved in 35 ml of trifluoroacetic acid and 70 ml of methylene chloride, the solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Thereafter ice water was poured onto the resulting residue and the aqueous layer was rendered alkaline with 28% aqueous ammonia. The mixture was then extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was converted with hydrogen chloride/ether into the hydrochloride. Thus 0.58 g (43.2%) of 4-aminomethyl-1-methyl-2-indoloylguanidine dihydrochloride was obtained.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)CC1CC2CCC1C2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC1CC2CCC1C2
Yield: 99.8 %

Procedure:
2-Norbornaneacetic acid (Aldrich, Catalog #127264, CAS #1007-01-8, 2.01 g, 13.0 mmol) was dissolved in thionyl chloride (7 mL, 96 mmol). The reaction was heated to reflux for 5 hours. The reaction mixture was concentrated in vacuo to provide the title compound as a colorless oil (2.24 g, 100%) that was used without additional purification.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@@H:11]([O:12][CH2:13][CH:14]=[CH2:15])[C@@H:10]1[NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCC(CC1)CN2>C(O)C.C1C=CC=CC=1.O.[Rh]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@@H:11]([O:12][CH:13]=[CH:14][CH3:15])[C@@H:10]1[NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Agent: Cl[Rh]
Agent: C1CN2CCC1CN2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: CC=CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Reaction time: 24 h

Procedure:
To a solution of Compound 5 (3.2 g., 5.84 mmol) in ethanol:benzene:water (7:3:1, v/v) (250 ml.) were added diazabicyclo[2.2.2]octane (0.2 g, 1.8 mmol) and tris(triphenylphosphine) rhodium(I) chloride (0.4 g., 0.43 mmol). The mixture was stirred for 24 h. under reflux. Solvents were evaporated and coevaporated with toluene. A portion of the product, purified on a column of silica gel, afforded an amorphous solid, [α]D25 -7.4°, [α]43625 -13/3° (chloroform).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[CH:23]=[CH:22][C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1.CN(C(ON1N=[N:39][C:34]2[CH:35]=[CH:36][CH:37]=N[C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC([O:52]C)(C)C>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])/[CH:16]=[CH:15]/[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:33]([C:34]2([NH2:39])[CH2:37][CH2:36][CH2:35]2)=[O:52])=[CH:23][CH:22]=1)[CH3:21]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: COC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(NC(=O)C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The acid from above (0.519 g, 2.0 mmol) was dissolved in DCM (10 mL). DIEA (1.39 mL, 8.0 mmol, 4 equivalents) was added, followed by ethyl 4-aminocinnamate (0.573 g, 3.0 mmol, 1.5 equivalent) and HATU (1.143 g, 3.0 mmol, 1.5 equivalents). The mixture was stirred at room temperature for 3 days. The reaction was poured into TBME (100 mL) and the solution washed successively with 10% aqueous citric acid (2×25 mL) and saturated aqueous NaHCO3 (25 mL), and dried over MgSO4. The solvent was removed under reduced pressure and the residue stirred with TFA (10 mL) for 30 min. Volatiles were then removed under reduced pressure and the residue was co-evaporated twice with hexane. The crude product was dissolved in TBME (60 mL) and the solution washed with 1N NaOH (2×25 mL). After drying (Na2SO4), volatiles were removed in vacuum to give the title compound as a light brown solid (0.500 g).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:42]2[N:41]=[C:40]([Cl:43])[N:39]=[C:23]([NH:24][CH2:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]=2[N:21]=[CH:20]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>CO.O>[Cl:43][C:40]1[N:39]=[C:23]([NH:24][CH2:25][CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:22]2[N:21]=[CH:20][N:19]([C:42]=2[N:41]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 11.2 %

Procedure:
2-Chloro-N-(2,2-diphenylethyl)-adenosine 2',3',5'-triacetate (2.0 g,3.29 mmol) was dissolved in methanol (120 ml) and the solution was stirred at room temperature with 2M aqueous sodium carbonate solution (10 ml). After 2h the mixture was diluted with water (350 ml) and extracted with ethyl acetate (2×10 ml). The extract was washed with water (100 ml) and dried (MgSO4) then evaporated to leave a froth (1.42 g). A sample (0.42 g) was purified by column chromatography on flash silica eluting with ethyl acetate:cyclohexane (3:1). Evaporation of appropriate fractions gave an oil which was treated with ether (20 ml) to give a solid, which was collected by filtration, washed with ether and dried in vacuo to give the title compound (0.177 g) as a solid [α]D -39° (CHCl3 c=1%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)Cl>[CH3:8][C@@H:7]([C@@H:9]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][C@@H:24]3[C@@:22]4([CH3:23])[CH2:21][CH2:20][C@H:18]([OH:19])[CH2:17][C@:16]54[O:37][C@H:15]5[CH2:14][C@H:13]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C

Procedure:
Pure cholesterol epoxides are not generally available from commercial sources, so they were synthesized from cholesterol. Analytical grade cholesterol, purified through the dibromide, was employed in these syntheses. Cholesterol 5α,6α-epoxide was synthesized by the procedure of Fieser, L. F. and Fieser, M., in "Reagents for Organic Synthesis," Vol. 1, 1967 John Wiley, New York, p. 136. Cholesterol (50 mmol) in methylene chloride (75 ml) solution was treated at 25° C. over a 30 minute interval with m-chloroperbenzoic acid (54 mmol) in methylene chloride (120 ml) solution. Excess peracid was destroyed by the addition of 10% sodium sulfite. Extraction of the organic layer with 5% aqueous sodium bicarbonate, water, and finally with saturated aqueous sodium chloride, followed by drying and evaporation produced a crude product readily purified by recrystallization from 88% aqueous acetone or by silica gel chromatography. Cholesterol 5α,6α-epoxide (>95% purity, m.p. 142°-143°) was obtained in >90% yield.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2[nH]1
Agent: O=S(=O)(O)O
Product: Cc1nc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-5-nitrobenzimidazole in concentrated sulfuric acid was added fuming nitric acid at −5° C. Upon addition of the fuming nitric acid, the reaction mixture was warmed to 0° C. held for 1 h and poured into crushed ice. The precipitate which formed was filtered, washed with water, and dried overnight at 40° C. to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH2:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]([F:23])([F:22])C([O-])=O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:18]([F:23])[F:22])=[N:14][CH:15]=2)=[CH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: C=C(c1ccc(=O)[nH]c1)c1cccc(Br)c1
Agent: [Na+]
Solvent: CC#N
Product: C=C(c1ccc(OC(F)F)nc1)c1cccc(Br)c1
Temperature: 100 °C

Procedure:
The 5-[1-(3-bromo-phenyl)-vinyl]-1H-pyridin-2-one (10 g, 1 eq) was dissolved in acetonitrile (180 ml) and degassed for 1 hour. Then sodium chlorodifluoroacetate (8.5 g, 1.2 eq) was added and the mixture heated to 100° C. overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, the solvent was removed, and the crude was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dried over sodium sulphate, and concentrated in vacuo. The crude product was purified by flash chromatography eluting with ethyl acetate. The 5-[1-(3-bromo-phenyl)-vinyl]-2-difluoromethoxy-pyridine was obtained as colorless oil (2.6 g, 26% of theory). MS (ISP): m/z=328 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)=O.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH2:8][CH2:7][N:6]=1
Reactant: COCC(=O)NCCc1ccsc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COCC1=NCCc2ccsc21

Procedure:
15.6 g (78.3 mmol) 2-methoxy-N-(2-thiophen-3-yl-ethyl)-acetamide are dissolved in 350 ml chloroform and combined with 35.8 ml (391.4 mmol) phosphorus oxychloride while cooling with an ice bath. The ice bath is removed and the mixture is refluxed for 5 hours. Then it is carefully added to 600 ml of warm sodium hydroxide solution (4N) and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The crude product is purified by flash chromatography on silica gel (eluant DCM/methanol 98:2→95:5).
Reaction SMILES: Cl.[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:26]1[CH:31]=[N:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1>ClCCl>[N:30]1[CH:31]=[CH:26][CH:27]=[C:28]([NH:32][C:33]([N:11]2[CH2:12][CH:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:3][CH:4]=3)[CH2:10]2)=[O:34])[CH:29]=1
Reactant: c1ccc(-c2ccc(OC3CNC3)cc2)cc1
Reactant: O=C=Nc1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccnc1)N1CC(Oc2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
3-(Biphenyl-4-yloxy)azetidine hydrochloride (3 g, 11.47 mmol) was suspended in dichloromethane (45 mL) under a nitrogen atmosphere, treated with triethylamine (4.0 mL, 28.68 mmol) and stirred for 10 minutes at room temperature. The mixture was cooled to 0° C. and treated portionwise with pyridine-3-isocyanate (1.15 g, 9.56 mmol). Stirred at 0° C. for 10 minutes, then at rt for 16 hours. The solution was diluted with further dichloromethane (200 mL), washed with H2O (2×100 mL), followed by brine (50 mL), dried (over MgSO4), and solvent evaporated in vacuo to yield an off-white solid. The solid was triturated with diethyl ether, then stirred for 3 days with MP-isocyanate resin in a dichloromethane/methanol/acetonitrile mixture. The mixture was filtered and reduced to dryness in vacuo. The resulting solid was triturated successively with diethyl ether, then acetonitrile and filtered to give the urea (1.2 g, 36%) as a white solid; Rf 0.10 (5% MeOH-DCM); LCMS retention time 2.08 minutes, m/z 346.2 [M+H]+; 1H nmr (400 MHz; DMSO-d6) δ 8.97 (s, 1H), 8.75 (d, 1H, J=2.3 Hz), 8.21 (d, 1H, J=4.7 Hz), 8.05-8.01 (m, 1H), 7.65-7.60 (m, 4H), 7.44 (t, 2H, J=7.9 Hz), 7.39 (dd, 1H, J=8.3 and 4.7 Hz), 7.32 (t, 1H, J=7.3 Hz), 6.96 (d, 2H, J=8.8 Hz), 5.14-5.08 (m, 1H), 4.49 (dd, 2H, J=9.5 and 6.5 Hz) and 3.97 (dd, 2H, J=9.5 and 3.8 Hz); 13C nmr (100 MHz; DMSO-d6) 156.2 (C), 155.9 (C), 141.4 (CH), 139.6 (C), 138.9 (CH), 137.3 (C), 133.4 (C), 128.9 (CH), 128.1 (CH), 126.9 (CH), 126.8 (CH), 126.3 (CH), 123.9 (CH), 115.1 (CH), 65.6 (CH) and 56.4 (CH2).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=1.C[Si](C)(C)[O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:11]([C:10]1[CH:9]=[CH:8][C:7]([N:6]([N:4]2[CH:3]=[N:2][N:1]=[CH:5]2)[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([OH:17])=[CH:19][CH:20]=2)=[CH:14][CH:13]=1)#[N:12]
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: C[Si](C)(C)Oc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N(C(=O)c2ccc(O)cc2)n2cnnc2)cc1
Yield: 36.1 %

Procedure:
A mixture composed of 10.43 g of 4-[N-(1,2,4-triazol-4-yl)amino]benzonitrile, 7.9 ml of triethylamine, and 56 ml of methylene chloride was stirred under cooling with ice, and a mixture composed of 23.7 g of 4-(trimethylsilyloxy)benzoyl chloride and 28 ml of methylene chloride was added dropwise thereto, followed by stirring at room temperature for 1 hour. Dilute hydrochloric acid was added to the reaction mixture, followed by stirring at room temperature overnight. After the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, the product was extracted with tetrahydrofuran-diethyl ether (1:1). After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (using a 4:1 mixture of chloroform and acetone as the eluent) to obtain 6.2 g of N-(4-cyanophenyl)-4-hydroxy-N-(1,2,4-triazol-4-yl)benzamide.