Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C[Sn:15](C)C.C[Sn](C)C>>[CH3:11][C:9]1([CH3:12])[C:8](=[O:13])[C:7]2[C:2]([Sn:15])=[CH:3][CH:4]=[CH:5][C:6]=2[O:10]1
Reactant: CC1(C)Oc2cccc(Br)c2C1=O
Reactant: C[Sn](C)C
Product: CC1(C)Oc2cccc([Sn])c2C1=O

Procedure:
In a slight variation in the method to the 2,4-diamino-5,6-disubstituted-5-deazapteridines described above, using a method taught by A. Pidcock et al (J. Organometallic Chem. 1981, 215, 49-58), 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone is reacted with hexamethylditin in the presence of tetrakis(triphenylphosphine)palladium(0)in toluene, yielding (2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)tin. The organometallic derivative is then reacted with 2-amino-3-cyano-5-iodo-4-methylpyridine, again in the presence of tetrakis(triphenylphosphine)palladium(0) in toluene, affording the corresponding 2-amino-3-cyano-5-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)-4-methylpyridine. This compound is then cyclized with guanidine in ethanol, as previously described, yielding the corresponding 2,4-diamino-5-methyl-6-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)-5-deazapteridine. Example 9 provides a detailed description of how this reaction is conducted.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]2[C@:9]3([OH:29])[C@@H:14]([OH:15])[CH2:13][C@@H:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@:10]3([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[O:11][C:7]=2[CH:6]=1.[CH3:32][NH:33][CH3:34]>>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C@:10]23[C@H:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:13][C@H:14]([OH:15])[C@@:9]2([OH:29])[C:8]2[CH:30]=[CH:31][C:5]([O:4][CH2:3][CH2:2][N:33]([CH3:34])[CH3:32])=[CH:6][C:7]=2[O:11]3)=[CH:27][CH:26]=1
Reactant: O[C@H]1C[C@@H](c2ccccc2)[C@]2(c3ccc(Cl)cc3)Oc3cc(OCCCl)ccc3[C@]12O
Reactant: CNC
Product: CN(C)CCOc1ccc2c(c1)O[C@@]1(c3ccc(Cl)cc3)[C@H](c3ccccc3)C[C@H](O)[C@@]21O

Procedure:
100 mg (0.22 mmol) of (1S*,3S*,3aR*,8bS*)-6-(2-chloroethoxy)-3a-(4-chlorophenyl)-3-phenyl-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran-1,8b-(1H)-diol (Example 48A) are heated in 10 ml of 33% strength ethanolic dimethylamine solution in a closed apparatus at 70° C. under argon overnight. Cooling is followed by concentration. Column chromatography on silica gel 60 (mobile phase: dichloromethane/methanol/triethylamine 95:5:1) results in 89 mg (87% of theory) of the product as racemic mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:15])=O)=[CH:9]2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:36])[NH2:15])=[CH:9]2)[CH3:2]
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Temperature: 55 °C
Reaction time: 2 h
Yield: 152.8 %

Procedure:
A mixture of 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (0.43 g) and Lawesson's reagent (0.28 g) in tetrahydrofuran (30 mL) was stirred at 55° C. for 2 h. The reaction mixture was concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (414 mg, 92%) as light yellow crystals. MS 392 (MH+).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.C(N(C(C)C)CC)(C)C.[Br:31][C:32]1[CH:46]=[CH:45][C:35]([O:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClC(Cl)C>[Br:31][C:32]1[CH:46]=[CH:45][C:35]([O:36][C:37]2[CH:44]=[CH:43][C:40]([CH2:41][N:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]3[CH2:4][N:3]([CH2:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[CH3:2])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(CN(C)CC2CCCCN2)cc1
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(C(=O)O)cc1)CC1CCCCN1Cc1ccc(Oc2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
A slurry of methyl 4-((methyl(piperidin-2-ylmethyl)amino)methyl)benzoate hydrochloride salt (200 mg, 0.58 mmol) in dichloroethane (6 mL) was stirred as diisopropylethylamine (225 mg, 1.74 mmol) was added. After 30 minutes, 4-(4-bromophenoxy)benzaldehyde (160 mg, 0.58 mmol) was added to the reaction mixture. After 20 minutes, solid triacetoxyborohydride (147 mg, 0.7 mmol) was added and the reaction was stirred for 17 hours. Solvent was removed under reduced pressure. The residue was dissolved in a mixture of THF and methanol and treated with lithium hydroxide to give a basic solution. The reaction was stirred for 17 hours, concentrated to dryness, and purified by reverse phase preparative HPLC using a gradient of acetonitrile in water containing 0.1% TFA. Relevant fractions were combined to give 40 mg of 4-[[[[(RS)-1-[[4-(4-bromophenoxy)phenyl]methyl]-2-piperidinyl]methyl]methylamino]methyl]benzoic acid; 1NMR (400 MHz, DMSO-d6) δ 7.93 (d, 2H), 7.57 (d, 2H), 7.52 (m, 4H), 7.06 (d, 2H), 6.96 (d, 2H), 4.61 (dbr, 2H), 4.18 (dbr, 2H), 3.24 (m, 1H), 2.34 (s, 3H), 2.00 (m, 1H), 1.63 (m, 5H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][O:21][NH2:22])=[CH:18][CH:17]=1)([O-:15])=[O:14].N1C=CC=CC=1>C(O)C>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:21][N:22]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=2)[CH3:10])=[CH:23][CH:24]=1)([O-:15])=[O:14]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccc(O)c(F)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NOCc1ccc([N+](=O)[O-])cc1)c1ccc(O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 3′-fluoro-4′-hydroxyacetophenone (0.063 g, 0.411 mmol), O-(4-nitrobenzyl)hydroxylamine hydrochloride (0.100 g, 0.491 mmol) and pyridine (0.13 ml, 1.61 mmol) in ethanol (5 ml) was stirred at reflux under nitrogen for 5h and cooled to room temperature. The solution was concentrated to a pale yellow oil which was diluted with dichloromethane/water. The resultant mixture was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to an off-white solid. The crude product was purified by column chromatography (SiO2), eluting with 8:2 petrol/ethyl acetate, to give a 3′-fluoro-4′-hydroxyacetophenone-O-4-nitrobenzyloxime (CP9-132) as light yellow solid (0.081 g, 65%),
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:26]1[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=1>>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3cnc(-n4ccnc4C)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from 2-(2-methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 3. LC (method 10): tR=1.39 min; Mass spectrum (ESI+): m/z=433 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[O:16][C:15](=O)[CH:14]=1>ClC1C=CC=CC=1Cl>[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:1]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[C:15](=[O:16])[CH:14]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cccc(-n2c(C)cc(O)cc2=O)c1
Temperature: 165 °C
Yield: 15.7 %

Procedure:
Methyl 3-aminobenzoate (75.00 g, 496.13 mmol) and 4-hydroxy-6-methyl-2-pyrone (62.57 g, 496.13 mmol) were suspended in 1,2-dichlorobenzene (150 mL) and heated to 165° C. for 15 minutes. The reaction was cooled to room temperature and extracted with 0.54M K2CO3 (4×250 mL). The aqueous layers were acidified (pH 2) with 4N HCl. The precipitate was collected by filtration to afford a yellow-orange solid (20.24 g, 16%). The resulting filtrate was extracted with ethyl acetate (3×1 L). The organic layers were washed with brine (500 mL), dried over MgSO4 and evaporated. The resulting solid was washed with hot H2O to afford a yellow-orange solid (3.84 g, 3%). The two solids were then combined. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (dt, J=1.31, 7.79 Hz, 1H), 7.69 (app t, J=1.78 Hz, 1H), 7.62 (t, J=7.78 Hz, 1H) 7.49 (ddd, J=1.07, 1.07, 7.85 Hz, 1H), 5.89 (dd, J=087, 2.48 Hz, 1H), 5.55 (app d, J=0.94 Hz, 1H), 3.83 (s, 3H), 1.80 (s, 3H). ES-HRMS m/z 260.0895 (M+H C14H13NO4 requires 260.0917).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][CH2:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17])([O-:3])=[O:2].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:31](O)[CH3:32]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][CH2:14][C:15]([F:19])([F:20])[C:16]([O:18][CH2:31][CH3:32])=[O:17])([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 3-[(2,6-dinitrophenyl)amino]-2,2-difluoropropanoic acid (3.52 g, 12.09 mmol) in ethanol (30.0 mL) was added sulfuric acid (4 mL) at 0° C. The reaction mixture was stirred at 100° C. for 1 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and the solvent was removed. The residue was extracted with ethyl acetate (×3) The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow oil (2.94 g, 9.210 mmol, 76%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:3])[CH3:2].CO.Cl>C1COCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[C:14]([F:15])([F:16])[F:17])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1ccc(CO)cc1C(F)(F)F
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of 4-isopropoxy-3-(trifluoromethyl)benzoic acid (191 g, 770 mmol) in THF (2 L) at 0° C. in a 5-L round bottomed flask under N2 was added BH3 THF (1M solution in THF, 1.08 L, 1.08 mol) slowly over 15 min. The mixture was allowed to stir at 0° C. for 30 min at which time the ice bath was removed and the reaction warmed to room temperature. The reaction was quenched with MeOH (80.0 mL, 506 mmol) followed by aq. HCl (1 M, 1000 mL, 1000 mmol) (slight exotherm to 36° C. was observed). The volatile organics were removed in vacuo and the aqueous phase was extracted with EtOAc (2×1 L). The organic layers were combined and washed with sat. NaHCO3 (750 mL) and brine (750 mL). Dried organics over MgSO4, filtered, and concentrated to give (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (181 g, 763 mmol, 99% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (d, J=6.1 Hz, 6 H), 1.66 (s, 1H) 4.59-4.69 (m, 3 H), 6.99 (d, J=8.5 Hz, 1 H), 7.46 (dd, J1=8.5, J2=2.2 Hz, 1 H), 7.56 (d, J=1.9 Hz, 1 H).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([CH2:19][NH2:20])[CH2:18][CH2:17]1.C([BH3-])#N.[Na+]>CO>[CH:16]1([CH2:19][NH:20][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:18][CH2:17]1
Reactant: NCC1CC1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(CNCC3CC3)cc2)cc1
Reaction time: 48 h
Yield: 78.4 %

Procedure:
4-Phenoxybenzaldehyde (3.0 g, 15.1 mmol) and cyclopropylmethylamine (1.1 g, 15.1 mmol) were dissolved in methanol (85 mL) under nitrogen at room temperature. Sodium cyanoborohydride (0.95 g, 15.1 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated under reduced pressure, and the residue was suspended in ether, washed with brine, and dried over Na2SO4The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol-methylene chloride to provide 3.0 g (78%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ0.08-0.15 (m, 2H), 0.45-0.55 (m, 2H), 0.93-1.05 (m, 1H), 1.45 (br s, 1H), 2.50 (d, J=7.5 Hz, 2H), 3.78 (s, 2H), 6.95-7.03 (m, 4H), 7.05-7.13 (m, 1H), 7.25-7.38 (m, 4H). MS (DCl/NH3) m/e 254 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:4]=1[OH:10].S([C:15]1[CH:21]=CC(C)=C[CH:16]=1)(O)(=O)=O.[OH-].[Na+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[O:10][C:15]([CH3:21])([CH3:16])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cccc(O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1cccc2c1OC(C)(C)O2

Procedure:
3-methoxycatechol (25 g) was dissolved in benzene, mixed with dimethoxyacetal (35 ml) and a catalytic amount of tosylic acid, and then, heat-refluxed for 6 hours. The resultant was allowed to stand for cooling, alkalified by adding an aqueous sodium hydroxide solution, and extracted with ether. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over manganese sulfate, and evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=99/1) to give Compound IIbv-a (19.4 g, 60.5%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.C(O)(=O)C>C(Cl)Cl>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH3:10])=[N:7][C:6]=3[CH:11]=2)[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc2cc(-n3cccc3)ccc2o1
Yield: 40 %

Procedure:
5-Amino-2-methylbenzoxazole (30.0 g, 0,203 mol) and 2,5-dimethoxytetrahydrofuran (30.0 g, 0.227 mol) were combined with 90 mL of acetic acid and the solution was heated at reflux for 1 hr. The mixture was evaporated to a red slurry and mixed with hexane to give a dark solid. The solid was dissolved in methylene chloride and extracted with basic water. The organic phase was removed, dried, and evaporated to a brown solid. Recrystallization from hexane/heptane afforded 18 g (45% yield) of product, m.p. 115°-121° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8](/[CH:9]=[C:10]2/[C:11]([CH3:26])=[C:12]([CH2:22][C:23](O)=[O:24])[C:13]3[C:18]/2=[CH:17][CH:16]=[C:15]([N:19]([CH3:21])[CH3:20])[CH:14]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)C([Cl:32])=O>C1COCC1>[CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8](/[CH:9]=[C:10]2/[C:11]([CH3:26])=[C:12]([CH2:22][C:23]([Cl:32])=[O:24])[C:13]3[C:18]/2=[CH:17][CH:16]=[C:15]([N:19]([CH3:21])[CH3:20])[CH:14]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1=C(CC(=O)O)c2cc(N(C)C)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC1=C(CC(=O)Cl)c2cc(N(C)C)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1

Procedure:
(Z)-1-(p-methylsulfonylbenzylidene)-5-dimethylamino-2-methyl-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Br:17]Br.CO>O>[Br:17][C:8]1[C:7]([Cl:12])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Clc1ccc2c(Br)c(Cl)ccc2n1
Temperature: 25 °C

Procedure:
2,6-Dichloroquinoline (30 g) and aluminium trichloride (60 g) were heated to 120° C. with stirring under a nitrogen atmosphere. Bromine (9.2 mL) was added dropwise over 1 hour and the mixture was then stirred at 120° C. for 1 hour before being cooled to room temperature. A methanol/deionised water mixture (150 mL, 1:1) was then slowly added and the mixture was concentrated in vacuo. Dichloromethane (500 mL) and deionised water (250 mL) were added, the layers were separated and the aqueous fraction was extracted with dichloromethane (2×250 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (250 mL) before being dried, filtered and concentrated. Purification by chromatography (SiO2, isohexane:dichloromethane 7:3 as eluant) gave the title compound as a solid (27 g).
Reaction SMILES: [C:1]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]N1C(=O)CCC1=O)=O)=[O:23])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.[CH2:40]([NH2:43])[C:41]#[CH:42]>CN(C=O)C>[C:1]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH:43][CH2:40][C:41]#[CH:42])=[O:32])=[O:23])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1
Reactant: C#CCN
Reactant: O=C(CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: C#CCNC(=O)CCCCCNC(=O)CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 8 h

Procedure:
To a stirred solution of 6-((6-((Biotinoyl)amino)hexanoyl)amino)hexanoic acid, succinimidyl ester (biotin-NHS ester) (0.2 g, 0.35 mmol) in dry DMF (5 ml), propargyl amine (0.04 ml, 0.6 mmol) was added. A white precipitate formed within 15 min and the mixture was stirred overnight. The solvent was removed in vacuo and the compound was dissolved in CHCl3. Next the CHCl3 was slowly added to a stirred solution of hexane, forming a white precipitate, which on drying afforded 0.15 g (83%). Mass Spect. (FAB) MW 508 [M+]; NMR assigned. Crisp, G. T.; Gore, J. Syn. Comm. 1997, 27, 2203-2125
Reaction SMILES: I(O)(O)(O)(O)(O)=[O:2].[OH:8][C@@H:9]1[C@H:25]2[C@@H:16]([CH2:17][CH2:18][C:19]3[C@:24]2([CH3:26])[CH2:23][CH2:22][C:21](=[O:27])[CH:20]=3)[C@H:15]2[C@@:11]([CH3:33])([C@@:12]([OH:32])([C:28](=[O:31])CO)[CH2:13][CH2:14]2)[CH2:10]1>O.C1COCC1.[OH-].[Na+]>[OH:8][C@@H:9]1[C@H:25]2[C@@H:16]([CH2:17][CH2:18][C:19]3[C@:24]2([CH3:26])[CH2:23][CH2:22][C:21](=[O:27])[CH:20]=3)[C@H:15]2[C@@:11]([CH3:33])([C@@:12]([OH:32])([C:28]([OH:2])=[O:31])[CH2:13][CH2:14]2)[CH2:10]1
Reactant: [O-][I+](O)(O)(O)(O)O
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A solution of orthoperiodic acid (21.4 g, 94 mmol) in water (80 ml) was added to a solution of (8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (Hydrocortisone, 17.0 g, 46.9 mmol) in THF (350 ml), and the reaction mixture was stirred at room temperature in an open flask for 2 hours. Then the mixture was poured onto ice. After the ice had molten, the mixture was extracted with ethyl acetate (3 times 150 ml). Evaporation of the solvent gave a white solid, which was dissolved in aqueous NaOH (1 M, 150 ml). The solution was washed with ethyl acetate, and acidified with conc. aqueous HCl. The precipitate formed was collected by filtration, and dried on the sinter overnight to afford the target compound as an off-white powder (15.51 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](B1OC(C)(C)C(C)(C)O1)=[CH:8][CH:7]=[CH:6]2.Cl[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:23]1[CH:24]=[C:25]([CH2:29][N:30]3[CH:34]=[CH:33][N:32]=[C:31]3[CH3:35])[N:26]=[N:27][CH:28]=1)=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc2c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: COc1ccc2c(-c3cnnc(Cn4ccnc4C)c3)cccc2c1

Procedure:
The title compound, MS: m/e=331.4 (M+H+), was prepared from 2-(6-methoxy-naphthalen-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([CH3:13])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.Cl.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[NH:24]N.Cl>C(O)C>[CH3:12][O:11][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][C:9]=1[CH3:13])[C:6]1[NH:24][C:18]3[C:17]([CH3:16])=[CH:22][C:21]([CH3:23])=[CH:20][C:19]=3[C:5]=1[CH2:4]2
Reactant: COc1c(C)cc2c(c1C)CCC2=O
Reactant: Cc1ccc(NN)c(C)c1
Agent: Cl
Solvent: CCO
Product: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2c(C)cc(C)cc12
Reaction time: 2 h

Procedure:
4,6-Dimethyl-5-methoxy-1-indanone (2.2 g, 11.6 mmol) and 2,4-dimethylphenylhydrazine hydrochloride (2.00 g, 1 eq) were heated to reflux in ethanol (15 cm3) containing conc. HCl (1 cm3). After 2 hours, the precipitate was filtered and washed with ammonium hydroxide solution. All the collected material was extracted with ethyl acetate with the aid of salting out. The solvent was dried, and evaporated in vacuo and the product purified by column chromatography, eluting with 5% EtOAc/60°-80° petrol. The indole was recrystallised from dichloromethane/60°-80° petrol as pale beige needles. M.p. 210° C. 1H NMR (CDCl3)δ: 8.03 (1H, br), 7.25 (1H, s), 7.15 (1H, s), 6.81 (1H, s), 3.76 (3H, s), 3.53 (2H, s), 2.49 (3H, s), 2.43 (3H, s), 2.37 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[C:7](=[O:21])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:9][CH:10]=1.C(O)(=O)C>CO.[Zn]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[C:7](=[O:21])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:9][CH:10]=1
Reactant: COC(=O)CCC1=CCN(Cc2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCC1=CCN(Cc2ccc(N)cc2)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.7 %

Procedure:
90 mg of 3-[1-(4-nitro-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (0.3 mM) was dissolved in methanol solution at room temperature. And then 290 mg of Zn (4.44 mM) and 0.02 ml of acetic acid (0.3 mM) were added thereto and the mixture was stirred for 48 hrs at room temperature. The resulting compound was purified by Silica gel column chromatography with ethylacetate as an eluant to give 20 mg of 3-[1-(4-amino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (h) (yield: 25%).