Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17](=[O:22])[CH2:18][S:19]([CH3:21])=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])[OH:32].[Na+]>CS(C)=O>[CH2:1]([N:8]([C@@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17](=[O:22])[CH:18]([OH:32])[S:19][CH3:21])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CS(=O)CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CSC(O)C(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
309.6 mg (0.763 mmol) of (3S)-3-(N,N-dibenzyl)amino-1-methylsulfinyl-2-oxo-4-phenylbutane was dissolved in 6 ml of dimethylsulfoxide, and 1.5 ml of 2 N hydrochloric acid was added thereto and stirred at room temperature for 16 hours. While being cooled in an ice bath, this was neutralized with 5 ml of a saturated aqueous solution of sodium hydrogen carbonate, and then subjected to phase separation with 20 ml of ethyl acetate and 10 ml of water. The resulting aqueous layer was extracted twice with 10 ml of ethyl acetate. The organic layers were combined, then washed with 20 ml of water and 20 ml of a saturated saline solution in that order, and thereafter dried with anhydrous sodium sulfate. This was filtered and concentrated to obtain 371.5 mg of a crude product of the above-entitled compound.
Reaction SMILES: C([O:4][C@H:5]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C:11]=3[C:12](=[O:39])[CH2:13][C@@H:14]2[C@H:15]([CH3:29])[CH2:16][CH2:17][CH2:18][C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O>CO>[OH:4][C@H:5]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C:11]=3[C:12](=[O:39])[CH2:13][C@@H:14]2[C@H:15]([CH3:29])[CH2:16][CH2:17][CH2:18][C:19]([F:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:22])([F:23])[F:21])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCCC(F)(C(F)(F)F)C(F)(F)F)[C@@]4(C)CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](CCCC(F)(C(F)(F)F)C(F)(F)F)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 69.5 %

Procedure:
A solution of 3β-acetoxy-25,26,26,26,27,27,27-heptafluoro-5α-cholest-8(14)-en-15-one (59 mg) in methanol (4 ml) was stirred with potassium carbonate (30 mg) for 5 h at room temperature. Ethyl acetate (10 ml) and water (20 ml) were added and the resulting mixture was extracted twice with ethyl acetate (25 ml portions). The organic extract was washed with water (10 ml), dried over anhydrous sodium sulfate, and evaporated to dryness. The resulting residue (51 mg) was subjected to chromatography on a silica gel column (3.5 cm×0.8 cm). Using 5% ethyl acetate in hexane (100 ml) and 10% ethyl acetate in hexane (250 ml) as the eluting solvents, fractions 50 ml in volume were collected. The contents of fractions 4-7 were pooled to give, after evaporation of the solvent, 49 mg of material which was then recrystallized from hexane to give 3β-hydroxy-25,26,26,26,27,27,27-heptafluoro-5α-cholest-8(14)-en- 15-one (38 mg; 69% yield); MP 177°-179° C. HPLC analyses at 259 nm and 210 nm on a Spherisorb ODS-II column (solvent, 7% methanol in water) showed a single component (>99.8% purity) with a retention time of 6.92 min. GC-MS analysis of the 3β-trimethylsilyl derivative showed a single component. The structure was confirmed by I.R., N.M.R., and M.S. analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=3)[C:9](=[O:19])[NH:8]2)=[CH:4][CH:3]=1.Cl.Cl[Sn]Cl.C(=O)(O)[O-].[Na+]>>[NH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=1)[NH:8][C:9]2=[O:19]
Reactant: O=c1[nH]n(Cc2ccc(Cl)cc2)c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Product: Nc1ccc2c(c1)c(=O)[nH]n2Cc1ccc(Cl)cc1
Temperature: 85 °C
Yield: 76.4 %

Procedure:
To 1-(4-chloro-benzyl)-5-nitro-1,2-dihydro-indazol-3-one (0.45 g) was added HCl (37% aq.) solution (5 mL) followed by SnCl2.dihydrate (1.9 g). The mixture was heated to 85° C. for one hour. The reaction was then neutralized with sodium bicarbonate solution, filtered, and the filtrate extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo. Flash column chromatography of the residue over silica gel eluting with methylene chloride/methanol afforded the desired 5-amino-1-(4-chloro-benzyl)-1,2-dihydro-indazol-3-one (0.31 g) as a dark brown solid. MS (ESI+): 274.4 [M+H]+).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[F:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18](B(O)O)=[C:17]([O:27][CH3:28])[CH:16]=1>>[F:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=2)=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: O=Cc1cc(C(F)(F)F)ccc1I
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O

Procedure:
Following the procedure described in EXAMPLE 81, 200 mg of 2-iodo-5-(trifluoromethyl)benzaldehyde (EXAMPLE 80, Step A) and 170 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78) gave the title compound. Mass spectrum (ESI) 341.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([NH:26][C:27]1[CH:39]=[C:38]([CH:40]=[CH2:41])[CH:37]=[CH:36][C:28]=1[C:29]([O:31]C(C)(C)C)=[O:30])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:18]([NH:26][C:27]1[CH:39]=[C:38]([CH2:40][CH2:41][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH:37]=[CH:36][C:28]=1[C:29]([OH:31])=[O:30])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(CCc2ccc(C(F)(F)F)cc2)ccc1C(=O)O)c1ccccc1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
0,087 mL of 4-bromobenzotrifluoride, 0.20 g of cesium carbonate, 30 mg of tetrabutylammonium bromide and 49 mg of polymer supported di(acetato)dicyclohexylphosphino palladium(II) were added to 2.0 mL of toluene solution containing 100 mg of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred at 110° C. for 48 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated, and the solvent was evaporated under reduced pressure after washed with 10% citric acid aqueous solution. 2.4 mL of tetrahydrofuran, 0.6 mL of water, 0.42 g of sodium formate, 0.44 mL of acetic acid and 50 mg of 3.9% palladium-carbon (ethylenediamine complex) were added to the obtained residue and stirred at 50° C. for 12 hours. The reaction mixture was cooled to room temperature and ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and the solvent was evaporated under reduced pressure. 10 mL of trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 21 mg of 2-(benzamido)-4-(2-(4-(trifluoromethyl)phenyl)ethyl)benzoic acid as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2([CH3:17])[CH3:16])#[CH:2].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([OH:13])[CH:12]=2)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]3([CH3:17])[CH3:16])=[CH:26][CH:27]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.035 g, 0.15 mmol), 4-iodo phenyl acetic acid methyl ester (0.060 g, 0.23 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh), and preparative normal phase HPLC using 10% ethyl acetate in hexane as the mobile phase, the title compound was obtained (0.015 g, 25%).
Reaction SMILES: [NH4+].[Cl-].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](F)([F:14])[C:9](F)([F:16])[CH:8]=[CH:7]2.C1COCC1>[NH4+].[OH-].[Zn]>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([F:14])=[C:9]([F:16])[CH:8]=[CH:7]2
Reactant: FC1(F)C=Cc2cc(Cl)ccc2C1(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Fc1ccc2cc(Cl)ccc2c1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 92.3 %

Procedure:
A cold solution of 2.3 g of NH4Cl in 10 ml of NH4OH was added to a stirred mixture of 2.00 g (8.45 mmol) of 6-chloro-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene, 5 ml of THF, and 0.84 g (13 mmol) of zinc that was cooled in an ice bath. The mixture was allowed to warm slowly to room temperature. After 22 h, 0.31 g (4.8 mmol) of additional zinc and 3 ml of NH4OH were added. After 24 h reaction time, the zinc was removed by filtration. The phases were separated, and the aqueous layer was extracted three times with hexanes. The combined organic phase was washed twice with brine, dried over MgSO4 and decolorized with activated carbon. The MgSO4 and carbon were filtered off, and the solvent was removed under vacuum. A colorless solid (1.6 g, 7.8 mmol, 92% yield) remained.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]1[CH2:13][CH2:12][NH:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[C:23]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>CN(C=O)C.CC(=O)OCC>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH:10]1[CH2:13][CH2:12][N:11]1[S:29]([C:24]1[C:23]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:31])=[O:30])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCN1S(=O)(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.3 %

Procedure:
To a cold (5° C.) solution of 2-(N-Boc-aminomethyl) azetidine (200 mg), DIEA (0.375 mL) in dry DMF (2 mL), was added portionwise biphenyl-2-sulfonyl chloride (272 mg). The reaction mixture was stirred at RT for 20 h. The reaction mixture was diluted with EA, washed with water. The organic extract was dried (MgSO4), filtered and concentrated to yield the crude product as light brown oil (295 mg, 68%) which was used for the next step without further purification.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][NH2+:19][CH2:18]3)=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=3[C:5]=2[CH:4]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:56]([CH2:58][C:59](O)=[O:60])#[N:57]>CN(C=O)C>[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:59](=[O:60])[CH2:58][C:56]#[N:57])[CH2:18]3)=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=3[C:5]=2[CH:4]=1
Reactant: N#CCC(=O)O
Reactant: O=c1[nH]ccc2nc(N[C@@H]3CCC[NH2+]C3)c3ccc(F)cc3c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@@H](Nc2nc3cc[nH]c(=O)c3c3cc(F)ccc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R)-3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-6-yl)amino]piperidinium chloride (40 mg, 0.09 mmol) in DMF (2 mL) were added triethylamine (0.13 mL, 0.94 mmol), HATU (0-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate) (36 mg, 0.094 mmol), and cyanoacetic acid (40 mg, 0.47 mmol). The solution was stirred at room temperature overnight. The crude solution was filtered and purified by reverse phase HPLC. LRMS (ESI) calc'd for (C20H19FN5O2) [M+H]+, 380.2; found 380.1.
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]([C:12]3[C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:25][NH2:26]>CCO>[N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]3[C:12]4[N:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18](=[O:19])[NH:25][N:26]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1cccnc1C(=O)c1ccc(-n2ccnc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccc(-n3ccnc3)cc2)c2ncccc12

Procedure:
A suspension of 2-[4-(1H-imidazol-1-yl)benzoyl]-3-carbomethoxypyridine (0.94 g, 3.06 mmol) in 50 mL of EtOH is treated with 0.36 g (7.17 mmol) of hydrazine monohydrate. The mixture is heated to reflux for 1 day, then allowed to cool and filtered to give crude product. Crystallization from DMF gives 8-[4-(1H-imidazol-1-yl)phenyl]-5-oxo-5,6-dihydropyrido[3,2-d]-pyridazine as white crystals. M.P. 376°-378° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].Cl.[CH2:31]([NH2:34])[C:32]#[CH:33]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:14])([CH3:15])[C:9]=2[C:8]=1[C:19]([NH:34][CH2:31][C:32]#[CH:33])=[O:21])=[O:5]
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Reactant: C#CCN
Agent: Cl
Product: C#CCNC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 45A and commercially available propargylamine hydrochloride using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.44 (s. 6H), 1.48 (s, 6H), 3.06-3.08 (m, 1H), 3.90-3.93 (m, 2H), 7.65-7.81 (m, 3H), 8.55 (t, J=5.6 Hz, 1H), 11.58 (br s, 1H). MS (ESI+) m/z 469 (M+H)+. Anal. calcd. for C22H20F4N2O3S: C, 56.40; H, 4.30; N, 5.98. Found: C, 56.36; H, 4.27; N, 5.94.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH2:10][S:11][CH2:12][CH2:13][NH2:14])[CH3:5].[OH-].[Na+].[N+](N[C:24]1[NH:29][C:28](=[O:30])[C:27]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:26][N:25]=1)([O-])=O>O.C(O)C>[CH3:5][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH2:10][S:11][CH2:12][CH2:13][NH:14][C:24]1[NH:29][C:28](=[O:30])[C:27]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:26][N:25]=1)[CH3:3]
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Reactant: CN(C)Cc1cccc(CSCCN)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1cccc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)c1

Procedure:
2-[3-(Dimethylaminomethyl)benzylthio]ethylamine dihydrochloride (4.2 g) was dissolved in water and the solution was made alkaline with aqueous sodium hydroxide and extracted with chloroform. The chloroform extract was evaporated to give the free base. 2-Nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (3.16 g) was added to the residue and the mixture was heated under reflux in ethanol (20 ml) for 35 hours and evaporated to dryness. Water (30 ml) was added to the residue and the mixture was adjusted to pH 13 with aqueous sodium hydroxide and extracted with chloroform. The latter chloroform extracts were evaporated and the residue was recrystallised from acetonitrile to give 2-[2-(3-(dimethylaminomethyl)-benzylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone m.p. 143°-145°. Treatment with hydrogen chloride in ethanol gives the trihydrochloride salt and treatment with hydrogen bromide in ethanol gives the trihydrobromide salt.
Reaction SMILES: [CH2:1]([C:3]1([C:9](=O)[CH:10]=[CH:11][C:12]([OH:14])=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].[NH2:16][NH2:17]>C(O)C>[CH2:1]([C:3]1([C:9]2[CH:10]=[CH:11][C:12](=[O:14])[NH:16][N:17]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(C(=O)C=CC(=O)O)CCCCC1
Reactant: NN
Solvent: CCO
Product: CCC1(c2ccc(=O)[nH]n2)CCCCC1
Reaction time: 18 h

Procedure:
To 14.0 g. of 4-(1-ethylcyclohexyl)-4-oxo-2-butenoic acid was added 100 ml. of ethanol and 4 g. of hydrazine. The mixture was stirred under reflux under a 300 watt sun-lamp in a 100 ml. Pyrex flask for 18 hours. The lamp was placed 5 cm. from the flask and emitted light of wave lengths primarily between 200 and 800 mμ. The mixture was then evaporated to dryness under vacuum, and to the residue was added 1000 ml. of diethyl ether. The ether solution was washed with 500 ml. of 0.1 N hydrochloric acid, 0.1 N sodium hydroxide and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum to an oil. The oil was taken up in a little hexane and triturated to obtain a crystalline solid. The solid was recrystallized from ethyl acetate/hexane to obtain 0.15 g. of the desired product, m.p. 138°-140°. It was identified by its infrared spectrum, showing absorption bands at 1650 and 1675 cm.-1, and by its mass spectroscopy spectrum, showing its molecular ion of mass 206.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.Cl.[N:12]1([NH:21][CH2:22][CH2:23][CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C([O-])([O-])=O.[Na+].[Na+]>CN1CCCC1=O.O>[N:12]1([N:21]([CH2:22][CH2:23][CH3:24])[C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CCCNn1ccc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCN(c1ncnc2[nH]cnc12)n1ccc2ccccc21
Temperature: 120 °C
Reaction time: 6 h
Yield: 25.1 %

Procedure:
To a solution of 6-chloropurine (5.0 g, 0.032 mole) in 50 ml 1-methyl-2-pyrrolidinone, was added 1 ml ethereal-HCl; followed by a solution of N-(1H-indol-1-yl)-N-propylamine (5.2 g, 0.030 mole) in 50 ml 1-methyl-2-pyrrolidinone. After stirring at 120° C. for six hours, the mixture was cooled, poured into 500 ml water and stirred for five minutes, pH adjusted to 10 with Na2CO3 ; then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solution was evaporated to an oil, about 8 g, which was eluted on a silica gel column with ethyl acetate via high pressure liquid chromatography. The desired fractions were combined, then evaporated to yield 2.2 g (25%) of N-(1H-indol-1-yl)-N-propyl-9H-purin-6-amine, m.p. 90°-5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22](C=C)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CSC>CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19](=[O:20])[C:24]4[C:25](=[C:26]([CH:27]=[O:28])[CH:21]=[CH:22][CH:23]=4)[O:28][C:27]=3[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C=Cc1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Solvent: ClCCl
Solvent: CSC
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C=O)cccc4c3=O)cc2)CCC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A solution of {1-[4-(4-oxo-2-phenyl-8-vinyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester in MeOH (1 mL) and DCM (4 mL) was cooled with stirring to −78° C. Ozone was bubbled through the reaction mixture for 75 min with stirring, followed by air for 5 min with stirring. Dimethylsulfide (0.027 ml, 0.366 mmol) was added and the resultant mixture was allowed to warm to RT and stirred for 2 h. The solvent was removed by bubbling nitrogen through the reaction mixture. The residue was dissolved in EtOAc and washed with brine. The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a gum (81 mg, 90%). LCMS (Method G): RT=4.24 min, [M+H]+=496.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(N2CCN(c3ccc(Cl)cc3)CC2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 1-(4-chloro-phenyl)-piperazine as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[C:9](F)[CH:8]=2)[CH3:2].Cl.[OH:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1.C(N(CC)CC)C.C(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4]1[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[C:9]([C:28]1[NH:29][CH:30]=[C:26]([CH2:25][OH:24])[N:27]=1)[CH:8]=2)[CH3:2]
Reactant: OCc1c[nH]cn1
Reactant: CCOC(=O)c1nc2cc(F)c([N+](=O)[O-])cc2nc1OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1nc2cc(-c3nc(CO)c[nH]3)c([N+](=O)[O-])cc2nc1OCC
Yield: 43 %

Procedure:
To a solution of ethyl 3-ethoxy-7-fluoro-6-nitroquinoxaline-2-carboxylate (6.90 g, 22.3 mmol) in acetonitrile (70 ml) were added dropwise 4-(hydroxymethyl)imidazole hydrochloride (15.1 g, 112 mmol) and successively triethylamine (23.4 ml, 168 mmol) under shading, and the mixture was refluxed for 16 hours. After cooling, methylene chloride was added to the reaction mixture, which was washed with water. The aqueous layer was extracted with methylene chloride, which was combined with foregoing organic layer. After dried over anhydrous sodium sulfate, solvent was distilled off. The residue obtained was purified by means of silica gel column chromatography [ethyl acetate] to obtain 3.69 g of the the title compound as brown power. Yield 43%. Moreover, 2.15 g of ethyl 3-ethoxy-7-fluoro-6-nitroquinoxaline-2-carboxylate were recovered. Yield 31%.