Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([O:22]CC)=[O:21])=[CH:9]1.O.[OH-].[Li+]>CO.O.C(#N)C>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([OH:22])=[O:21])=[CH:9]1
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cc(C)cnc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Cc1cnc2c(=O)c(C(=O)O)cn(Cc3ccccc3-c3ccccc3)c2c1
Reaction time: 15 h
Yield: 20.2 %

Procedure:
To a solution of ethyl 1-(biphenyl-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (20) (80 mg, 0.2 mmol) in methanol (10 mL) was added the solid lithium hydroxide monohydrate (168 mg, 4.02 mmol) at room temperature under nitrogen atmosphere. It gave a clear solution within 30 minutes and this light yellow solution was stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, it was diluted with water and the methanol was removed under vacuum. The basic aqueous layer was diluted with water and then extracted with ethyl acetate (50 mL) to remove any neutral impurities. Then, the basic aqueous layer was neutralized with 1.0N HCl. Then, the acid was extracted with ethyl acetate (2×30 mL) and the combined extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the yellow solids which were dissolved in acetonitrile and water. The mixture was frozen and then lyophilized under high vacuum to obtain 1-(biphenyl-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (21) (15 mg, 20% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C=O.F[C:11](F)(F)C(O)=O.[CH2:17]=[C:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][O:21][C:20]2[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:19]1=2>ClCC(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:11][CH:17]=[C:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]3[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:19]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: C=C1c2ccccc2COc2ccc(C(=O)OC)cc21
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: ClCC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(=CCN1CCN(C)CC1)c1ccccc1CO2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-Methylpiperazine, 30 ml, and 74 g of paraformaldehyde were dissolved in 2 l of tetrachloroethane and 100 ml of trifluoroacetic acid was dropwise added to the solution. After stirring at 60° C. for 2 hours, a solution of 36 g of methyl 11-methylene-6,11-dihydrodibenz[b,e]-oxepin-2-carboxylate in 600 ml of tetrachloroethane was dropwise added to the reaction mixture followed by stirring at 90° C. for further 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and 4 N hydrochloric acid aqueous solution was added to the residue to adjust pH to 1. Then, the mixture was washed with diethyl ether. Thereafter, 10 N sodium hydroxide aqueous solution was added to adjust pH to 13. Extraction was performed with 3 l of methylene chloride. After washing with saturated sodium chloride aqueous solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate:triethylamine=5:5:1) to give 44 g of methyl 11-[2-(4-methyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate as colorless oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30](Cl)(=[O:32])=[O:31].O>N1C=CC=CC=1>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=3)[CH2:3][CH:4]2[CH2:8]1)(=[O:31])=[O:32]
Reactant: CCOC(=O)c1cnc(N2CC3CNCC3C2)nc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(N2CC3CN(S(=O)(=O)c4ccc5ccccc5c4)CC3C2)nc1
Reaction time: 3 h
Yield: 51 %

Procedure:
To a suspension of ethyl 2-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylpyrimidine-5-carboxylate (0.271 g, 1.0 mmol) in pyridine (5 ml) was added 2-naphthalene sulfonyl chloride (0.269 g, 1.18 mmol). The mixture was stirred for 3 h, then water (25 ml) was added and the product collected by filtration. The product was washed with further water and then dried overnight under vacuum to give the title compound (0.231 g, 51%). 1H NMR (300 MHz, CDCl3) δ: 1.39 (3H, t, J=6.9 Hz), 2.92-3.07 (2H, m), 3.29 (2H, dd, J=3.9, 10.2 Hz), 3.45 (2H, dd, J=3.9, 12.3 Hz), 3.59 (2H, dd, J=7.2, 10.2 Hz), 4.35 (2H, q, J=7.2 Hz), 7.58-7.75 (2H, m), 7.82 (1H, dd, J=1.8, 8.7 Hz), 7.90-8.05 (2H, m), 8.40 (1H, s), 8.77 (2H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:9][CH:10]=1)[OH:5].[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[O:9][CH:10]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[N:7]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCC(O)c1coc(-c2ccc(F)cc2)n1
Product: O=C(NCCC(O)c1coc(-c2ccc(F)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 19 %

Procedure:
This compound was synthesized from 3-amino-1-(2-(4-fluorophenyl)oxazol-4-yl)propan-1-ol and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (35 mg, yield 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8.80-8.77 (t, J=5.3 Hz, 1H), 8.51 (s, 1H), 8.20-8.18 (d, J=7.6 Hz, 1H), 8.13-8.11 (d, J=7.9 Hz, 1H), 8.00 (s, 1H), 7.99-7.96 (dd, J=8.8 Hz, 5.5 Hz, 2H), 7.72-7.68 (t, J=7.8 Hz, 1H), 7.37-7.32 (t, J=8.8 Hz, 2H), 5.44-5.43 (d, J=5.2 Hz, 1H), 4.69-4.65 (m, 1H), 3.47-3.42 (m, 2H), 2.17-2.08 (m, 1H), 1.99-1.90 (m, 1H). MS (ESI) m/z: Calculated for C22H16F4N4O4: 476.11. found: 477.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:27])=[O:26]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:37]2[CH2:38][CH2:39][CH:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:25]([CH3:24])(=[O:27])=[O:26])[CH2:35][CH2:36]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)c1ccccc1C1CCNCC1
Reactant: CN1C(=O)c2ccccc2[C@H]1[C@@H](CC=O)c1ccc(Cl)c(Cl)c1
Solvent: CO
Product: CN1C(=O)c2ccccc2[C@H]1[C@@H](CCN1CCC(c2ccccc2S(C)(=O)=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 124.8 %

Procedure:
A solution of (3S)-3-(3,4-Dichlorophenyl)-3-((1R)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.468 g) in methanol (10 mL) was treated with 4-(2-methylsulfonylphenyl)piperidine (0.3 g) as described in Example 8. The resulting material was not purified by chromatography but was transformed into the hydrochloride to afford the title compound (0.51 g); [α]D =21° (c=1.0 Ethanol); mp 190°-200° C. (dec); MS: m/z=571(M+1); NMR(CD3SOCD3): 1.99 (broad,2), 2.37 (broad,2), 3.35 (s,3), 3.60 (s,3), 4.9 (d,1, J=3.6), 6.8 (dd,1, J=8.4, 2), 7.0 (s,1), 7.3-7.98 (m,9). Analysis for C30H32Cl2N2O2S.HCl.H2O: Calculated: C, 57.55; H, 5.63; N, 4.47; Found: C, 57.32; H, 5.33; N, 4.50.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[C:12]2([CH2:17][CH:16](O)[CH2:15][CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[OH2:24]>ClCCl>[CH3:19][S:20]([O:22][CH:15]1[CH2:16][CH2:17][C:12]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:13][CH2:14]1)(=[O:24])=[O:21]
Reactant: O
Reactant: OC1CCCC2(C1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Triethylamine (2.4 mL, 17 mmol) was added to a solution of 1,4-dioxaspiro[4,5]decan-9-ol (884 mg, 5.59 mmol) in dichloromethane (22 mL) under a nitrogen atmosphere. The solution was cooled to 0° C. in an ice bath. Methanesulfonyl chloride (0.87 mL, 11.2 mmol) was added and the reaction stirred for 4 h while warming up to room temperature. Water was added and the mixture was extracted with dichloromethane (2×). The combined organic layers were washed with brine (1×), dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc/hexane) to afford 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate as a light yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 4.81-4.68 (m, 1H), 3.91-3.78 (m, 4H), 3.16 (s, 3H), 1.87 (ddd, J=4.2, 8.1, 16.6, 2H), 1.82-1.71 (m, 2H), 1.67 (ddd, J=4.3, 7.9, 12.3, 2H), 1.58 (ddd, J=4.8, 8.7, 13.3, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2].[H-].[Na+].[CH3:19][O:20][CH2:21][CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:20][CH2:21][CH2:22][N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:13]([F:16])([F:14])[F:15])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1cc2[nH]ccc2cc1C(F)(F)F
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCn1ccc2cc(C(F)(F)F)c([N+](=O)[O-])cc21
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
6-nitro-5-(trifluoromethyl)-1H-indole (50 mg, 0.22 mmol) was dissolved in DMF (2 mL) and treated with sodium hydride (35 mg, 0.87 mmol) to form a dark red opaque solution. The solution was stirred for 20 minutes and then added dropwise to a solution of 2-bromoethyl methyl ether (121 mg, 82 μL, 0.87 mmol) in 1 mL DMF. The reaction mixture was heated at 50° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 50% saturated NaHCO3 (2×10 mL) and brine. The organic layer was dried over Na2SO4, filtered and dried to obtain 1-(2-methoxyethyl)-6-nitro-5-(trifluoromethyl)-1H-indole, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=1>>[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:11]([C@@H:12]([C:13](=[O:14])[NH2:15])[C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:28][CH:27]=1
Reactant: NC(=O)[C@H](NS(=O)(=O)c1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(CO)cc1
Product: COC(=O)c1ccc(CN([C@@H](C(N)=O)c2ccc(F)cc2)S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared employing the procedure in Example 2 using (R)-2-(4-chloro-benzenesulfonylamino)-2-(4-fluoro-phenyl)-acetamide and methyl-4-hydroxymethylbenzoate to afford the desired product. Diagnostic 13CNMR (100 MHz, CDCl3) 49.9, 52.3, 63.4, 116.0, 116.2, 127.9, 129.1, 129.5, 129.6, 132.0, 132.1, 139.8, 142.3. MS 491.2 m/z (M+1).
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][CH:18]=[CH:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>>[CH:1]([C@H:14]1[CH2:19][C@H:18]2[C@H:17]([O:28]2)[CH2:16][O:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:1]([C@H:14]1[CH2:19][C@@H:18]2[C@@H:17]([O:28]2)[CH2:16][O:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Product: c1ccc(C(c2ccccc2)[C@H]2C[C@H]3O[C@H]3CO2)cc1
Yield: 52 %
Yield: 41 %

Procedure:
(2R)-2-benzhydryl-3,6-dihydro-2H-pyran 27b (0.2 g, 0.79 mmol) was reacted with mCPBA (0.27 g, 70%, 1.58 mmol) (Procedure D) to yield the corresponding (1R, 4R, 6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28c 0.11 g (52%, [α]D=(+)60.4, c=1, MeOH)) and (1S, 4R, 6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28d 0.086 g (41%, [α]D=(+)78, c=1, MeOH). The 1HNMR and 13CNMR were identical for both (1S, 4S, 6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane and (1R, 4S, 6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane.
Reaction SMILES: [N:1]([CH2:4][C:5]([OH:34])([CH3:33])[CH2:6][O:7][CH2:8][C:9]1[NH:10][C:11]([CH3:32])=[C:12]([C:28]([O:30][CH3:31])=[O:29])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[Cl:27])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+]=[N-].C(S)CCS.C(N(CC)CC)C.C[OH:48]>>[C:8]([OH:7])(=[O:48])/[CH:9]=[CH:14]/[C:15]([OH:17])=[O:16].[NH2:1][CH2:4][C:5]([OH:34])([CH3:33])[CH2:6][O:7][CH2:8][C:9]1[NH:10][C:11]([CH3:32])=[C:12]([C:28]([O:30][CH3:31])=[O:29])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[Cl:27])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(COCC(C)(O)CN=[N+]=[N-])NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CO
Agent: SCCCS
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCC(C)(O)CN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Product: O=C(O)/C=C/C(=O)O

Procedure:
A solution of 1-azido-3-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-hydroxy-2-methylpropane (1.54 g), propane-1,3-dithiol (1.2 ml) and triethylamine (1.7 ml) in methanol (30 ml) was stirred at room temperature for eight days, filtered and evaporated. The residue was partitioned between ethyl acetate and water and the layers separated. The organic layer was washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on SiO2 (15 g) using dichloromethane plus 0-40% methanol as the eluant. Appropriate fractions were combined and evaporated. The residue was taken up in ethyl acetate and the solution was treated with excess fumaric acid. The resulting solid was collected, washed with ethyl acetate and dried to give the title compound (0.49 g), m.p. 110°-115° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.O>[N:34]([CH2:13][C:10]1[CH:11]=[CH:12][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[N:9]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccn(-c2ccc(I)cc2)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccn(-c2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
A mixture of 1-(4-iodophenyl)-3-methyl-1H-pyrazole (0.98 g, 3.45 mmol), NBS (0.80 g, 4.49 mmol) and AIBN (0.17 g, 1.03 mmol) in CCl4 (15 mL) was heated at reflux for 5 hrs. After being cooled to room temperature, it was filtered. The filtrate was concentrated in vacuo. The residue was dissolved in DMF (8 mL), NaN3 (0.400 g, 6.15 mmol) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with hexane, then with 4-6% EtOAc in hexane to give 3-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (0.10 g).
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2CCN(C)C.[CH2:30]([N:32]([CH:36](C)C)[CH:33](C)C)[CH3:31]>CN(C)C=O>[CH3:33][N:32]([CH3:36])[CH2:30][CH2:31][N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:13])=[O:12])[CH:21]=[CH:22]1
Reactant: CN(C)CCc1c[nH]c2c(N)cccc12
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCn1ccc2cccc(NS(=O)(=O)c3cccc4ccccc34)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.8 %

Procedure:
149.5 mg (0.66 mMol) of naphtalene-1-sulfonyl chloride were added to a solution of 122 mg (0.6 mMol) of 7-amino-3-(2-dimethylaminoethyl)-1H-indole in 2 ml of dimethylformamide and 116 mg of N-ethyldiisopropylamine. The reaction mixture was stirred at the room temperature for 20 hours. Then it was evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase was repeatedly washed with water and saturated solution of sodium bicarbonate, it was separated and dried with anhydrous sodium sulfate. The organic solution was evaporated to dryness and the resulting solid was purified by chromatography, obtaining 120 mg (51%) of N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-naphtalene-1-sulfonamide as a solid cream.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH:12]=[C:13]2[C:18](=[O:19])OC(C)(C)OC2=O)[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(C2C=CC=CC=2)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[N:11][CH:12]=[CH:13][C:18]=2[OH:19])[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(NC=C2C(=O)OC(C)(C)OC2=O)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)Nc1ccc2c(O)ccnc2n1
Temperature: 250 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
5-((6-Acetamido-2-pyridylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.3 g, 4.3 mmol) was added in portions to a stirred mixture of biphenyl (13.3 ml) and phenyl ether (36.8 ml) heated at 250° C. and the resulting mixture was stirred for 1 hour at 250° C. The mixture was allowed to cool and was diluted with hexane. The precipitate was collected by filtration and dried to give 2-acetamido-5-hydroxy-1,8-naphthyridine (720 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>C(#N)C>[CH3:1][O:2][C:3]([C@H:4]([NH:5][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:10]
Reactant: O=S1(=O)CCCO1
Reactant: COC(=O)[C@H](N)CC(C)C
Solvent: CC#N
Product: COC(=O)[C@@H](CC(C)C)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To a solution of D-Leucine methylester (1.58 g, 10.9 mmol) in acetonitrile (35 mL) was added 1,3-propanesultone (1.21 g, 9.9 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, recrystallized from EtOH and dried in vacuo, affording the title compound (1.59 g, 60%). 1H NMR (D2O, 500 MHz) δ ppm 3.98 (m, 1H), 3.70 (s, 3H), 3.11 (m, 2H), 2.85 (m, 2H), 2.00 (m, 2H), 1.72 (m, 1H), 1.60 (m, 2H), 0.81 (m, 6H). 13C (D2O, 125 MHz) δ ppm 170.51, 58.78, 53.69, 47.97, 45.36, 38.09, 24.34, 22.07, 21.51, 20.82. [α]D=+13.1° (c=0.0019 in water), ES-MS 266 (M−1).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][NH2:32])[CH:26]=1.ClC1C=C(N2C(C3C=C(OC(F)(F)F)C=C(F)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:31]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)[N:32]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Reactant: NNc1cccnc1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1

Procedure:
1.10 g (2.40 mmol) of the compound from example 3A is reacted with 525 mg (3.61 mmol) 3-pyridylhydrazine hydrochloride in a manner analogous to the synthesis of the compound from example 8A. Following hydrolysis, 557 mg (54% of theoretical yield) of the title compound is produced.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].Cl>C(Cl)Cl>[S:16]([O-:18])(=[O:8])(=[O:17])[CH3:15].[O:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: OCC1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (13.7 mL, 98 mmol) was added to a solution of tetrahydro-3-furanmethanol (10.0 g, 98 mmol) in methylene chloride (100 mL) at 0° C. followed by addition of methanesulfonyl chloride (12.3 g, 108 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to ambient temperature and stirred overnight. Aqueous hydrochloric acid (1N, 100 mL) was added and the two layers were separated. The organic layer was washed with 1N aqueous hydrochloric acid (100 mL×2), saturated aqueous sodium bicarbonate (100 mL×3), and brine (50 mL×1), respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford crude mesylate of tetrahydro-3-furanmethanol.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].C(N(CC)CC)C.[Br:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1COCC1>[CH3:3][CH:2]([NH:1][S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][Br:16])=[CH:23][CH:22]=1)(=[O:25])=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(C)N
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCC(C)NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of 2-aminoheptane (1.67 ml, 0.011 mol) and triethylamine (1.55 ml, 0.011 mol) in dry THF (100 ml) was added powdered 4-bromomethylbenzenesulphonyl chloride (3.0 g, 0.011 mol) in one portion. The mixture was stirred for 3 h at room temperature. The reaction mixture was treated with saturated ammonium chloride (60 ml), extracted with ethyl acetate (3×80 ml), the organics combined and washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulphate, filtered and evaporated. The resulting oil was purified by chromatography (silica: 1:2 hexane:ethyl acetate) to give N-1-methylhexyl 4-bromomethylbenzenesulphonamide (1.45 g, 39%) as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9](C(=O)C(F)(F)F)[CH2:10]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].O.CO.C(Cl)Cl>CO>[N+:15]([C:14]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]2[CH:7]3[CH2:18][CH:11]([CH2:10][NH:9][CH2:8]3)[C:12]=2[CH:13]=1)([O-:17])=[O:16]
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])C1CNCC2C1

Procedure:
1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-triflouroethanone (3.7 g, 10.7 mmol) and Na2CO3 (2.3 g, 21.4 mmol) were combined in MeOH (50 mL)) and H2O (20 mL) then warmed to reflux for 18 hours. The reaction was cooled, concentrated, treated with H2O and extracted with CH2Cl2 (3×50 mL) then dried through a cotton plug. After concentration. the residue was chromatographed to provide brown solids. (1.9 g. 71%). (TLC 5% MeOH/CH2Cl2 (NH3) Rf0.36). 1H NMR (400 MHz, CDCl3) δ7.69 (s, 2H), 3.17 (br s, 2H), 3.11 (d, J=12.6 Hz, 2H), 2.53 (m, 1H), 2.07 (d, J=11.0 Hz, 1H). GCMS m/e 249 (M+).