Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:21]2[CH2:22][CH2:23][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH2:19][CH2:20]2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N2CCN(c3ccccn3)CC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 1-(2-pyridyl)-piperazine (3.5 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 48 h. The reaction mixture was cooled to room temperature and poured into water. The crude yellow solid was collected by vacuum filtration, air dried, and recrystallized from CHCl3 (0.36 g, 17%).
Reaction SMILES: [OH:1][C:2]1[C:25]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:3]=1[C:4](=[O:21])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH2:16][O:17][CH3:18])=[C:9]([O:19][CH3:20])[CH:8]=1.[H][H]>[Pd].C(OCC)(=O)C>[OH:1][C:2]1[C:25]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:3]=1[C:4](=[O:21])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH2:16][O:17][CH3:18])=[C:9]([O:19][CH3:20])[CH:8]=1
Reactant: COCOc1c(OC)cc(C=CC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2O)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1c(OC)cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1OC
Reaction time: 8 h
Yield: 92.1 %

Procedure:
An ethyl acetate solution of 2.8 g of the so-obtained 2'-hydroxy-3,5,4',6'-tetramethoxy-4-methoxymethoxy-3'-(3-methyl-2-butenyl)chalcone was added to 20 ml of an ethyl acetate solution of 0.4 g of palladium/carbon, in which hydrogen had been adsorbed in advance, and hydrogen was further adsorbed with strong stirring. Then, the mixture was stirred overnight, the palladium/carbon was removed by using Celite, and the residue was dissolved in ether and crystallized from hexane to obtain 2.6 g (yield=94%) of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1-propanone in the form of a white solid.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC>ClCCl>[Cl:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: ClCCCNCCc1ccccc1
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)N(CCCCl)CCc1ccccc1
Reaction time: 0.03 h

Procedure:
To a solution of valeryl chloride (342 mg, 338 μl, 2.83 mmol) in dichloromethane (6 ml) and cooled to 0° C. is added a solution of (3-chloro-propyl)-phenethyl-amine (Starting material Q-01e, 560 mg, 2.83 mmol). The colourless solution turns yellow and after 2 min, a solid crystallizes out. Upon dropwise addition of Et3N (315 mg, 409 μl, 2.83 mmol) the solution turns colourless again and the solid dissolves instantaneously. The mixture is allowed to stir for 4 h at which time yet again a solid had crystallized out. Saturated aqueous NH4Cl solution is added and the organic phase is washed once with some saturated aqueous NaHCO3 solution and dried over Na2SO4. The solvent is removed in vacuo and the residue is dried under high vacuum, yielding the title compound as an orange oil: tR=2.48 min (LC-2), ESI-MS (pos.): m/z 282.07 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 0.86-0.97 (m, 3H, CH3), 1.23-1.44 (m, 4H, CH2CH3), 1.55 (quint., 1H, CH2CH2CH3), 1.65 (quint., 1H, CH2CH2CH3), 1.95 (quint., 2H, CH2CH2N), 2.03-2.19 (m, 2H, CH2C═O), 2.90 (t, 2H, CH2Ph), 3.35-3.59 (m, 6H), 7.15-7.34 (m, 2Harom).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.C1(N=C=NC2CCCCC2)CCCCC1.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)C(C)C.[CH:61]1[N:65]([CH2:66][O:67][CH2:68][CH2:69]O)[C:64]2[N:71]=[C:72]([NH2:76])[N:73]=[C:74]([OH:75])[C:63]=2[N:62]=1>CN(C)C=O>[CH3:5][CH:3]([C@H:2]([NH2:1])[C:6]([O:8][CH2:69][CH2:68][O:67][CH2:66][N:65]1[C:64]2[NH:71][C:72]([NH2:76])=[N:73][C:74](=[O:75])[C:63]=2[N:62]=[CH:61]1)=[O:7])[CH3:4]
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of Boc-Val and dicyclohexyl carbodiimide (DCC) in dimethylformamide (DMF) in a ratio of 1:2 DCC/Boc-Val was stirred for 1 hr at 0° C. under nitrogen atmosphere. A solution of acyclovir (1) and 4-N,N (dimethylamino)pyridine (DMAP) was added to the reaction mixture, stirred for 18 hrs and then filtered. The solvent of the filtrate was partially removed in vacuo and the impure solution was added dropwise to cold diethyl ether. The resulting precipitate (2) was filtered and dried, followed by acidolytic removal (treating Boc-Val-ACV with trifluoroacetic acid (TFA) for 30 min at 0° C.) of the Boc protecting group to yield Val-ACV (3). Compound (3) was neutralized by triethylamine (TEA) and treated with the amino acid anhydride of Boc-Val for about 5 hrs. The solvent was removed from the reaction mixture in vacuo and the reaction mixture was added dropwise to the cold diethyl ether. The resulting precipitate (4) was filtered, dried and the Boc group was deprotected (acidolytic removal) to yield the desired dipeptide ester of acyclovir Val-Val-ACV (5).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[NH:50][CH:49]=1)[C:39]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:67]=[C:68]1[CH:72]=[CH:71][C:70](=[O:73])[N:69]1[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][C:79]([NH:81][NH2:82])=[O:80]>>[O:73]=[C:70]1[CH:71]=[CH:72][C:68](=[O:67])[N:69]1[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][C:79]([NH:81][NH:82][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[NH:50][CH:49]=1)[C:39]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:80]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157 from 10 mg (11 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:35][N:36]([CH3:38])[NH2:37].CCN(C(C)C)C(C)C>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:35][N:36]([CH3:38])[NH:37][C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:9]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CN(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)NN(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To the acid 3-(methoxycarbonyl)benzoic acid (253 mg, 1.40 mmol) in CH2Cl2 at rt, EDCI (312 mg, 1.64 mmol) and HOBT (189 mg, 1.40 mmol) were added and stirred at rt for 20 min. To that mixture, N,N-dimethyl hydrazine was added followed by DIPEA (404 mg, 14.0 mmol). Reaction mixture was stirred at rt for 16 h. Then reaction mixture was diluted with chloroform, washed with water, brine and dried. Crude residue was purified by column chromatography to yield 60% of methyl 3-(2,2-dimethylhydrazinecarbonyl)benzoate.
Reaction SMILES: [C:1]([C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1)(=O)[NH2:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[C:1]([C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(N)=O)C1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C#N)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-carbamoyl-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (437 mg) and triethylamine (0.344 ml) in THF (5.6 mL) was added trifluoroacetic anhydride (0.171 mL), and the mixture was stirred at 0° C. for 2 hr. Then, the mixture was stirred at room temperature for 1 hr, distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (205 mg).
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:14])(=[NH:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[S:24])=[CH:18][CH:17]=1>C1C=CC=CC=1.CCCCC>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:13][C:7](=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[S:24])=[CH:18][CH:17]=1
Reactant: CCCCCC(=N)N
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: CCCCC
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCCC(=N)NC(=S)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 42 but using 3.4 g. sodium in 300 ml. dry acetone, 22.5 g. hexanamidine hydrochloride, and 25.9 g. 4-chlorophenyl isothiocyanate in 150 ml. dry acetone there was obtained 1-(4-chlorophenyl)-3-(hexanimidoyl)-2-thiourea, m.p. 100°-102°C. (from benzene-n-pentane); hydrochloride (21 g.), m.p. 175°C. (from acetonitrile).
Reaction SMILES: [Br:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:16][Mg]Br.C(OCC)(=O)C.Cl>O1CCCC1>[Br:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](=[O:5])[CH3:16]
Reactant: C[Mg]Br
Reactant: COc1cccc(C(=O)N(C)OC)c1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(C(C)=O)c1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, 2-bromo-N,3-dimethoxy-N-methylbenzamide (16.8 g, 61.5 mmol) which had been obtained in Reference example 1(1a) was dissolved in tetrahydrofuran (300 mL), and added dropwise with a 1.0 M solution of methyl magnesium bromide in tetrahydrofuran (123 mL, 123 mmol) at 0° C. Upon the completion of the dropwise addition, the temperature of the reaction solution was raised to room temperature and stirred for 15 hours. The reaction solution was added with ethyl acetate and 1 N aqueous hydrochloric acid solution for fractionation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0 to 60:40, V/V) to give the title compound as a colorless oily substance (12.7 g, yield 90%).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][OH:25])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.S(=O)(=O)(O)O>CN(C)C=O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:25][C:27]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:34])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CO
Reactant: O=C1CCCC(=O)O1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CCCC(=O)O
Yield: 56.2 %

Procedure:
In 10 ml of dimethylformamide is dissolved 0.5 g of 16β-ethyl-17β-glycoloyloxy-4-estren-3-one, and 0.2 g of glutaric anhydride and then 0.3 ml of triethylamine are added to the above solution. The mixture is allowed to stand at room temperature (15°-25° C.) for 3 hours and poured into 20 ml of 10% aqueous sulfuric acid, followed by extraction with 100 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography, elution being carried out with 200 ml of ethyl acetate. The eluate is evaporated under reduced pressure to remove the solvent, giving a colorless oil, which is allowed to stand to give 0.37 g of the above-identified compound as a solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:15])[N:31]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17](=[O:19])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]
Reactant: NCCc1ccccc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(CCc1ccccc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with phenethylamine (0.16 mL, 1.3 mmol). Purification using silica gel, eluting with 3:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 112 as a white solid (m.p. 235-240° C.).
Reaction SMILES: [I-].C([O:9][C:10](=[O:37])[CH2:11][C@@H:12]([NH:18][S:19]([C:22]1[S:23][C:24]([C:27]2[N:31]([CH3:32])[N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:25][CH:26]=1)(=[O:21])=[O:20])[CH2:13][N+:14]([CH3:17])([CH3:16])[CH3:15])C1C=CC=CC=1.[OH-:38].[Na+].C[OH:41]>>[F:34][C:33]([F:36])([F:35])[C:29]([O-:41])=[O:38].[C:10]([CH2:11][C@@H:12]([NH:18][S:19]([C:22]1[S:23][C:24]([C:27]2[N:31]([CH3:32])[N:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)=[CH:25][CH:26]=1)(=[O:21])=[O:20])[CH2:13][N+:14]([CH3:17])([CH3:16])[CH3:15])([OH:37])=[O:9]
Reactant: CO
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)C[N+](C)(C)C)s1
Reactant: [OH-]
Agent: [I-]
Agent: [Na+]
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)N[C@H](CC(=O)O)C[N+](C)(C)C)s1
Product: O=C([O-])C(F)(F)F
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of (R)-4-(benzyloxy)-N,N,N-trimethyl-2-(5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonamido)-4-oxobutan-1-aminium iodide in MeOH (1 mL) was added 1 N NaOH (1 mL). The reaction was stirred for 1 h and acidified to pH 1. The mixture was purified by preparatory HPLC to give the title compound as a white solid (12 mg, 44%). 1H NMR (400 MHz, CD3OD) δ 7.67 (d, 1H, J=3.8 Hz), 7.31 (d, 1H, J=3.9 Hz), 6.83 (s, 1H), 4.29-4.26 (m, 1H), 3.87 (s, 3H), 3.62-3.56 (m, 1H), 3.42-3.39 (m, 1H), 3.16 (s, 9H), 2.47-2.41 (m, 1H), 2.19-2.15 (m, 1H); MS ESI 455.2 [M+H]+, calcd for [C16H21F3N4O4S2+H]+ 455.10
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1COCC1.CC([O-])(C)C.[K+].C1(CS([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)(=[O:45])=[O:44])=[CH:39][N:38]=2)(=O)=O)C=CC=CC=1>O.C1(C)C=CC=CC=1>[C:9]1([C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)(=[O:44])=[O:45])=[CH:39][N:38]=3)=[CH:7][CH:6]=2)=[O:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: O=S(=O)(Cc1ccccc1)c1ccc(S(=O)(=O)Cc2ccccc2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(Oc2ccc(S(=O)(=O)Cc3ccccc3)cn2)cc1
Yield: 44 %

Procedure:
To 4.96 g of p-hydroxybenzophenone in a 25 ml THF/25 ml DMSO mixture was added 3.1 g of t-BuOK and then 9.69 g of 2.5-bis((phenylmethyl)sulfonyl)pyridine and the resulting mixture heated at 60° C. for 11/2 hrs. The reaction mixture was allowed to cool overnight, diluted with 4 volumes of water, and the golden-brown precipitate which formed removed by filtration. Recrystallization from CH2Cl2 /ethanol and then from toluene gave the product, phenyl(4-((5-((phenylmethyl)sulfonyl)-2-pyridinyl)oxy)phenyl)methanone, (44% yield), as tan prisms, m.p. 146°-147° C.
Reaction SMILES: CN([CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1)C.CI.[I-]>CO>[CH2:4]=[C:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1
Reactant: CN(C)CC1CCc2onc(-c3ccccc3)c2C1=O
Agent: [I-]
Solvent: CI
Solvent: CO
Product: C=C1CCc2onc(-c3ccccc3)c2C1=O
Yield: 82 %

Procedure:
6,7-Dihydro-5-dimethylaminomethyl-3-phenyl- 1,2-benzisoxazole- 4(5H)-one free base (3.0 g) was dissolved in 3 ml of methanol and added in one portion to 5 ml (excess) of methyl iodide. As the quaternary iodide began to separate, additional methanol was added to facilitate stirring. After stirring overnight the reaction mixture was poured into 5% sodium bicarbonate solution and extracted with ether. The organic phase was washed with 5% HCl and then dried, evaporated, and recrystallized from hexane to give 2.05 g of 6,7-dihydro-5-methylene-3-phenyl-1,2-benzisoxazol-4(5H)-one, m.p. 97°-990° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[Br:19])=[O:11].F[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1>>[Br:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[C:10]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]1[CH2:2][NH:1][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1)=[O:11]
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-bromo-5-methylphenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 470, 472 [M]+, [M+2]+.
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[O:22])[NH:12][C:11]1=[O:23])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26]>>[CH2:1]([NH:7][C:8]([N:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13](=[O:22])[N:12]([C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[C:11]1=[O:23])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)n1cc(-c2ccccc2)c(=O)[nH]c1=O
Reactant: CC(C)COC(=O)Cl
Product: CCCCCCNC(=O)n1cc(-c2ccccc2)c(=O)n(C(=O)OCC(C)C)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 39 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 24, starting from N-hexyl-2,4-dioxo-5-phenyl-pyrimidine-1-carboxamide (Example 14) (0.05 g, 0.17 mmol); 9.0 equivalents of isobutyl chloroformate were used herein. Another portion of isobutyl chloroformate (9.0 equivalents) was added after 5 hrs and the reaction stirred at room temperature for 15 hrs. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 90:10) to afford the title compound (0.043 g, 39%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J=6.8 Hz, 3H), 1.02 (d, J=6.8 Hz, 6H), 1.29-1.41 (m, 6H), 1.57-1.65 (m, 2H), 2.12 (h, J=6.7 Hz, 1H), 3.41 (td, J=7.1, 5.7 Hz, 2H), 4.27 (d, J=6.7 Hz, 2H), 7.36-7.45 (m, 3H), 7.53-7.57 (m, 3H), 8.57 (s, 1H), 8.96 (t, J=5.0 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 14.14, 18.96, 22.65, 26.63, 27.84, 29.26, 31.52, 41.65, 76.42, 116.58, 128.58, 128.78, 128.92, 131.19, 135.34, 149.45, 149.54, 149.78, 159.35. MS (ESI) m/z: 416 [M-H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>CS(C)=O.ClCCl>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([O:15][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:6][N:7]=2)[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C1CCC(c2ccc(Cl)nc2)=NN1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3ccc(=O)[nH]n3)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To 6-(6-chloro-pyridin-3-yl)-4,5-dihydro-2H-pyridazin-3-one (3 g, 14.4 mmol) in DMSO (40 mL) was added 4-hydroxy-boc-piperidine (2.9 g, 14.4 mmol), followed by 1M KtOBu (19 mL). After overnight stirring at 100° C. open to air, the reaction was cooled, diluted with dichloromethane and washed several times with water/brine, dried over sodium sulfate, and concentrated under vacuum to obtain 4.9 g crude product (92%); MS m/z 373 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[N:17]([O-])=O.[Na+].[Sn](Cl)Cl>Cl>[Br:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:17][NH:1]2)=[CH:4][CH:5]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Brc1ccc2c(-c3ccccc3)n[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
To a stirred mixture of (2-amino-4-bromophenyl)(phenyl)methanone (1.0 g, 3.6 mmol) in hydrochloric acid (6N aqueous solution, 5 mL) was added sodium nitrite (0.5 g, 7.2 mmol) over 3 min at 0° C. The mixture was stirred at 0° C. for 30 min before a solution of tin(II) chloride (2.7 g, 14.4 mmol in 5 mL concentrated hydrochloric acid) was added at 0° C. over 5 min. After stirring at 0° C. for 10 min and rt for 1 hr, the reaction mixture was filtered. The solid was washed with water (10 mL), 4N aqueous sodium hydroxide solution, and water (10 mL). The solid was dissolved in dichloromethane (20 mL), washed with brine (10 mL), dried (Na2SO4), and concentrated. Silica gel flash chromatography gave 6-bromo-3-phenyl-1H-indazole (0.42 g, 1.5 mmol, 42% yield).