Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=O)[NH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:13][N:14]=1.S(Cl)(Cl)=O.O1CCCC1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[CH2:31]([NH:38][C:10]1[N:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:13]=[N:14][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=c1[nH]c(-c2ccccn2)nnc1-c1ccc(Cl)cc1Cl
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: O
Product: Clc1ccc(-c2nnc(-c3ccccn3)nc2NCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A mixture of 6-(2,4-dichlorophenyl)-3-(2-pyridyl)-1,2,4-triazin-5-one (5.00 g, 15.7 mmol) and thionyl chloride (50 ml) was heated under reflux for two hours. The mixture was allowed to cool to room temperature, and the solvent was removed by distillation under reduced pressure. To the residue were added tetrahydrofuran (50 ml), benzylamine (4.20 g, 39.2 mmol, 2.5 eq.), and the mixture was heated under reflux for two hours. The mixture was allowed to cool to room temperature, and water (150 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride (600 ml), and washed with a 5% aqueous potassium hydrogen carbonate solution (150 ml), and further washed with a 5% brine (150 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by flash silica gel column chromatography (methylene chloride) to give the title compound as pale yellow crystals (3.64 g, 57%).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].Cl.[OH-].[Na+]>C(O)(=O)C.CO>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:3]([OH:4])[CH3:2]
Reactant: CC(=O)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CC(O)c1ccccn1
Reaction time: 4 h

Procedure:
To a solution of 110 g. of sodium borohylride in 1250 ml. of methanol at 0° C. is added 350 g. of 2-pyridyl methyl ketone in 300 ml. of methanol with stirring. After stirring for 4 hours at 0°-5° C., glacial acetic acid is cautiously added dropwise, followed by ice and concentrated hydrochloric acid. The acidic solution is made basic with aqueous sodium hydroxide and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, concentrated and distilled to give 1-(2-pyridyl)ethanol.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:23])[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]([S:18](Cl)(=[O:20])=[O:19])=[C:10]([CH3:22])[CH:9]=1>N1C=CC=CC=1>[C:8]1([CH3:23])[C:13]([S:14]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:12][C:11]([S:18]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:20])=[O:19])=[C:10]([CH3:22])[CH:9]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1S(=O)(=O)Cl
Reactant: OC1CCCCC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)OC2CCCCC2)cc1S(=O)(=O)OC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a one liter, four-necked, round bottom flask, equipped with stirrer, condenser and thermometer, 100.0 parts of pyridine and 16.55 parts of cyclohexanol were mixed under a nitrogen atmosphere and chilled to 0° C. with an ice water bath. To this solution 25.0 parts of 1,3-xylene-4,6-disulfonyl dichloride were added in portions over thirty minutes. The solution was stirred for one hour at 0° C. and then allowed to stand for twenty-four hours at 15° C. The mixture was poured into one liter of ice water and subsequently extracted with 300 parts of methylene chloride. The organic layer was washed successively with cold 6N sulfuric acid (until the water layer was acidic to pH paper), dilute sodium bicarbonate (three times with 300 part-portions), and water (twice with 300 part-portions). It was then dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield the dicyclohexyl 1,3-xylene-4,6-disulfonate.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][C@H:9]([NH:13][C:14](=[O:33])[C@@H:15]([NH:26][C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][CH:18]=1)[C:10]([OH:12])=O)(C)(C)C.[ClH:35].[NH2:36][C@@H:37]([CH2:49][C:50]([NH2:52])=[O:51])[C:38]([NH:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C=O)C>[ClH:35].[CH2:30]([O:29][C:27]([NH:26][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][CH:18]=1)[C:14]([NH:13][C@H:9]([C:10](=[O:12])[NH:36][C@H:37]([C:38](=[O:39])[NH:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:49][C:50](=[O:51])[NH2:52])[CH2:8][CH2:7][C:6]([OH:5])=[O:34])=[O:33])=[O:28])[CH:31]=[CH2:32]
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O
Reactant: NC(=O)C[C@H](N)C(=O)NCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-(S)-[2-(S)-allyloxycarbonylamino-3-(4-carbamimidoyl-phenyl)-propionylamino]-pentanedioic acid 5-tert-butyl ester (48 mg, 0.1 mmol) and 2-(S)-amino-N1-phenylethyl-succinamide hydrochloride (27 mg, 0.1 mmol) in 5 ml of DMF were added at 0° C. HATU (39 mg, 0.1 mmol) and collidine (24.2 mg, 0.2 mmol). The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation the residue was purified by chromatography on Sephadex LH20 employing n-butanol/glacial acetic acid/water (17/1/2) as eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water and the aqueous solution was freeze-dried. Yield: 45 mg (66%). MS: m/z=638.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:21]([C:17]3[S:16][CH:20]=[CH:19][CH:18]=3)(=[O:23])=[O:22])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3cccs3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 2-thiophene sulfonyl chloride (241 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12i as a solid (300 mg, 91.4%). HPLC: 99.74% (Rt=7.22 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:18][C:19]1[NH:23][N:22]=[CH:21][CH:20]=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]([NH:18][C:19]2[NH:23][N:22]=[CH:21][CH:20]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccn[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccn[nH]1)c1cccnc1Cl

Procedure:
175 g. of 2-chloro-3-pyridinecarboxylic acid chloride are dissolved in 750 ml. of anhydrous dioxane containing 110 g. of triethylamine. At 10°, 83 g. of 5-aminopyrazole dissolved in 100 ml. of dioxane are added dropwise with stirring. After the addition is completed, the mixture is stirred overnight at room temperature, filtered and the precipitate washed with dioxane. The solvent is removed in vacuo and the oily residue crystallized with ethyl acetate. The product, 2-chloro-N-(1H-pyrazol-5-yl)-3-pyridinecarboxamide, is recrystallized from ethyl acetate, yield: 103 g. (46%); m.p. 162.8°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([C:22]([F:25])([F:24])[F:23])[N:3]=1>[OH-].[Na+].O1CCOCC1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[CH:5]=[C:4]([C:22]([F:24])([F:25])[F:23])[N:3]=[C:2]([Cl:1])[CH:7]=2)(=[O:10])=[O:11])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Yield: 34.1 %

Procedure:
0.20 g (0.0005 mol) of N-[4-(2-chloro-6-trifluoromethyl-pyridin-4-ylsulfamoyl)-phenyl]-acetamide was dissolved in a mixture of 5 ml of 1N NaOH and 5 ml of dioxan and boiled at reflux or 5 hours. After cooling the dioxan was distilled off, the residue as adjusted to pH 6 with 0.1 N HCl, the aqueous phase was extracted with ethyl acetate, back-washed with saturated sodium chloride solution and the organic phase was dried over Na2SO4. Subsequently, chromatography was carried out on silica gel with ethyl acetate/hexane 1:4. There was obtained 0.06 g (34%) of 4-amino-N-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-benzenesulfonamide as pale yellow crystals; m.p.: 179-181° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Cl[C:6]1[CH:11]=[C:10]([SH:12])[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=1>CO>[SH:12][C:10]1[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=[C:6]([O:2][CH3:1])[CH:11]=1
Reactant: C[O-]
Reactant: Sc1cc(Cl)nc2ncnn12
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc(S)n2ncnc2n1

Procedure:
To a sodium methoxide solution, prepared from 1.4 g of sodium and 50 ml of methanol, was added all at once the product obtained in Step 1 of Example 43 (4.6 g under ice cooling. The mixture was refluxed for one hour, the solution was concentrated under reduced pressure, and the remaining yellow oil was dissolved in 50 ml water. The pH was adjusted to 1.0 with 1N hydrochloric acid, and the formed crystals were collected by filtration and washed with 30 ml ethanol, giving 1.7 g of the objective compound as faint yellow crystals.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[H-].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[CH:29][CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[C:40]([O:42][CH3:43])=[O:41])[CH:33]=[N:32]1>C1COCC1.C(O)(=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@H:4]([NH:3][CH2:29][CH2:30][N:31]1[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][C:38]=3[C:40]([O:42][CH3:43])=[O:41])[CH:33]=[N:32]1)[CH2:5]2
Reactant: COC(=O)c1cccc2cnn(CC=O)c12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cccc2cnn(CCN[C@@H]3CN4CCC3CC4)c12
Reaction time: 1.5 h

Procedure:
To a stirred solution of (S)-(−)-3-aminoquinuclidine dihydrochloride (0.3 g, 1.3 mmol) in THF (13 mL) was added sodium hydride (0.1 g, 2.7 mmol) and the mixture was stirred for 1.5 h. Acetic acid (0.5 mL) and sodium triacetoxyborohydride (380 mg, 1.8 mmol) were added and stirred for 0.5 h. A solution of methyl 1-(2-oxoethyl)-1H-indazole-7-carboxylate (0.3 g, 1.3 mmol) from Step E above in THF (13 mL) was added dropwise, and the resulting suspension was stirred overnight at ambient temperature. The solvent was removed under reduced pressure, and the crude material was purified by preparative thin layer chromatography (90:9:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate: 1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.03 (dd, J=8.0, 1.0 Hz, 1H), 7.85 (dd, J=7.0, 1.0 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 4.68-4.65 (m, 2H), 3.94 (s, 3H), 2.84-2.70 (m, 3H), 2.64-2.45 (m, 2H), 2.03-1.99 (m, 2H), 1.86-1.75 (m, 2H), 1.58-1.51 (m, 3H), 1.45-1.32 (m, 1H), 1.08-1.01 (m, 1H); MS (ESI+) m/z 329 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O1CCCC1.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(OC2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.5 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzaldehyde (12.0 g, 76.64 mmol) in 175 mL methylene chloride and 10 mL tetrahydrofuran was added 3,4-dihydro-2H-pyran (17.5 mL, 191.6 mmol) and pyridinium p-toluenesulfonate (1.93 g, 7.66 mmol). The reaction mixture was stirred at room temperature for 4 days. Additional 3,4-dihydro-2H-pyran (17.0 mL, 186.3 mmol) and pyridinium p-toluenesulfonate (1.85 g, 7.36 mmol) were added, followed by 5A molecular sieves, and the reaction mixture continued to stir at room temperature for 3 days. Saturated aqueous sodium bicarbonate and water were added. The layers were separated and the aqueous layer was extracted with a second portion of methylene chloride. The combined organic layers were dried (sodium sulfate), filtered, and concentrated. Silica gel flash chromatography of the residue (20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 13.37 g (72%) of the title compound of Step A. MS 241.0 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[OH-].[Na+].Cl[CH:16]([F:18])[F:17].Cl>ClCCl.O.C(O)(C)C>[Cl:1][C:2]1[C:3]([O:12][CH:16]([F:18])[F:17])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: FC(F)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(OC(F)F)c(Cl)cc1F
Reaction time: 4 h

Procedure:
To 0.53 g of 2-chloro-4-fluoro-5-nitrophenol XV-1 were added 3 ml of isopropanol, 3 ml of water and 0.72 g of sodium hydroxide, and the resultant mixture was heated at 50° to 60° C. while introducing chlorodifluoromethane gas for 4 hours. The mixture was stirred for 4 hours and during that period mixed twice with 0.50 g of sodium hydroxide at intervals of 1.5 hours. After cooling, the reaction mixture was neutralized with 2N hydrochloride acid and shaken with dichloromethane. The dichloromethane layer was dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with n-hexane-ethylacetate (100:5 v/v). The eluate was concentrated to give 0.24 g of the titled compound XII-1.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]=O.C(O)(=O)C>N1CCCCC1.C1(C)C=CC=CC=1>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]=[C:4]([C:3](=[O:9])[CH2:2][CH3:1])[C:5](=[O:8])[CH2:6][CH3:7]
Reactant: O=Cc1c(F)cccc1F
Reactant: CCC(=O)CC(=O)CC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCC(=O)C(=Cc1c(F)cccc1F)C(=O)CC
Temperature: 70 °C
Reaction time: 7 h
Yield: 30.7 %

Procedure:
A mixture of 3,5-heptanedione (1.36 ml, 10 mmol), 2,6-difluorobenzaldehyde (1.08 ml, 10 mmol), piperidine (20 μL, 0.2 mmol), glacial acetic acid (149 μL, 2.6 mmol), molecular sieves and toluene (7 ml) was heated at 70° C., under a nitrogen atmosphere for 3 hours. Further 2,6-difluorobenzaldehyde (540 μL, 5 mmol) was added and the resulting mixture was stirred at 70° C. for a further 7 hours. After cooling, the molecular sieves were filtered off. The filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with pentane:dichloromethane (4:1, by volume) and then with a solvent gradient of pentane:diethylether (20:1, by volume) gradually changing to pentane:diethylether (10:1, by volume) to afford the title compound (775 mg) as a colourless oil.
Reaction SMILES: [CH2:1]([C@H:8]1[C:37](=[O:38])[N:36]([CH3:39])[C@@H:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:34](=[O:44])[NH:33][C@@H:32]([C@H:45]([OH:47])[CH3:46])[C:31](=[O:48])[N:30]([CH3:49])[CH2:29][C:28](=[O:50])[N:27]([CH3:51])[C@@H:26]([CH2:52][CH:53]([CH3:55])[CH3:54])[C:25](=[O:56])[NH:24][C@@H:23]([CH2:57][O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[C:22](=[O:63])[N:21]([CH3:64])[C@@H:20]([C@H:65]([CH2:67][CH3:68])[CH3:66])[C:19](=[O:69])[NH:18][C@H:17]([C:70]([N:72]2[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]2)=[O:71])[CH2:16]S[CH2:14][C:13](=[O:78])[N:12]([CH3:79])[C@@H:11]([CH3:80])[C:10](=[O:81])[N:9]1[CH3:82])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[O:85][S:86]([O-:88])=O.[K+].CS(C)=O>CO>[CH2:1]([CH:8]1[C:37](=[O:38])[N:36]([CH3:39])[CH:35]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:34](=[O:44])[NH:33][CH:32]([C@H:45]([OH:47])[CH3:46])[C:31](=[O:48])[N:30]([CH3:49])[CH2:29][C:28](=[O:50])[N:27]([CH3:51])[CH:26]([CH2:52][CH:53]([CH3:54])[CH3:55])[C:25](=[O:56])[NH:24][CH:23]([CH2:57][O:58][C:59]([CH3:60])([CH3:62])[CH3:61])[C:22](=[O:63])[N:21]([CH3:64])[CH:20]([C@H:65]([CH2:67][CH3:68])[CH3:66])[C:19](=[O:69])[NH:18][CH:17]([C:70]([N:72]2[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]2)=[O:71])[CH2:16][S:86](=[O:88])(=[O:85])[CH2:14][C:13](=[O:78])[N:12]([CH3:79])[CH:11]([CH3:80])[C:10](=[O:81])[N:9]1[CH3:82])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@H]1C(=O)N[C@H](C(=O)N2CCCCC2)CSCC(=O)N(C)[C@@H](C)C(=O)N(C)[C@@H](Cc2ccccc2)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N1C
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: CC[C@H](C)C1C(=O)NC(C(=O)N2CCCCC2)CS(=O)(=O)CC(=O)N(C)C(C)C(=O)N(C)C(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)NC([C@@H](C)O)C(=O)N(C)CC(=O)N(C)C(CC(C)C)C(=O)NC(COC(C)(C)C)C(=O)N1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.2 %

Procedure:
(5S,8S,11S,14S,20S,23S,26S,29R)-8-Benzyl-23-(tert-butoxymethyl)-26-((S)-sec-butyl)-14-((R)-1-hydroxyethyl)-11,20-diisobutyl-4,5,7,10,16,19,25-heptamethyl-29-(piperidine-1-carbonyl)-1-thia-4,7,10,13,16,19,22,25,28-nonaazacyclotriacontane-3,6,9,12,15,18,21,24,27-nonone (9.6 mg, 8.19×10−3 mmol) was dissolved in methanol (0.6 ml), and water (0.3 ml) was added. While stirring the solution, oxone (15.1 mg, 2.46×10−2 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours, and DMSO (80 μl) was then added. The mixture was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=60/40→0/100) to afford 5S,8S,11S,14S,20S,23S,26S,29R)-8-benzyl-23-(tert-butoxymethyl)-26-((S)-sec-butyl)-14-((R)-1-hydroxyethyl)-11,20-diisobutyl-4,5,7,10,16,19,25-heptamethyl-29-(piperidine-1-carbonyl)-1-thia-4,7,10,13,16,19,22,25,28-nonaazacyclotriacontane-3,6,9,12,15,18,21,24,27-nonaone 1,1-dioxide (8.3 mg, 84%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[CH3:15]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(C(C)=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 5-acetyl-2-hydroxybenzoate (95.3 g, 490.6 mmol) was added to DMF (381 mL) and potassium carbonate (82.2 g, 588.8 mmol) at RT under an atmosphere of nitrogen. To the resulting suspension was added methyl iodide (90.5 g, 637.8 mmol) whilst maintaining good agitation. After stirring at RT for 30 minutes, the crude reaction mixture was analysed by GC demonstrating complete reaction. Water (380 mL) was added followed by further water (380 mL) and the resulting white solid filtered off to afford 82.5 g of the desired, water wet product (7).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15])[CH3:5].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[C:21]([F:29])[CH:20]=1.CCN(CC)CC.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([CH2:6][N:4]([CH3:3])[CH3:5])=[C:8]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)=[O:27])=[C:21]([F:29])[CH:20]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CN(C)Cc1ccc(N)cc1C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a solution of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline dihydrochloride (4 g, 13.74 mmol), 2-(4-bromo-2-fluorophenyl)acetic acid (3.20 g, 13.74 mmol) and Et3N (9.57 mL, 68.7 mmol) in DCM (100 mL) stirred under a N2 atmosphere at 20° C. were added EDC (2.63 g, 13.74 mmol) and HOBt (2.104 g, 13.74 mmol) in one charge. The reaction mixture was stirred at 20° C. for 2 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=3:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf 0.6) were combined and concentrated to yield a light yellow solid of 2-(4-bromo-2-fluorophenyl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)acetamide (5.5 g, 9.14 mmol, 66.5% yield): 1H NMR (400 MHz, CDCl3) δ 7.79 (br. s., 2H), 7.70 (d, J=5.02 Hz, 2H), 7.30 (br. s., 2H), 3.73 (s, 2H), 3.53 (s, 2H), 2.47 (s, 6H); ES-LCMS m/z 435.0 (M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[PH:10](=[O:13])([OH:12])[OH:11].[CH2:14]([C:16]([CH2:44][CH3:45])([C:18](=O)[C:19]1[N:23]=[CH:22][N:21]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)[CH3:17])[CH3:15]>C(O)C>[PH:10](=[O:11])([OH:13])[OH:12].[CH2:14]([C:16]([CH2:44][CH3:45])([C:18](=[N:2][OH:3])[C:19]1[N:23]=[CH:22][N:21]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)[CH3:17])[CH3:15]
Reactant: NO
Reactant: CCC(C)(CC)C(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=[PH](O)O
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(C)(CC)C(=NO)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
Hydroxylamine hydrochloride (0.29 g), then pyridine (7.7 ml), was added under nitrogen to a stirred solution of diethyl 3-oxo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 42) in ethanol (20 ml). The mixture was stirred at room temperature for three hours, then evaporated under reduced pressure. The residue was treated with water, basified to pH 8 with 1M sodium hydroxide solution, and extracted with chloroform. The organic layers were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 3-oximino-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.90 g, m.p. 190-192° C.), probably as a single geometric isomer of unknown configuration. NMR (CDCl3): δ 1.2(6H,t), 1.95-2.1(2H,m), 3.05(2H,m), 3.95(4H,m), 7.1-7.3(15H,m), 8.0(1H,s), 9.1(1H,br).