Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]CC(O)=O)=[CH:5][C:4]=1C.[C:16](Cl)(=[O:20])[C:17](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[CH3:10][C:9]1[CH:17]=[C:16]2[C:4]([C:3](=[O:2])[CH2:8][CH2:7][O:20]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(CCCC(=O)O)cc1C
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)OCCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A stirred solution of 5.0 grams (0.028 mole) of 3-(3-methylphenoxy)propanoic acid (i) and 5.3 grams (0.042 mole) of oxalyl chloride in 100 mL of methylene chloride was cooled to −5° C. and a few drops of DMF was added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about two hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue: which was 3-(3-methylphenoxy)propanoic acid chloride. The acid chloride was stored under a nitrogen atmosphere for about 18 hours, and then it was dissolved in 50 mL of methylene chloride. The stirred solution was cooled to −4° C. and 4.1 grams (0.031 mole) of aluminum chloride was added portionwise while maintaining the reaction mixture temperature at 5° C. or less. Upon completion of addition, the reaction mixture was maintained at 5° C. for about three hours. After this time, the reaction mixture was poured into ice and extracted with three 100 mL portions of methylene chloride. The combined extracts were washed with two 50 mL portions of water and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of ethyl acetate and hexane as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 3.5 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=1.FC(F)(F)C(O)=O.[CH:23]([C:26]1[S:27][CH:28]=[C:29]([C:31]([N:33]2[CH2:38][C:37]3([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[O:36][CH2:35][CH2:34]2)=[O:32])[N:30]=1)([CH3:25])[CH3:24]>C(#N)C>[OH:11][CH2:10][CH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[C:12]([F:15])([F:14])[F:13])[CH2:2][N:41]1[CH2:42][CH2:43][C:37]2([O:36][CH2:35][CH2:34][N:33]([C:31]([C:29]3[N:30]=[C:26]([CH:23]([CH3:24])[CH3:25])[S:27][CH:28]=3)=[O:32])[CH2:38]2)[CH2:39][CH2:40]1
Reactant: OCCc1cc(CBr)ccc1C(F)(F)F
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(C(F)(F)F)c(CCO)c4)CC3)C2)cs1

Procedure:
The subtitled compound was prepared using a similar method to that described in Example 6 step (b) using a solution of 2-(5-(bromomethyl)-2-(trifluoromethyl)phenyl)ethanol (0.38 g) (Example 270 step a) in acetonitrile which was added dropwise over 30 minutes to (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (Example 22 step b). Purification was by silica gel chromatography eluting 5% triethylamine in ethyl acetate. Yield 0.32 g.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:20]=[C:19]3[C:14]([N:15]=[CH:16][C:17]([N:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[N:9][CH:10]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(#N)C>[N:21]1([C:17]2[CH:16]=[N:15][C:14]3[C:19]([N:18]=2)=[CH:20][C:11]([C:7]2[CH:6]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:10]=[N:9][CH:8]=2)=[CH:12][CH:13]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(-c4cncc(S(N)(=O)=O)c4)cc3n2)CC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cncc(-c2ccc3ncc(N4CCNCC4)nc3c2)c1

Procedure:
A solution of 1,1-dimethylethyl 4-{7-[5-(aminosulfonyl)-3-pyridinyl]-2-quinoxalinyl}-1-piperazinecarboxylate (0.21 mmol) (prepared according to Scheme 1) in acetonitrile (4 mL) was treated with concentrated trifluoroacetic acid (4 mL) for 2 hours. The reaction mixture was then concentrate and neutralized with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to yield the title product. MS(ES)+ m/e 371.0 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:33](=[O:36])(=[O:35])[NH2:34])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]CC2C=CC=CC=2)=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[H][H]>O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:33](=[O:36])(=[O:35])[NH2:34])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccc(O)cc1

Procedure:
A suspension of 3-benzylamino-4-(4-benzyloxyphenoxy)-5-sulphamyl-benzoic acid (0.5 g) in water (5 ml) was adjusted to a pH of 11 by addition of 1N sodium hydroxide. The resulting soluton was hydrogenated at room temperature and 1.1 atmospheres hydrogen pressure after addition of Pd-on-carbon powder catalyst (0.025 g catalyst containing 10% of Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and from the filtrate the 3-benzylamino-4-(4-hydroxyphenoxy)-5-sulphamyl-benzoic acid was precipitated by addition of 4N hyrochloric acid until a pH of 2. After isolation by filtration and recrystallization from aqueous ethanol, the compound was obtained with a melting point of 276-277°C (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].O=[C:30]1[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH:32]1[CH2:33][CH:30]([N:26]2[CH2:25][CH:24]=[C:23]([C:20]3[C:15]4[CH:16]=[N:17][C:18]([NH2:19])=[C:13]([O:12][C@@H:10]([C:3]5[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=5[Cl:1])[CH3:11])[C:14]=4[O:22][CH:21]=3)[CH2:28][CH2:27]2)[CH2:31]1
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C4CNC4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (8.11 mg, 0.0474 mmol), sodium triacetoxyborohydride (25.1 mg, 0.118 mmol) and 1,2-dichloroethane (1.0 mL, 13 mmol) were mixed and stirred at 70° C. overnight. After extraction with DCM and water, the organic layer was dried and dissolved in DCM (1.0 mL, 16 mmol). TFA (1.0 mL, 13 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 hour. The crude was passed through SCX-2 SPE and product was released by 2 M NH3 in methanol for purification by the MDPS. MS (ES+): m/z 477.10/479.15 (100/80) [MH+]. HPLC: tR=0.57 min (HPLC-ACQUITY, Analytical). 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=6.8 Hz, 3H), 2.54 (br. s., 2H), 2.64-2.68 (m, 2H), 3.11-3.18 (m, 2H), 3.53 (t, J=6.9 Hz, 1H), 3.94-4.08 (m, 4H), 6.27 (br. s., 1H), 6.50 (q, J=7.0 Hz, 1H), 7.22 (t, J=8.6 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.63 (s, 1H), 8.18 (s, 1H).
Reaction SMILES: [OH-:1].[OH-].[Mg+2:3].[S:4](=[O:6])=[O:5]>>[S:4](=[O:1])([OH:6])[O-:5].[Mg+2:3].[S:4](=[O:1])([OH:6])[O-:5]
Reactant: [OH-]
Reactant: O=S=O
Agent: [Mg+2]
Product: O=S([O-])O

Procedure:
Referring to FIG. 1, wood chips are heated with a magnesium bisulphite cooking acid (C/A) in digesters 10 and the pulp and spent sulphite liquor are discharged into washers 12. The liquor is passed through a filter and the filtrate having 13-15% solids is fed to a weak liquor storage tank 16. Some of the weak liquor is recycled to the washers. The weak liquor is concentrated in an evaporator 18 and transferred to a heavy liquor storage tank 20 at a concentration between 55-57% solids as required for operation of the recovery system. The heavy liquor is fired in a recovery boiler 22 and the combustion products of the sulphur and magnesium in the liquor are discharged from the boiler in a gas stream as sulphur dioxide and solid particles of magnesium oxide ash. The major portion of the magnesium oxide is removed from the gas stream in a precipitator 24 and washed in a washer 26. The magnesium oxide from the washer is fed to slakers 28 to produce magnesium hydroxide which is stored in a slurry tank 30. This magnesium hydroxide slurry together with some makeup is fed to a scrubber 32. The sulphur dioxide from the precipitator 24 is forced to flow upwardly through the scrubber 32 by an induced draft fan 34, countercurrent to the magnesium hydroxide flow, so as to recover the sulphur dioxide by reaction with the magnesium hydroxide to produce magnesium bisulphite acid. This acid is fed to a conventional clarifier 36 and then to a fortification tower 38 where it is fortified with makeup sulphur dioxide coming from a sulphur burner 40 through coolers 42. Some SO2 makeup is also fed to the scrubber through the fortification tower. The finished cooking acid is fed through filters 44 and stored in a cooking acid storage tank 46 for reuse in the digesters 10.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.O[N:52]1[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2N=N1.NC1C=CC=CC=1>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH:52][C:56]1[CH:55]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: On1nnc2ccccc21
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)Nc6ccccc6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (100 mg, 0.14 mmol) in THF (3 mL) was added polystyrene-carbodiimide (261 mg, 0.29 mmol), 1-hydroxybenzotriazole hydrate (39 mg, 0.29 mmol) and aniline (127 mg, 1.43 mmol). The reaction mixture was stirred at room temperature under nitrogen for 6 h. The reaction was filtered through a micro filter. The crude material was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) and preparative HPLC (10:90 acetonitrile/water to 100% acetonitrile with 0.05% TFA over 50 min) to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-phenyl-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide as a mixture of diastereomers (5.0 mg, 4%) and as a red solid: 1H NMR (500 MHz, CDCl3) δ 14.25 (s, 0.3H), 14.19 (s, 0.7H), 11.64 (br s, 1H), 8.28 (s, 0.3H), 8.24 (s, 0.7H), 7.50-7.42 (m, 3H), 7.38-7.32 (m, 3H), 7.16 (t, J=14.0 Hz, 2H), 6.91 (d, J=8.5 Hz, 0.3H), 6.86 (d, J=8.5 Hz, 0.7H), 6.54 (s, 1H), 6.20 (s, 0.3H), 6.18 (s, 0.7H), 5.85 (s, 1H), 5.18-5.13 (m, 1H), 4.98 (d, J=8.5 Hz, 1H), 4.67-4.62 (m, 1H), 3.81 (s, 3H), 3.79 (s, 2H), 3.60 (s, 3H), 3.56-3.51 (m, 2H), 3.44 (s, 2H), 3.38 (s, 1H), 3.15-3.10 (m, 1H), 2.51 (s, 3H), 1.37 (d, J=6.0 Hz, 3H); MS (ESI−) m/z 757 (M−H); HPLC 97.0% (AUC), tR 12.95 min.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:42][CH:43]1[CH2:46][O:45][CH2:44]1>CN(C)C=O>[C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:42][CH:43]4[CH2:46][O:45][CH2:44]4)=[CH:19][C:18]=3[C:24]([F:25])([F:26])[F:27])(=[O:15])=[O:16])[CH2:11][CH:10]2[C:28]([N:30]2[CH2:31][C:32]([F:34])([F:35])[CH2:33]2)=[O:29])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: OC1COC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)C2CC(S(=O)(=O)c3ccc(OC4COC4)cc3C(F)(F)F)CC2C(=O)N2CC(F)(F)C2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 36.8 %

Procedure:
A mixture of (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 118, 87 mg, 0.16 mmol), cesium carbonate (162 mg, 0.49 mmol) and 3-hydroxyoxetane (35 mg, 0.5 mmol) in N,N-dimethylformamide (3 mL) was stirred at 50° C. for 16 h. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogenocarbonate. The aqueous layer was extracted with ethyl acetate then the combined organic layers were washed with water and brine then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of dichloromethane/methanol (98:2 v/v) as eluant to afford the title compound (34 mg, 35%) as a white solid. MS (EI): 578.13 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[CH2:27](I)[CH:28]([CH3:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)CI
Product: COc1cn(C(CC(C)C)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
309 mg (0.80 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and 191 mg (1.04 mmol) of isobutyl iodide were reacted according to General Method 7A. Yield: 178 mg (purity 92%, 48% of theory) of product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N+:6]([O-:8])[CH:7]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:16])=[O:10])=[N+:6]([O-:8])[CH:7]=1
Reactant: O=C(O)c1ccc(Br)c[n+]1[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c[n+]1[O-]

Procedure:
To a solution of 5-bromo-2-carboxypyridine 1-oxide (19.6 g) in methanol (300 mL) was added dropwise thionyl chloride (37.1 g) at 0° C., and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (22.0 g) as a crude amorphous solid. This compound was used for the next step without further purification.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:46]([OH:48])=[O:47])[CH2:41][CH2:42][S:43]([CH3:45])=[O:44])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(=O)C.[ClH:53].CCOCC>O1CCOCC1>[ClH:53].[NH2:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:46]([OH:48])=[O:47])[CH2:41][CH2:42][S:43]([CH3:45])=[O:44])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: CS(=O)CC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CS(=O)CC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.0 Parts N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-phenylalanyl-L-methionine sulfoxide is suspended in 100 parts by volume acetic acid and treated with 50 parts by volume 6 M HCl in dioxane. The resulting mixture is stirred at room temperature for two hours and then stripped of solvent under reduced pressure. Trituration of the residue with ether affords solid L-tyrosylglycylglycyl-L-phenylalanyl-L-methionine sulfoxide hydrochloride. This compound is represented by the following formula. ##STR6##
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH2:16]([O:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC#N>[CH2:16]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:15])[CH2:22][CH2:21]1)[CH2:17][CH3:18]
Reactant: O=C1CCc2ccccc2N1CCCCl
Reactant: CCCOC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCOC1CCN(CCCN2C(=O)CCc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 4.1 %

Procedure:
A 4 mL vial was charged with crude 1-(3-chloro-propyl)-3,4-dihydro-1H-quinolin-2-one (85LM31) (0.200 g), 4-propoxy-piperidine (79KS-66) (0.130 g, 0.897 mmol), potassium carbonate (0.247 g, 1.79 mmol) and sodium iodide (0.269 g, 1.79 mmol) in MeCN (2 mL) and shaken at 50° C. for 20 h. The reaction mixture was quenched with water (1 mL), and the product was extracted into EtOAc (3×1 mL). The combined organic layers were dried over Na2SO4, evaporated and purified by flash CC (SiO2; MeOH/DCM 0:1-3:7) to give the title compound (85LM32) (0.012 g, total yield 3%). 1H NMR (CDCl3) δ 7.25 (t, J=7.4 Hz, 1H), 7.18-7.08 (m, 2H), 6.98 (t, J=7.4 Hz, 1H), 3.98 (t, J=7.6 Hz, CH2), 3.38 (t, J=6.8 Hz, CH2), 3.35-3.25 (m, 1H), 2.87 (t, J=7.6 Hz, CH2), 2.80-2.70 (m, 2H), 2.65-2.60 (m, 2H), 2.45-2.35 (m, 2H), 2.20-2.10 (m, 2H), 1.95-1.80 (m, 4H), 1.65-1.50 (m, 4H), 0.95 (t, J=7.6 Hz, CH3); 13C NMR (CDCl3) δ 170.2, 140.0, 128.2, 127.5, 126.6, 122.8, 115.3, 70.0, 56.0, 51.8, 40.5, 32.0, 31.5, 25.8, 25.2, 22.8, 10.7; HPLC-MS (ammonium acetate) [M+H]+=331.3.
Reaction SMILES: [Mg].[CH2:2]([O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:21][N:20]=1.C(=O)([O-])O.[Na+]>C(OCC)C.CC(P(C1C=CC=CC=1)C1C=CC=CC=1)C.C1C=CC(PC2C=CC=CC=2)=CC=1.[Cl-].[Ni].O1CCCC1>[CH2:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[CH:21][N:20]=2)=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCOc1ccc(Br)cc1
Reactant: Clc1ccc(COC2CCCCO2)cn1
Agent: [Ni]
Agent: CC(C)P(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc(COC3CCCCO3)cn2)cc1
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A Grignard reagent solution prepared from 0.8 g of magnesium, 10.3 g of (4-bromophenyl) octyl ether and 50 ml of tetrahydrofuran was added dropwise at 0°-5° C. within 30 minutes to a mixture of 7.5 g of crude 2-chloro-5-[(tetrahydro-2-pyranyloxy)methyl]pyridine, 75 ml of tetrahydrofuran and 0.36 g of 1,3-bis(diphenylphosphino)-propanenickel-(II) chloride. The reaction mixture was stirred for 3 hours, left to stand overnight, then adjusted to pH 8 with aqueous sodium hydrogen carbonate solution and diluted with diethyl ether. The organic phase was washed neutral with water, dried over sodium sulfate and concentrated. Chromatographic purification of the residue (14.6 g) on 210 g of silica gel with hexane/ethyl acetate (vol. 4:1) yielded 8.8 g of 2-[4-(octyloxy)-phenyl]-5-[(tetrahydro-2-pyranyloxy)methyl]pyridine.
Reaction SMILES: [N:1]1([C:8]2[C:9](=[O:22])[NH:10][CH:11]3[CH:16]([N:17]=2)[CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:12]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[N:1]1([C:8]2[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1=CC2N=C(N3CCCCCC3)C(=O)NC2C=C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-oxo-1,2,4a,8a-tetrahydroquinoxaline-6-carboxylate (150.0 mg, 0.50 mmol) in dichloromethane (50 mL) was added pyridine (210 mg, 2.64 mmol) and Tf2O (375 mg, 1.32 mmol) with stirring overnight under atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (50 mL), extracted with dichloromethane (3×15 mL), the organic layers combined and dried over anhydrous magnesium sulfate, concentrated in vacuo to afford methyl 3-(azepan-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (250 mg, crude), which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[C:30](O)=[O:31].[OH:34][N:35]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C=O)C.C(OCC)(=O)C>[OH:34][NH:35][C:30]([CH:3]1[C:2]([CH3:33])([CH3:1])[S:7][CH2:6][CH2:5][N:4]1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:31]
Reactant: On1nnc2ccccc21
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.4 %

Procedure:
To a solution of 0.28 g (0.56 mmol) of 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylic acid and 0.091 g (0.675 mmol) of 1-hydroxybenzotriazole in 2.5 mL of DMF was added 0.151 g (0.788 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirred at room temperature for 1 h. Then 0.173 mL (2.8 mmol) of 50% aqueous hydroxylamine was added and the reaction was stirred for 18 h. The resulting mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol/dichloromethane. The product was triturated with ether to provide 0.024 g (8%) of N-hydroxy-2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxamide as a white solid. Electrospray Mass Spec: 513.4 (M+H)+