Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:31]#[N:32].CO>CN(C=O)C.O.C(OCC)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:31]#[N:32]
Reactant: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OC
Reactant: Nc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2cc3ncc(C#N)c(Nc4ccc(Cl)cc4Cl)c3cc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A mixture of 178.2 mg (1.1 mmol) of 2,4-dichloroaniline and 44.0 mg (1.1 mmol) of sodium hydride in anhydrous DMF is stirred at room temperature for 0.5 hours. To the mixture is added 149.4 mg (0.5 mmol) of 4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile. The resulting mixture is heated at 50–60° C. for 1 hour. After cooling, the mixture is diluted with water and extracted with ethyl acetate. The organic phase is washed with brine and dried over sodium sulfate. Removal of the solvent yields a dark residue which is purified on preparative TLC (developing solvent: 97:3 methylene chloride/methanol), giving a yellow foam. Trituration of the foam with diethyl ether containing several drops of methanol yields 126.1 mg (59.5%) of the product as a yellow solid, mp 271–273° C.
Reaction SMILES: [Li+].[OH-].Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]=[C:17]([O:27][C@H:28]4[C@H:32]5[O:33][CH2:34][C@@H:35]([OH:36])[C@H:31]5[O:30][CH2:29]4)[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]3=[CH:12][C:11]=2[Cl:37])=[CH:6][CH:5]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCOCC1.O>[Cl:37][C:11]1[CH:12]=[C:13]2[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([O:27][C@H:28]3[C@H:32]4[O:33][CH2:34][C@@H:35]([OH:36])[C@H:31]4[O:30][CH2:29]3)=[N:16][C:14]2=[N:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Reactant: OB(O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 80 °C

Procedure:
LiOH (1.3 ml, 3.90 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (107.7 mg, 0.132 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[5-(4-bromophenyl)-6-chloro-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (776.2 mg, 1.332 mmol) and phenylboronic acid (201.9 mg, 1.656 mmol) in dioxane (10.5 ml) and water (1.3 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. for 20 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (100 ml) and water (100 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give an amber residue. This material was purified by flash chromatography, utilizing a 40 g silica RediSep Rf® column and employing a 0-70% EtOAc/hexane gradient followed by 70% EtOAc/hexane. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a yellow solid. LC-MS: calculated for C30H34ClN3O5Si 579.2 observed m/e: 580.24 (M+H)+ (Rt 1.36/2 min).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nn1nc(-c2ccc(Cl)nc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccc(Cl)nc2)c2ccccc2c1=O

Procedure:
The product of Example 4B was treated with 2-(4-chlorophenyl)acetyl chloride similar to the method described in Example 4C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.76 (s, 1H), 8.65 (dd, J=2.5, 0.8 Hz, 1H), 8.39-8.43 (m, 1H), 8.13 (dd, J=8.2, 2.5 Hz, 1H), 7.86-8.02 (m, 2H), 7.67-7.81 (m, 2H), 7.37-7.44 (m, 4H), 3.71 (s, 2H); MS (ESI+) M/Z 425 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:14]([CH2:23][C:24]2S[CH:26]=[CH:27][N:28]=2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH3:2].Br[C:30]1[CH:35]=CC=CN=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:14]([CH2:23][C:24]2[CH:35]=[CH:30][CH:26]=[CH:27][N:28]=2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH3:2]
Reactant: CCOc1cc(N(Cc2nccs2)c2ccc(C#N)cc2)ccc1OC(C)C
Reactant: Brc1ccccn1
Product: CCOc1cc(N(Cc2ccccn2)c2ccc(C#N)cc2)ccc1OC(C)C

Procedure:
According to the procedure for Intermediate 2.1, 2-bromopyridine (100 mg, 0.633 mmol) afforded 177 mg of Intermediate 4.1.
Reaction SMILES: C1(OC)C(=CC=CC=1)O.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+].C(OCC=C)C=C.[CH2:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:31]=1[OH:38])[CH:28]=[CH2:29].C1(O)C=CC=CC=1.[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1(C)C=C(C)C=C(C)C=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(C)(C)C>[CH2:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:31]=1[O:38][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH:28]=[CH2:29]
Reactant: BrCc1ccccc1
Reactant: C=CCc1cccc(OC)c1O
Agent: C=CCOCC=C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1ccccc1O
Solvent: C=CCBr
Solvent: Oc1ccccc1
Solvent: CC(C)(C)O
Product: C=CCc1cccc(OC)c1OCc1ccccc1
Yield: 45 %

Procedure:
Treatment of guaiacol (25.00 g, 0.201 mol) with allyl bromide (29.24 g, 0.242 mol) and potassium carbonate (83.50 g, 0.604 mol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 afforded 2-allyl-6-methoxyphenol as a brown oil. Treatment of the phenol with potassium carbonate (83.5 g, 0.604 mol), benzyl bromide (36.19 g, 0.212 mol), and tetrabutylammonium iodide (7.42 g, 0.020 mol) generally according to the procedure described for Intermediate 1 gave 23.61 g (45%) of 1-allyl-2-(benzyloxy)-3-methoxybenzene as a pale yellow oil. Rf=0.71 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C17H18O2: C, 80.28; H, 7.13. Found: C, 79.09; H, 6.93.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][CH2:24][N:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.[OH-].[OH-].[Pd+2]>[CH2:1]([O:8][C:9](=[O:36])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]2=[O:34])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCC#Cc1ccc(C#CCCN2C(=O)c3ccccc3C2=O)cc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NCCCCc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
A suspension containing 58 (6.0 g, 12.59 mmol) and palladium dihydroxide (20% Pd(OH)2 on carbon, 50% wet, 3.0 g, 21.43 mmol) dissolved in anhydrous tetrahydrofuran 75 mL) was bubbled with nitrogen for 20 min. The reaction mixture was vacuumed, then charged with H2 gas (45 psi), and allowed to stir at rt for 24 h. The solution was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the desired product 59 (4.88 g, 80%) as a thick, brown oil: 1H NMR (500 MHz, CDCl3) δ 7.85 (dd, 2H), 7.74 (dd, 2H), 7.35-728 (m, 6H), 7.06 (d, 4H), 3.70 (t, 2H), 3.19 (t, 2H), 2.63-2.56 (m, 4H), 2.00 (d, 2H), 1.73-1.50 (m, 8H); m/z (ESI) 485 [C30H32N2O4+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O>CS(C)=O.C(OCC)(=O)C>[CH2:19]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:10]=[O:11])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Dissolve 2-(S)-dibenzylamino-3-phenylpropan-1-ol (5.00 g, 15.08 mmol) in DMSO (15 mL) and cool in an ice bath. Add triethylamine (8.4 mL, 60.0 mmol) followed by sulfur trioxide-pyridine complex (4.80 g, 30.2 mmol), stir 30 min then slowly add water (15 mL). Dilute with ethyl acetate and wash with 5% aqueous citric acid (3×), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as a light yellow residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:16]C)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.B(Br)(Br)Br.O.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(OC)cc(Cl)c2[nH]1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)cc(Cl)c2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of ethyl 7-chloro-5-methoxyindole-2-carboxylate (82 mg, 0.323 mmol) in dichloromethane (5 ml) at −78° C. was added boron tribromide (1.07 ml of a 1.0M solution in DCM, 1.07 mmol) and the reaction stirred at −78° C. for 30 minutes then allowed to warm to ambient temperature overnight. Water was carefully added and the pH adjusted to pH 6–7 by addition of 2M sodium hydroxide. The mixture was extracted with ethyl acetate (2×50 ml), and the organic solution washed with brine, dried (MgSO4), filtered and evaporated to give ethyl 7-chloro-5-hydroxyindole-2-carboxylate (55 mg, 71%) as an orange solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:19]1[NH:23][N:22]=[C:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][C:33]([CH3:36])=[N:32]3)=[C:27]([F:37])[CH:26]=2)[N:20]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([F:18])[CH:8]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC(C)=O>[F:37][C:27]1[CH:26]=[C:25]([NH:24][C:21]2[N:20]=[C:19]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([F:18])[CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:23]3[N:22]=2)[CH:30]=[CH:29][C:28]=1[N:31]1[CH:35]=[N:34][C:33]([CH3:36])=[N:32]1
Reactant: Cc1ncn(-c2ccc(Nc3n[nH]c(C(CCCCCl)c4ccc(OC(F)(F)F)c(F)c4)n3)cc2F)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncn(-c2ccc(Nc3nc4n(n3)CCCCC4c3ccc(OC(F)(F)F)c(F)c3)cc2F)n1
Yield: 22.8 %

Procedure:
A solution of 5-(5-chloro-1-(3-fluoro-4-(trifluoromethoxy)phenyl)pentyl)-N-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (989 mg, 1.83 mmol), sodium iodide (1.37 g, 9.13 mmol), and diisopropylethylamine (1.60 mL, 9.13 mmol) in acetone (25 mL) was heated in a sealed vessel at 100° C. for 6 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (70% EtOAc/chloroform). The purified product was recrystallized from EtOAc/hexane to afford 211 mg (22% yield) of the titled compound as a white solid. LC-MS (M+H)+ 506.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (1 H, d, J=2.4 Hz), 7.68 (1 H, dd, J=13.9, 2.3 Hz), 7.62 (1 H, t, J=8.7 Hz), 7.31 (1 H, t, J=8.1 Hz), 7.08 (1 H, dd, J=11.0, 2.1 Hz), 7.03 (1 H, dd, J=8.9, 2.4 Hz), 6.98 (1 H, d, J=8.5 Hz), 6.68 (1 H, s), 4.20-4.33 (3 H, m), 2.50 (3 H, s), 2.08-2.22 (2 H, m), 1.94-2.06 (2 H, m), 1.84-1.93 (2 H, m).
Reaction SMILES: O.[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH:9]=1)[OH:8].C(O)(=O)[CH:12]([CH2:14][C:15](O)=O)[OH:13].S(=O)(O)[O-].[Na+].C(=O)=O>S(=O)(=O)(O)O>[OH:8][C:7]1[CH:6]=[C:5]2[C:4]([CH:15]=[CH:14][C:12](=[O:13])[O:10]2)=[C:3]([CH3:2])[CH:9]=1
Reactant: O=C(O)CC(O)C(=O)O
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: O
Product: Cc1cc(O)cc2oc(=O)ccc12
Temperature: 90 °C
Yield: 62 %

Procedure:
5-methylresorcinol monohydrate (284 gm, 2.0 mol; Aldrich) was thoroughly mixed with malic acid (280 gm, 2.10 mol; Aldrich) and then placed in a reaction flask containing sulfuric acid (600 ml) and a trace of sodium bisulfite (1.0 gm; Aldrich). The reaction mixture was heated to 90° C. while being mechanically stirred until evolution of carbon dioxide subsided (about 5 hours). The resulting reddish-orange solution was poured into sufficient ice (with vigorous stirring) to make up 1 liter. The receiving flask was maintained at 0° C. by external cooling until the addition of the reaction mixture was complete. The resulting light-orange product that precipitated was collected by suction filtration then washed thoroughly with water. The crude product was air dried on the filter, then recrystallized twice from tetramethylene glycol (1800 ml) to give pure 7-hydroxy-5-methylcoumarin (H5MC,1) as product (220 gm, 62% yield; mp 252-255° C.).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([OH:16])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.C1COCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([O:16][C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[O:15])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Oc2ccc(S(N)(=O)=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.3 %

Procedure:
Into a round bottom flask, there are introduced 2.86 g (10 mmoles) of 3-(1-adamantyl)-4-methoxybenzoic acid, 1.73 g (10 mmoles) of 4-hydroxybenzenesulfonamide and 50 ml of THF. There are added, successively, 2.1 g (10 mmoles) of 1,3-dicyclohexylcarbodiimide and then 1.22 (10 mmoles) of 4-dimethylaminopyridine. The medium is stirred at ambient temperature for 4 hours. The reaction medium is poured into water and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The resulting solid is purified by chromatography on a silica column eluted by a 60:40 mixture of ethyl ether and hexane. After evaporation of the solvents, 2 g (46% yield) of 4-[3-(1-adamantyl)-4-methoxybenzoyloxy] benzenesulfonamide having a melting point of 223°-224° C. are recovered.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH2:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:22][C:23]([CH3:39])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:24]>>[CH2:32]([O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]([NH:24][C:2]1[C:3](=[O:21])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH2:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1)([CH3:22])[CH3:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(N)c1ccccc1OCc1ccccc1
Reactant: CCc1ccc(C(=O)OC)cc1-n1cc(Br)nc(Br)c1=O
Product: CCc1ccc(C(=O)OC)cc1-n1cc(Br)nc(NC(C)(C)c2ccccc2OCc2ccccc2)c1=O

Procedure:
The subtitle compound was prepared from methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-ethylbenzoate (Example 288b) and α,α-dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example 198d) using a similar method to that described for Example 252h.
Reaction SMILES: [CH2:1]([S:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:19]O>CS(O)(=O)=O>[CH2:1]([S:11]([CH2:14][CH2:15][C:16]([O:18][OH:19])=[O:17])(=[O:12])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: OO
Reactant: CCCCCCCCCCS(=O)(=O)CCC(=O)O
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCS(=O)(=O)CCC(=O)OO
Temperature: 40 °C
Yield: 87.6 %

Procedure:
The product of Example 12 was converted to the corresponding carboxylic acid by alkaline hydrolysis followed by acidification and then to the corresponding sulfone carboxylic acid by oxidation in accordance with a procedure found in U.S. Pat. No. 3,857,875 to Brady et al. A stirred mixture of 5 g of 3-(n-decylsulfonyl)propionic acid and 50 mL of methanesulfonic acid was heated to 40±3° C. The 3-(n-decylsulfonyl)propionic acid dissolved only partially in the methanesulfonic acid at this temperature. Then 2.04 g of 90% hydrogen peroxide was added dropwise via pipette over ten minutes. Before the addition of the hydrogen peroxide was completed, the reaction mixture became thick from precipitation of a solid. After the addition of the 90% hydrogen peroxide was completed, the heating of the reaction mixture was continued at 40±3° C. until the reaction time totalled ninety minutes beginning at the start of the addition of the hydrogen peroxide. The reaction mixture was then cooled in an ice bath at 10° C. The solid was then filtered from solution using a coarse sinteredglass funnel, then transferred to a beaker containing 200 mL of ice water prepared from deionized water. The product was washed twice with ice water, filtered and dried to provide 4.63 g of the desired product (87.6% of theoretical based upon the weight of starting 3-(n-decylsulfonyl)propionic acid). The product was found to have 5.32% active oxygen. The product was stabilized with an equal weight of boric acid and put through a #30 polyethylene sieve which provided a particle size of less than 600 microns. The stabilized product contained 2.58% by weight active oxygen.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)=[O:9])=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([NH:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38])=[O:14])=[O:9])=[CH:18][CH:19]=1
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccc(Cl)cc1

Procedure:
The subject compound was prepared from 0.85 g (2.98 mmol) p-chlorobenzyloxycarbonyl-L-proline, 0.41 g (2.98 mmol) isobutyl chloroformate, 0.30 g (2.97 mmol) N-methylmorpholine, and 0.31 g (2.98 mmol) L-valinol, substantially according to the mixed anhydride procedure described in Example 1. N-(p-chlorobenzyloxycarbonyl)-L-prolyl-L-valinol obtained after recrystallization from ethyl acetate/n-hexane melted at 143°-144.5°.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.Cl.[CH3:43][O:44][C:45](=[O:50])[C@H:46]([CH2:48][OH:49])[NH2:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[CH3:43][O:44][C:45](=[O:50])[CH:46]([NH:47][C:16](=[O:18])[CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:4]2([CH3:3])[O:5][CH2:6][CH2:7][O:8]2)[CH:10]=1)[CH2:48][OH:49]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC1(c2cccc(CC(=O)O)c2)OCCO1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)C(CO)NC(=O)Cc1cccc(C2(C)OCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-acetic acid (2.20 g, 9.90 mmol) in CH2Cl2 (100 mL) was treated sequentially with DMAP (301 mg, 2.47 mmol), HOBT (1.61 g, 11.90 mmol), EDC (4.74 g, 24.75 mmol) and DIPEA (6.78 mL, 39.60 mmol). After stirring for 30 min at rt, serine methylester hydrochloride (1.62 g, 10.39 mmol) was added and the reaction mixture stirred overnight at rt. Water (100 mL) was added and the mixture was extracted twice with CH2Cl2 (100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (97:3 EA-MeOH) gave the title compound as a brown oil. TLC: rf (97:3 EA-MeOH)=0.45. LC-MS-conditions 02: tR=0.74 min; [M+H]+=324.41.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][C:7]([C:10]1[CH:15]=[C:14]([SH:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])[CH3:8].N1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:9][C:7]([C:10]1[CH:15]=[C:14]([S:16][CH2:2][C:3](=[O:5])[CH3:4])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:6])[CH3:8]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
Chloroacetone (2.0 mL, 25.2 mM) is added to a 0° C. of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (3.0 g, 12.6 mM) and pyridine (2.0 mL, 25.2 mM) in methylene chloride (100 mL). The reaction mixture is allowed to warm to room temperature then cooled again to 0° C., and an additional amount of chloroacetone (2.0 mL, 25.2 mM) and pyridine (2.0 mL, 25.2 mM) is added along with K2CO3 (100 mg). The reaction mixture is again allowed to warm to room temperature. The mixture is diluted with ethyl acetate and washed once with dilute aqueous hydrochloric acid, four times with water, and once with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is crystallized from ethyl acetate:hexane to give 2.8 g (75.5%) of white crystals, mp 105°-106° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@@H:4]([CH3:7])[CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.[C:40]([OH:43])(=[S:42])[CH3:41].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:8])[C@@H:4]([CH3:7])[CH2:5][S:42][C:40](=[O:43])[CH3:41]
Reactant: CC(O)=S
Reactant: COC(=O)[C@@H](C)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)CSC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of (S)-( +)-3-hydroxy-2-methylpropionic acid methyl ester (8.00 g) and triphenyl phosphin (26.64 g) in tetrahydrofuran (170 ml) was added azodicarboxylic acid diethyl ester (16 ml) was added, followed by stirring at 0° C. for 30 minutes. After addition of thioacetic acid at 0° C., the reaction mixture was stirred at room temperature for 16 hours, after which saturated aqueous solution of sodium hydrogen carbonate was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was washed with hexane and the flitrate was concentrated. The resulting residue was distilled (83-87° C./0.2 mmHg) to yield the title compound (4.95 g, yield 41%) as a colorless oily substance.