Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[O:10][C:11]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:12]=3[C:13](=O)[N:14]=2)=[CH:4][CH:3]=1.[NH:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[NH2:22].C([OH:34])C>>[OH:34][C:4]1[CH:3]=[CH:2][C:7]([CH3:8])=[CH:6][C:5]=1[C:9]1[N:14]=[C:13]([C:12]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:11]=2[OH:10])[N:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=2)[N:22]=1
Reactant: Cc1ccc2oc(-c3ccc(O)c(C)c3)nc(=O)c2c1
Reactant: CCO
Reactant: NNc1ccc(C(=O)O)cc1
Product: Cc1ccc(O)c(-c2nc(-c3cc(C)ccc3O)n(-c3ccc(C(=O)O)cc3)n2)c1

Procedure:
1.15 g of 2-(6-hydroxy-m-tolyl)-6-methyl-4H-[1,3]benzoxazin-4-one in [CAS-Reg.-No.:24798-7] and 0.6 g of 4-hydrazinobenzoic acid are boiled under reflux for 2 h in 15 ml of ethanol. The crystals precipitating on cooling are crystallized from isopropanol. After drying, 4-[3,5-bis(2-hydroxy-5-methylphenyl)-[1,2,4]triazol-1-yl]benzoic acid remains as colorless crystals of m.p. 268-269° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[C:20]([O:23]C(=O)C)(=O)[CH3:21].[N+:27]([O-])([OH:29])=[O:28]>C(Cl)Cl.[Cl-].[Na+].O>[C:13]([OH:17])(=[O:14])[CH3:12].[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28])[C:20]([CH3:21])=[O:23]
Reactant: Nc1ccc(CCN2CCC3(CC2)OCCO3)cc1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCN2CCC3(CC2)OCCO3)cc1[N+](=O)[O-]
Product: CC(=O)O
Temperature: -5 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A mechanically stirred solution of N(2-(4-aminophenyl)ethyl)-1,4-dioxa-8-azaspiro[4.5]-decane in methylene chloride (400 mL) cooled to -5° C. under an argon atmosphere was treated dropwise with acetic anhydride (58.8 mL, 622 mmoles). The reaction was allowed to reach room temperature and was stirred for 18 hr. After the addition of an additional 29.5 mL (312 mmoles) of acetic anhydride, the reaction was cooled to -5° C., and a solution of nitric acid (d=1.49, 22.0 mL, 468 mmoles) in methylene chloride (1:1 by volume) was added dropwise. The reaction mixture was allowed to reach room temperature and was stirred for 4 hours. The mixture was cooled in an ice bath and 100 mL of saturated brine was added. The layers were separated and the aqueous phase was extracted with methylene chloride. The combined organic portion was dried (Na2SO4), concentrated and flushed with toluene (3×200 mL). The crude product crystallized during concentration, was filtered, and triturated with ethyl acetate (550 mL) to yield 56.7 g (89%) of N(2-(4-acetamino-3-nitrophenyl)ethyl)-1,4-dioxa-8-azaspiro[4.5]-decane acetic acid salt. TLC Rf=0.80 (silica gel, 5% methanol in methylene chloride saturated with ammonia).
Reaction SMILES: C=CC=C.[CH2:5]([C:7]1([CH2:24][CH3:25])[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[N:9]=[CH:8]1)[CH3:6]>>[CH2:24]([C:7]1([CH2:5][CH3:6])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[N:9]=[CH:8]1)[CH3:25]
Reactant: CCC(CC)C1CC=CCCC=CCC(CC)(CC)C=N1
Agent: C=CC=C
Product: CCC(CC)C1CCCCCCCCC(CC)(CC)C=N1

Procedure:
Reaction of 1-(3-pentyl)-4,4-diethyl-2-aza-1,3-butadiene [produced by reaction of 2-ethylbutyraldehyde with ammonia, according to the U.S. Pat. No. 2,319,848] with 1,3-butadiene to 3,3-diethyl-12-(3-pentyl)-1-aza-1,5,9-cyclododecatriene (b.p. 90°-92° C./0.13 Pa; nD20 =1.4840), and hydrogenation to give 3,3-diethyl-12-(3-pentyl)-1-aza-cyclododecene; b.p. 95° C./4 Pa.
Reaction SMILES: CC(C)[CH2:3][O:4]CC1OC1.N1CCCC1.C[CH:16]([CH3:28])[CH2:17][O:18][CH2:19][CH:20]([OH:27])[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH3:3][O:4][CH:16]([CH3:28])[CH2:17][O:18][CH2:19][CH:20]([OH:27])[CH2:21][N:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)COCC1CO1
Reactant: CC(C)COCC(O)CN1CCCC1
Solvent: CCO
Solvent: C1CCNC1
Product: COC(C)COCC(O)CN1CCCC1
Reaction time: 1 h

Procedure:
20 g. 1-(2-Methylpropoxy)-2,3-epoxypropane are dissolved in 40 ml. ethanol and the solution is warmed to 55° C. Subsequently, in the course of an hour and while stirring, there is added dropwise a solution of 13 g. pyrrolidine in 25 ml. ethanol. The temperature should thereby not increase above 70° C. After completion of the addition, stirring is continued for 1 hour at 70° C., the reaction mixture is then evaporated and the residue is distilled in a vacuum. There are obtained 35 g. 3-(2-methylpropoxy)-1-pyrrolidinopropan-2-ol; b.p. 134° C./14 mm.Hg.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[CH3:11][N:12]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>C(O)C>[CH3:11][N:12]([CH:20]1[CH2:21][CH2:22][N:23]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][CH2:25]1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Clc1nc[nH]c2nccc1-2
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ncnc3[nH]ccc23)CC1

Procedure:
a mixture of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (307 mg, 2 mmol, commercially available from e.g. Aldrich, Apollo or Matrix) and 1,1-dimethylethyl methyl(4-piperidinyl)carbamate (429 mg, 2.000 mmol, commercially available from e.g. Fluorochem, Astatech or Apollo)) in Ethanol (4 ml) was microwaved at 120° C. for 1 h on normal absorption. After evaporation of the solvent, the crude product was purified via MDAP using the High pH extended method. Fractions containing product from each MDAP were combined and evaporated to give D12 as a white solid in 158 mg. LCMS [M+H]+332.06@0.76 min (2 min run)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@:13]2([CH2:16][CH2:17][OH:18])[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and pyridine-2-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=1.462 min, m/z=420.18; 1H NMR (CDCl3) 1.48 (d, 3H), 2.03-2.30 (m, 5H), 2.85 (m, 1H), 3.50 (m, 1H), 3.72 (m, 1H), 5.65 (m, 1H), 6.98 (m, 4H), 7.24 (m, 2H), 7.60 (m, 1H), 7.74 (m, 3H), 8.62 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[CH:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:13](=[O:27])[CH:12]([CH3:28])[CH2:11]1.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=2)[C:13](=[O:27])[CH:12]([CH3:28])[CH2:11]1
Reactant: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Product: CC1CC(c2c(O)cccc2F)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A cooled (−78° C.) solution of 5-(2-fluoro-6-methoxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (518 mg; 1.30 mmol) in anh. DCM (7 ml) was treated dropwise with a solution of boron tribromide BBr3 (1.0 M in DCM; 6.52 ml; 6.52 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Water was added dropwise, and the separated aq. layer was extracted with DCM. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered and concentrated to dryness under reduced pressure affording 5-(2-fluoro-6-hydroxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 383.89 g/mol.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[NH3:34]>>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:22][CH2:23][C:24]([NH2:34])=[O:25])([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)s1
Reactant: N
Product: Cc1nc(C)c(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccc(F)cc4)OC3=O)cc2)s1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-(2,4-dimethylthiazol-5-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one employing a procedure analogous to that described in Example 12 Step 2, followed by a procedure analogous to that described in Example 8 Step 2 using ammonia. LC-MS Method 1 tR=1.38 min, m/z=482 (M+1); 1H NMR (CDCl3) 7.32 (m, 5H), 7.18 (d, 2H), 7.04 (m, 4H), 5.69 (q, 1H), 2.84 (s, 3H), 2.45 (s, 3H), 2.02 (m, 1H), 1.55 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:13]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(-c2cccc(OC(F)(F)F)c2)cc1
Yield: 23 %

Procedure:
The title compound was prepared according to the procedure described in Example-2 using 5-(2-chloro-6-fluorophenyl)-2-(4-iodophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (step-4 of Intermediate-2, 0.100 g, 0.242 mmol), [3-(trifluoromethoxy)phenyl]boronic acid (0.075 g, 0.363 mmol), K2CO3 (0.100 g, 0.726 mmol), tetrakistriphenyl phosphine palladium (0) (0.055 g, 0.048 mmol) and DMSO (3.0 mL) to afford 0.025 g of desired product. 1H NMR (300 MHz, CDCl3): δ 7.19 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.46 (d, J=6.6 Hz, 1H), 7.53 (t, J=7.8 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 8.12 (d, J=8.4 Hz, 214), 10.01 (br s, 1H).
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[NH:23]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2B(O)O)=[N:26][N:25]=[N:24]1.[OH-].[Na+]>CO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][CH2:18][CH2:17][CH2:16][C:15]([N:7]([C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[NH:23][N:24]=[N:25][N:26]=2)=[CH:22][CH:21]=1)=[O:20]
Reactant: OB(O)c1ccccc1-c1nnn[nH]1
Reactant: CCCCC(=O)N(Cc1ccc(I)cc1)[C@H](C(=O)O)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Temperature: 70 °C
Yield: 85.1 %

Procedure:
Nitrogen is bubbled for 5 min. To a mixture made up of 0.20 g (0.48 mmol) of N-(4-iodobenzyl)-N-valeryl-L-valine, 0.115 g (0.61 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid, 0.017 g (0.024 mmol) of bis(triphenylphosphine)palladium chloride and 0.115 g (2.87 mmol) of NaOH in 2.4 mL of methanol and 0.7 mL of water are added. The reaction is heated to 70° C. under nitrogen atmosphere. Once 3 h has elapsed the reaction is considered to be completed and the methanol is distilled. The crude product is treated with 25 mL of HCl 1N and 25 mL of AcOEt. The AcOEt phase is dried with anhydrous sodium sulphate and after distilling the solvent the crude product obtained is purified by silica gel chromatography (eluent AcOEt/heptane/AcOH 1.5:5:0.2) to provide 0.178 g (85%) of Valsartan.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[C-:27]#[N:28].[K+]>C(Cl)Cl.CCCCCC>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[C:27]#[N:28]
Reactant: O=Cc1ccccc1Cl
Reactant: [C-]#N
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCC
Product: N#CC(c1ccccc1Cl)N1CCOCC1

Procedure:
As in Example 35, the following reactions are carried out. o-Chlorobenzaldehyde is reacted with p-toluenesulfonic acid, morpholine and KCN to give α-(o-chlorophenyl)-4-morpholineacetonitrile as crystals (from CH2Cl2 -hexane), m.p. 40°-42° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:41]1[CH2:45][CH2:44][NH:43][C:42]1=[O:46].O>CS(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:41]2[CH2:45][CH2:44][NH:43][C:42]2=[O:46])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C1NCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
15.8 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate are dissolved, in 70 ml of dimethylsulfoxide, and 5.8 g of anhydrous potassium carbonate are added thereto. The mixture is stirred at room temperature for 20 minutes. 6.6 g of 3-bromo-2-pyrrolidone are added to said mixture, and the mixture is stirred at room temperature for 20 hours. The mixture is poured into 800 ml of water, and crystalline precipitates are collected by filtration and washed with water. The crystals are dissolved in chloroform, washed with water and then dried. Then, the chloroform solution is evaporated under reduced pressure to remove solvent. 100 ml of ethyl acetate are added to the residue, and allowed to stand at room temperature. Crystalline precipitates thus obtained are collected by filtration and dried. 16.0 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl[C:8]1[N:9]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:10]2[C:15]([C:16]=1[CH:17]=O)=[CH:14][CH:13]=[CH:12][CH:11]=2.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:24][O:23][CH2:22][CH2:21][O:20][CH2:19][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[C:2]([C:3]([O:5][CH3:6])=[O:4])[S:1][C:8]1=2
Reactant: COC(=O)CS
Reactant: COCCOCn1c(Cl)c(C=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCCOCn1c2ccccc2c2cc(C(=O)OC)sc21
Reaction time: 8 h

Procedure:
400 μl of methyl 2-mercaptoacetate was added to a slurry of 1 g of (78) and 1.1 g of K2CO3 in 10 ml of MeOH. The reaction was stirred overnight, and then 20 ml of water was added. The mixture was extracted with EtOAc, and the organic layer washed with water, dried and evaporated to give (79) as a yellow oil. Yield 880 mg. 1H-NMR (ppm): 8.1(s, 1H); 7.8(d, 1H); 7.5(d, 1H); 7.3(m, 2H); 5.6(s, 2H); 3.9(s, 3H); 3.5(m, 4H); 3.35(s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.O.[C:15]([OH:19])(=[O:18])[CH:16]=O>C(O)(=O)C.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:16]/[C:15]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: CSc1ccc(/C=C/C(C)=O)cc1
Reactant: O=CC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(/C=C/C(=O)/C=C/C(=O)O)cc1

Procedure:
A solution of 10.5 g (54.6 mmol) of (E)-4-[4-(methylthio)phenyl]but-3-en-2-one and 5.02 g (54.6 mmol) of glyoxylic acid monohydrate in 15 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with methylene chloride. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether yielded (E,E)-6-[4-(methylthio)-phenyl]-4-oxo-2,5-hexadienoic acid of melting point 160°-163°.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24]([O:31][CH:32](Cl)[CH3:33])(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(C)C=CC=CC=1.CCCCCC.[K+].[Br-]>>[C:24]([O:31][CH:32]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:33])(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(=O)OC(C)Cl
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 11, piroxicam (2.00 g, 6.0 mmol) and alpha-chloroethyl hexanoate (3.51 g, 19.6 mmol) were converted to chromatographed title product as yellow oil which was crystallized from toluene/hexane (1.21 g, 2.5 mmol, 42.1%): mp 62°-65° C.; IR (KBr) 1755, 1676 cm-1 ; 1H NMR (CDCl3) delta 0.81 (t, J=7 Hz, 3H), 1.00-1.30 (m 4H), 1.35-1.53 (m, 2H), 1.73 (d, J=6 Hz, 3H), 2.08-2.32 (m, 2H), 3.12 (s, 3H), 6.39 (q, J=6 Hz, 1H), 7.05-7.32 (m, 1H), 7.57-7.95 (m, 5H), 8.30-8.43 (m, 2H), 9.58 (br s, 1H): precise mass calcd for C23H28N3O6S m/e (P+ +H) 474.1703, found 474.1645.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH3:21])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.C(OCC)(=O)C>CN(C=O)C.[Cu]=O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH3:21])[C:14]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1c(Br)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Reactant: c1cn[nH]c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(-n2cccn2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 100 °C
Yield: 26.9 %

Procedure:
A mixture of 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoic acid (Intermediate 133, 0.1 g), copper (II) oxide (0.004 g), cesium carbonate (0.254 g) and pyrazole (0.018 g) in DMF (2 ml) was sealed in a microwave vial in an atmosphere of nitrogen and heated at 100° C. for 18 hours. After cooling, ethyl acetate was added, and the mixture was filtered through celite. The filtrate was evaporated to dryness and the residue was purified by HPLC, eluting with a mixture of acetonitrile and water containing 0.1% formic acid with a gradient of 40-60% to give 6-(benzenesulphonylmethyl)-2-methoxy-3-(pyrazol-1-yl)benzoic acid (0.026 g) as a white solid.
Reaction SMILES: C(=O)([O:3]C(C)(C)C)[NH2:2].[CH3:9][C:10]([CH3:56])([O:12][C:13]([NH:15][CH:16]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[CH:43][CH:42]=1)[CH:17]([OH:39])[CH2:18][NH:19][CH2:20][CH:21]([OH:38])[CH:22]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:14])[CH3:11].C(Cl)(Cl)Cl>CO>[NH4+:2].[OH-:3].[CH3:11][C:10]([CH3:56])([O:12][C:13]([NH:15][CH:16]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH2:49][N:50]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)=[CH:45][CH:46]=1)[CH:17]([OH:39])[CH2:18][NH:19][CH2:20][CH:21]([OH:38])[CH:22]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:14])[CH3:9]
Reactant: CC(C)(C)OC(N)=O
Agent: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CNCC(O)C(Cc1ccc(OCCN2CCOCC2)cc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [NH4+]
Product: [OH-]

Procedure:
Alternatively, Compound 175e was prepared as follows. Compound 174 was converted to the title Compound 175e by a procedure analogous to that used for the synthesis of Compound 21. Flash chromatography (100% CHCl3 to CHCl3 --MeOH--NH4OH: 0:4.5:0.5) on a silica gel column gave Compound 175e as a white solid which was lyophilized from 1,4-dioxane to give a white lyophilate.
Reaction SMILES: [CH:1]1([N:7]([CH3:16])[C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[ClH:26].[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[CH2:35][CH2:36][CH2:37][NH2:38])=[CH:30][CH:29]=1.C(OCC)C>CN(C=O)C>[ClH:26].[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[CH2:35][CH2:36][CH2:37][NH:38][C:9](=[O:11])[C@@H:8]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH3:16])[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:30][CH:29]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C1CCCCC1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 76.2 %

Procedure:
(S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid (0.300 g, 1.32 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.690 mL, 3.96 mmol) and solid O-benzotriazol-1-yl-N,N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.501 g, 1.32 mmol). The resulting reaction mixture was stirred at that temperature for 40 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.393 g, 1.32 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 30 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an oil. The crude product was further purified by flash chromatography (50% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.51 g (75%) of the pure titled compound as a white foam; mp 73-83° C. APCI-MS m/z 471.4 (MH+).