Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16](O)[CH:17]2[CH2:21][O:20][N:19]([CH3:22])[C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])[CH:16]=[C:17]1[CH2:21][O:20][N:19]([CH3:22])[C:18]1=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1OCC(C(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CN1OCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O

Procedure:
A mixture of 20 g (60 mmol) of 4-[(3,5-di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-methyl-3-isoxazolidinone and 0.4 g of p-toluenesulfonic acid monohydrate in 300 ml of benzene was refluxed for 5 hours. The reaction mixture was concentrated and the concentrate triturated in 150 ml of ether to yield 10 g of the E-isomer of 4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-methyl-3-isoxazolidinone having a melting point of 194°-196° C.
Reaction SMILES: [F:1][C:2]1C=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:15][C:16]2[C:17]3[NH:13][CH2:8][C:7](=[O:12])[CH2:6][C:5]=3[CH2:4][CH2:9][C:10]=2[CH:11]=1
Reactant: C1CCNC1
Reactant: O=C1CCc2cc(F)ccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1CNC2=C(CCc3cc(F)ccc32)C1

Procedure:
16.7 g of 6-fluoro-3,4-dihydro-2(1H)-naphthalenone were boiled at reflux for 2.5 hours in 200 ml of benzene and 8.4 ml of pyrrolidine in the presence of 0.35 g of anhydrous p-toluenesulphonic acid. The crude 1-(6-fluoro-3,4-dihydro-2-naphthyl)pyrrolidine obtained was, without further purification, treated with 10.8 g of acrylamide and 0.5 g of p-toluenesulphonic acid. The mixture was heated under nitrogen to 100° for 2 hours and to 150° for 2 hours. The reaction mixture was dissolved in 180 ml of chloroform and washed with water. The organic phase was filtered over 150 g of silica gel (particle size 0.2-0.5 mm) while eluting with chloroform. After recrystallization from ethyl acetate there was obtained 8-fluoro-1,4,5,6-tetrahydrobenzo[h]quinolin-3(2H)-one of melting point 223°-224°.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]=O)=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.[CH3:51][O:52][NH2:53]>C(O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]=[N:53][O:52][CH3:51])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Yield: 66.4 %

Procedure:
To a solution of (2S,3S,4R,5S,6S)-2-(4-chloro-3-(4-(2-oxoethoxy)benzyl)phenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (200 mg, 0.365 mmol), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.147 mL, 1.82 mmol), sodium acetate (299 mg, 3.65 mmol) and O-methylhydroxylamine hydrochloride (152 mg, 1.82 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (3×25 mL). The organic layer was separated, washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1.5:8.5 Acetone:Pet. Ether) to afford the title compound (140 mg, 64.5%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[N:4]([CH3:24])[CH:5]=[C:6]([C:8]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[Cl:18])[CH3:10])[CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([O:17][C:14]2[CH:15]=[CH:16][C:11]([CH:9]([CH3:10])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[C:3](=[O:25])[N:4]([CH3:24])[CH:5]=3)([OH:23])[C:19]([F:21])([F:22])[F:20])=[C:12]([Cl:18])[CH:13]=2)=[CH:28][C:27]=1[Cl:26]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cc(Cl)c(=O)n(C)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3cc(Cl)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 151, step 8, 3-chloro-5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=564.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]([CH2:13][CH2:14][O:15][CH3:16])[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC1C=CC(S([CH2:27][N+:28]#[C-:29])(=O)=O)=CC=1.[H-].[Na+].C(Cl)Cl>CS(C)=O.CCOCC.CCOCC.[Cl-].[Na+].O>[CH2:11]([O:10][C:8]([C:7]1[C:6]([CH:5]([CH2:13][CH2:14][O:15][CH3:16])[CH2:4][CH2:3][O:2][CH3:1])=[CH:29][NH:28][CH:27]=1)=[O:9])[CH3:12]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=CC(CCOC)CCOC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)c1c[nH]cc1C(CCOC)CCOC
Reaction time: 3 h
Yield: 73.9 %

Procedure:
A solution of 24 (3.00 g, 13.03 mmol) and TosMIC (2.54 g, 13.02 mmol) in DMSO/Et2O (1:2, 25 mL) was added via cannula to a vigorously stirred suspension of NaH (649 mg, 27.04 mmol) in Et2O (11.3 mL) under argon. Stirring was continued for 3 h. Brine and CH2Cl2 were added in small portions. The aqueous layer was extracted with CH2Cl2. The organic extract was washed with brine. The solvent was removed at reduced pressure. The oily residue was chromatographed [silica, CH2Cl2/ethyl acetate (9:1)] to yield a pale yellow oil (2.59 g, 74%): 1H NMR δ 1.32 (t, J=7.2 Hz, 3H), 1.88-1.95 (m, 4H), 3.26-3.33 (m, 10H), 4.24 (q, J=7.2 Hz, 2H), 6.54 (s, 1H), 7.37 (s, 1H), 8.74 (br, 1H); 13C NMR δ 14.59, 30.35, 36.04, 58.50, 59.47, 71.65, 114.69, 116.66, 124.92, 129.05, 165.28; FAB-MS obsd 270.1703, calcd 270.1705 [(M+H)+, M=C14H23NO4].
Reaction SMILES: [N:1]12[CH2:6][CH:5]1[CH2:4][CH2:3][S:2]2(=[O:8])=[O:7].[Br:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18].[H-].[Na+].O>CN(C)C(=O)C>[Br:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH:5]2[CH2:4][CH2:3][S:2](=[O:8])(=[O:7])[NH:1][CH2:6]2)=[CH:12][C:11]=1[CH3:18]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=S1(=O)CCC2CN21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(OC2CCS(=O)(=O)NC2)cc(C)c1Br
Temperature: 130 °C
Reaction time: 5 h

Procedure:
2-Thia-1-aza-bicyclo[3.1.0]hexane 2,2-dioxide (Liang, Jiang-Lin et al., Organic Letters, 2002, vol. 4, #25 p. 4507-4510) (300 mg) is added to a suspension of 4-bromo-3,5-dimethylphenol (1.14 g) and sodium hydride (140 mg of a 60% mineral oil suspension) in 25 mL of N,N-dimethylacetamide. The reaction mixture is stirred at 130° C. for 5 h. Water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→30:70) to give the title compound. Yield: 220 mg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](OCC)(OCC)(OCC)[CH3:15]>>[C:9]([C:6]1[C:7]2[O:8][C:14]([CH3:15])=[N:1][C:2]=2[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][CH:5]=1)#[N:10]
Reactant: CCOC(C)(OCC)OCC
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1O
Product: Cc1nc2c([N+](=O)[O-])ccc(C#N)c2o1
Yield: 62.4 %

Procedure:
Compound 477B (0.360 g, 2.01 mmol) and triethyl orthoacetate (1.30 g, 8.04 mmol) were combined and heated at reflux under nitrogen for 1 h. The solvent was removed in vacuo and the resulting residue purified by flash chromatography eluting with 5% ether/CH2Cl2 to give 0.255 g (63%) of compound 477C as a brown solid. HPLC: 98.4% at 1.80 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 204.28 [M+H]+.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][N:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[C:18]([CH:19]3[CH2:24][O:23][CH2:22][CH2:21][O:20]3)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=2[N:14]=1)=[O:8].[CH3:30][O:31][CH2:32][CH2:33][OH:34].C(Cl)(Cl)Cl>O1CCOCC1.CN(C=O)C>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:27]=[CH:28][N:29]=[C:4]([O:34][CH2:33][CH2:32][O:31][CH3:30])[CH:5]=3)=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COCCOc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide sodium hydride and 2-methoxyethanol in dioxane and DMF. [α]D20=+17.6° (c=0.15, CHCl3), ES-MS m/e (%): 446 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:13][NH2:14].[Br:15][C:16]1[S:20][C:19]2=[N:21][C:22]([C:24](O)=[O:25])=[CH:23][N:18]2[CH:17]=1>>[Br:15][C:16]1[S:20][C:19]2=[N:21][C:22]([C:24]([NH:14][CH2:13][C:3]3[CH:4]=[C:5]([O:8][C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:7][C:2]=3[F:1])=[O:25])=[CH:23][N:18]2[CH:17]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: NCc1cc(OC(F)(F)F)ccc1F
Product: O=C(NCc1cc(OC(F)(F)F)ccc1F)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (2-fluoro-5-(trifluoromethoxy)phenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: O(CC1S[CH:14]2[CH:11](C(=O)[N:13]2[C:16](=C(O)C)[C:17]([O-:19])=O)N=1)C1C=CC=CC=1.CS(Cl)(=O)=O.[O:29]([CH2:36][C:37]1[S:43][CH:42]2[CH:39]([C:40](=[O:65])[N:41]2[C:44](=[C:58](OS(C)(=O)=O)[CH3:59])[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=2)=[O:46])[N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1CCOCC1>O1CCCC1.C(N(CC)CC)C>[O:29]([CH2:36][C:37]1[S:43][CH:42]2[CH:39]([C:40](=[O:65])[N:41]2[C:44](=[C:58]([N:13]2[CH2:16][CH2:17][O:19][CH2:11][CH2:14]2)[CH3:59])[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=2)=[O:46])[N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: CC(O)=C(C(=O)[O-])N1C(=O)C2N=C(COc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 1.5 h

Procedure:
One dissolves p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl -α-(1-hydroxyethylidene)acetate (940 mg) in tetrahydrofuran (14 ml), adds triethylamine (0.61 ml) and methanesulfonyl chloride (0.172 ml), and stirs for 1 hour ε+ -15° to -20° C. To the produced solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds morpholine (0.209 ml), stirs for 1.5 hours at -15° to -20° C., and for 2 hours at 0° C., to give a solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -15° C., adds pyridine (0.174 ml) followed by after 5 minutes a solution of bromine in carbon tetrachloride (1 mole/liter: 2.1 ml), stirs for 15 minutes at the same temperature, pours into water (50 ml), and extracts with ethyl acetate (50 ml). The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give residue (1.7 g). Purification of the residue by chromatography over silica gel containing 10% water gives from the fractions eluted with a mixture of benzene and ethyl acetate (2:1) p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethylidine)acetate (1.109 g; Yield: 89.7%) and p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethyl)-α-methanesulfonylacetate (85 mg; Yield: 7.7%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([O:55][C:56]1[C:61]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[CH:60][CH:59]=[CH:58][N:57]=1)[CH3:54]>CN(C=O)C>[CH2:53]([O:55][C:56]1[C:61]([C:62]2[CH:63]=[C:64]([NH:68][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=2)=[CH:60][CH:59]=[CH:58][N:57]=1)[CH3:54]
Reactant: CCOc1ncccc1-c1cccc(N)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ncccc1-c1cccc(NC(=O)c2cc3cccc(OC(F)(F)F)c3oc2=O)c1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
DIEA (0.013 mL, 0.077 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-Ethoxy-pyridin-3-yl)-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.016 g of product in 48% yield: LCMS (ESI) m/z 471 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].CC[O-].[Na+].[CH2:14]([O:16][C:17](=[O:23])[C:18](OCC)=O)[CH3:15]>CCO>[OH:8][C:7]1[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:1]=[C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:23])[N:9]=1
Reactant: NC(=O)c1sccc1N
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc(O)c2sccc2n1
Yield: 73.7 %

Procedure:
A mixture of 3-aminothiophene-2-carboxamide (1.23 g, 8.65 mmol) and EtOH (25 mL) was treated with NaOEt (1.2 g, 17.3 mmol) and diethyloxalate (2.3 mL, 17.3 mmol), refluxed for 18 h, cooled, concentrated in vacuo, treated with water, acidified with HOAc and filtered to give the title compound (1.43 g, 74%) as a cream solid: IR νmax Nujol)/cm−1 3180, 3119, 3078, 3006, 2955, 2924, 2854, 1737, 1667, 1651, 1300 and 1176; NMR δH (400 MHz, DMSO) 1.37 (3H, t, J 7.0 Hz), 4.40 (2H, q, J 7.0 Hz), 7.58 (1H, d, J 5.0 Hz), 8.30 (1H, d, J 5.1 Hz), and 12.92 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:34])[C@H:13]([CH3:33])[NH:14][C:15](C(OC)=O)([C:25]([O:27][CH3:28])=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]>CO.O>[C:1]([O:5][C:6](=[O:35])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:34])[C@H:13]([CH3:33])[NH:14][CH:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C(CCC(=O)c1cccs1)(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OC
Solvent: CO
Solvent: O
Product: COC(=O)C(CCC(=O)c1cccs1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
Aqueous N-sodium hydroxide solution (6.2 ml.) was added to a solution of N-[1,1-dimethoxycarbonyl-4-oxo-4-(2-thienyl)butyl]-L-alanyl-L-proline t-butyl ester (Example 31; 3.0 g.) in a mixture of methanol (3 ml.) and water (1.5 ml.) and the mixture was stirred at laboratory temperature for 16 hours and then evaporated to dryness under reduced pressure. The mixture was partitioned between water and ethyl acetate and the aqueous layer was separated, acidified to pH 5 with aqueous N-hydrochloric acid and extracted with dichloromethane. The extract was dried over magnesium sulphate and evaporated to dryness. There was thus obtained as residual oil N-[1-methoxycarbonyl-4-oxo-4-(2-thienyl)butyl]-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:26][CH2:27][CH3:28])=[C:4]([C:17]([CH3:25])=[C:18]([F:24])[C:19](OCC)=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].ClC1C(OCC)=C(/C(/C)=C(/F)\C(OCC)=O)C=C2C=1OC(C)(C)C=C2C(C)C.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:1][C:2]1[C:3]([O:26][CH2:27][CH3:28])=[C:4](/[C:17](/[CH3:25])=[C:18](/[F:24])\[CH2:19][OH:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)C(F)=C(C)c1cc2c(c(Cl)c1OCC)OC(C)(C)C=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Cl)c1OCC)OC(C)(C)C=C2C(C)C
Agent: [H-]
Product: CCOc1c(/C(C)=C(/F)CO)cc2c(c1Cl)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure L, ethyl 3-(8-chloro-4-isopropyl-7-ethoxy-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-enoate (Compound 148, 2.04 g, 5.66 mmol) and diisobutylaluminum hydride (1M in hexanes, 11.7 mL, 11.7 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 to 1:4 ethyl acetate/hexane).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+](=[C:13]([C:17](=[O:19])[CH3:18])[C:14](=[O:16])[CH3:15])=[N-]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:13]([C:17](=[O:19])[CH3:18])[C:14](=[O:16])[CH3:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(O)cc1
Reactant: CC(=O)C(=[N+]=[N-])C(C)=O
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: CC(=O)C(Oc1ccc(C(C)C)cc1)C(C)=O
Temperature: 25 °C
Yield: 39.4 %

Procedure:
To a refluxing solution of 4-isopropylphenol (0.548 g, 4.02 mmol) and rhodium(II) acetate (ca. 15 mgs) in benzene (10 mL) was added a solution of 3-diazo-pentane-2,4-dione (0.507 g, 4.02 mmol) in benzene (20 mL) over 40 minutes. The reaction mixture was allowed to cool to room temperature and was concentrated to afford a green oil. Flash chromatography over silica (ethyl acetate/hexanes) provided 0.371 g (39%) of the product as a white solid: 1H NMR (CDCl3) δ 14.4 (s, 1H), 7.15 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H), 2.87 (sept, J=7.0 Hz, 1H), 2.04, (s, 6H), 1.23 (d, J=7.0 Hz, 6H) ppm.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]([O:11]C)=O)=[C:7]([OH:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[S:4]1(=[O:19])=[O:18])[CH3:2].[NH2:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=1>C1(C)C(C)=CC=CC=1>[Cl:27][C:23]1[N:22]=[C:21]([NH:20][C:9]([C:8]2[N:3]([CH2:1][CH3:2])[S:4](=[O:19])(=[O:18])[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=3[C:7]=2[OH:13])=[O:11])[CH:26]=[N:25][CH:24]=1
Reactant: CCN1C(C(=O)OC)=C(O)c2ccccc2S1(=O)=O
Reactant: Nc1cncc(Cl)n1
Solvent: Cc1ccccc1C
Product: CCN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O
Yield: 63.9 %

Procedure:
8.5 g (30 mmols) of methyl 2-ethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 3.9 g (30 mmols) of 2-amino-6-chloro-pyrazine were reacted in 600 ml of xylene and worked up analogous to Example 1, yielding 7.3 g (64% of theory) of N-(6-chloro-pyrazin-2-yl)-2-ethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9](=[O:45])[C:10]([N:12]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:44])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](=[O:43])(=[O:42])[NH:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40])=[CH:31][CH:30]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.COC(=O)C(N(C1C=C(Cl)C=CC=1C(=O)CCC1C=CC(S(=O)(=O)NCC2COC(C)(C)O2)=CC=1)C1C=CC=CC=1)=O>CO>[CH3:7][O:8][C:9]([C:10]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[C:20]([C:26](=[O:44])[C:27]=1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](=[O:43])(=[O:42])[NH:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40])=[CH:31][CH:30]=1)=[CH:21][CH:22]=[C:23]([Cl:25])[CH:24]=2)=[O:45]
Reactant: COC(=O)C(=O)N(c1ccccc1)c1cc(Cl)ccc1C(=O)CCc1ccc(S(=O)(=O)NCC(O)CO)cc1
Agent: COC(=O)C(=O)N(c1ccccc1)c1cc(Cl)ccc1C(=O)CCc1ccc(S(=O)(=O)NCC2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(Cc2ccc(S(=O)(=O)NCC(O)CO)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
K2CO3 (12 mg) was added the mixture of N-(5-chloro-2-{3-[4-(2,3-dihydroxy-propylsulfamoyl)-phenyl]-propionyl}-phenyl)-N-phenyl-oxalamic acid methyl ester and N-(5-chloro-2-{3-[4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethylsulfamoyl)-phenyl]-propionyl}-phenyl)-N-phenyl-oxalamic acid methyl ester (0.05 mmol) in MeOH (5 mL), and the resulting mixture stirred at 80° C. for 1.5 h. The reaction mixture was then cooled and evaporated under reduced pressure. The residue was partitioned between water and EtOAc, the organic layer separated, and the aqueous layer extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified twice by preparative TLC (DCM/MeOH, 9:1) and then (DCM/MeOH, 95:5) to provide 7-chloro-3-[4-(2,3-dihydroxy-propylsulfamoyl)-benzyl]-4-oxo-1-phenyl-1,4-di-hydroquinoline-2-carboxylic acid methyl ester as light brown powder. MS=556.8 [M+H]+ and 554.9 [M−H]−.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[CH:11]#[C:12][CH3:13]>CN(C)C=O.CN(C)C(N(C)C)=N.[Cu]I.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>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:11]=[C:12]([CH3:13])[O:10][C:3]=2[CH:4]=1
Reactant: C#CC
Reactant: COc1ccc(I)c(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc2cc(C)oc2c1
Temperature: -78 °C
Yield: 69.2 %

Procedure:
A solution of 2-iodo-5-methoxy-phenol (39 g, 156 mmol) in dimethylformamide (300 mL) and N,N,N′,N′-tetramethylguanidine (150 mL) is treated with copper(I) Iodide (1.89 g, 9.82 mmol) and bis(triphenylphosphine)palladium(II) chloride (1.9 g; 2.71 mmol; 1.900 g). The mixture is cooled to −78° C. Propyne (100 g; 2.50 moles) is bubbled through the mixture for 1 hour. The reaction mixture is stirred and allowed to warm to room temperature gradually over 6 hours and stirred for 2 days. The reaction mixture is quenched with water (800 mL) and extracted with EtOAc (500 mL). The organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography eluting with 10% EtOAc/Hexanes. The appropriate fractions are concentrated. The material is dried in vacuo to afford the title compound (17.5 g, 69%). 1H NMR (400 MHz, CDCl3): δ 7.31-7.29 (d, 1H), 6.95 (s, 1H), 6.81-6.79 (d, 1H), 6.26 (s, 1H), 3.81 (s, 3H), 2.40 (s, 3H).