Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[I:9])N.Cl.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH2:20]=[N:21][OH:22].S([O-])([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[I:9])[CH:20]=[N:21][OH:22]
Reactant: Nc1ccc(I)c(F)c1
Reactant: C=NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: ON=Cc1ccc(I)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Fluoro-4-iodoaniline (15.36 g, 0.069 M) and concentrated hydrochloric acid (18.51 g) were dissolved in a mixture of water (30 ml) and ice (30 g). The solution was treated at 0–5° with a solution of sodium nitrite (4.81 g, 0.07 M) in water (15 ml). The pH of the resulting red-brown solution was adjusted to 5–6 by the addition of sodium acetate (6.05 g, 0.044 M). To the solution of formaldoxime was added sodium acetate (45.38 g, 0.333 M), hydrated copper sulfate (1.72 g, 6.9 mM) and sodium sulfite (0.275 g, 2.18 mM), giving a deep green solution, which was cooled to 10–15°. The solution of the diazonium salt was then slowly introduced with vigorous stirring, and stirring continued for 1 hour. The mixture was extracted with diethyl ether (3×100 ml), the combined extracts washed with water (100 ml), and dried (magnesium sulfate). The residue after filtration and evaporation was chromatographed in four portions on 50 g silica Mega Bond Elut® columns, eluting with a gradient from dichloromethane to 5% methanol in dichloromethane. Relevant fractions were combined to give the desired product (3.52 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[F:16][C:17]([F:22])([F:21])[C:18](O)=O>>[Cl:13][C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2)=[C:2]2[NH:1][C:18]([C:17]([F:22])([F:21])[F:16])=[N:12][C:11]=12
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Reactant: O=C(O)C(F)(F)F
Product: Oc1nc2cc(Cl)c3nc(C(F)(F)F)[nH]c3c2nc1O
Temperature: 0 °C
Yield: 68 %

Procedure:
A mixture of 0,3 g (1,35 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 8 ml trifluoroacetic acid was refluxed for 3 h. After cooling to 0° C., the precipitated product was filtered off and washed with ice-cooled trifluoroacetic acid and ether to give 0,28 g (68%) 4-chloro-7,8-dihydroxy-2-trifluoromethyl-1H-imidazo(4,5-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6) 7.10 (1H,s).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:35][C@H:34]([CH2:36][O:37]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4C)[C@H:13]3[O:14]C(=O)C3C=CC=CC=3)[C:6]=2[N:7]=1.[C:46]([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:23]([OH:24])[C@@:13]3([CH3:46])[OH:14])[C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1C(=O)O[C@H]1[C@@H](OC(=O)c2ccccc2)[C@H](n2c(=O)sc3cnc(N)nc32)O[C@@H]1COC(=O)c1ccccc1
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(=O)sc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a suspension of nucleoside 3 (380 mg, 0.606 mmol) in MeOH (20 mL) was added K2CO3 (17 mg, 0.12 mmol) at rt. The resulting mixture was stirred 18 h at rt whereupon it was treated with HOAc (15 μL, 0.25 mmol), concentrated and submitted to HPLC purification (MeCN—H2O), affording 20 mg (10%) of the title compound 4 as a white solid after lyophilization: 1H (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 6.86 (br s, 2H), 6.09 (br s, 1H), 5.19 (br s, 1H), 4.88 (br s, 1H), 4.55 (t, J=5.87, 1H), 3.97 (br s, 1H), 3.76-3.81 (m, 1H), 3.61 (br s, 2H), 1.04 (s, 3H); [M+H]+ m/z 315. Analysis calc'd for C11H14N4O5S.H2O: C, 39.75; H, 4.85; N, 16.86; S, 9.65.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6][C:7]([C:10]1[S:14][C:13]([NH2:15])=[N:12][N:11]=1)([CH3:9])[CH3:8]>C(OC(=O)C)C>[CH3:5][S:6][C:7]([C:10]1[S:14][C:13]([N:15]=[C:1]=[O:2])=[N:12][N:11]=1)([CH3:9])[CH3:8]
Reactant: O=C(Cl)Cl
Reactant: CSC(C)(C)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CSC(C)(C)c1nnc(N=C=O)s1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A 300 milliliter, 3-neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotometer was charged with 50 milliliters of ethyl acetate and then with 20 grams of phosgene. An additional 50 milliliters of ethylacetate and 6.6 grams (0.035 mole) of 5-(1-methylthio-1-methylethyl)-2-amino-1,3,4-thiadiazole (prepared above) at a temperature of 0° C. was added. The resulting mixture was stirred for 17 hours at room temperature and then the flask was purged with nitrogen until no COCl2 was detected. The slurry was filtered, and the filter cake was dried in a vacuum oven to a m.p. of 161°-164° C., and the filtrate was topped on a roto-vac to yield more crystals with a m.p. of 161°-162° C., which were combined with the first crystals to yield 7.1 grams of 5-(1-methylthio-1-methylethyl)-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([CH2:19][O:20][C:21]3[C:26]([F:27])=[CH:25][C:24]([CH2:28][CH:29]([CH3:35])[C:30](OCC)=[O:31])=[CH:23][C:22]=3[F:36])=[C:17]([C:37]([F:40])([F:39])[F:38])[S:16][N:15]=2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([CH2:19][O:20][C:21]3[C:26]([F:27])=[CH:25][C:24]([CH2:28][CH:29]([CH3:35])[CH2:30][OH:31])=[CH:23][C:22]=3[F:36])=[C:17]([C:37]([F:39])([F:40])[F:38])[S:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)Cc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(CO)Cc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 111 by LAH reduction of ethyl 3-(4-((3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoate to afford the desired product as an off-white solid. 1H NMR (CDCl3): 7.82 (d, J=7.2 Hz, 2H), 7.52 (d, J=7.2 Hz, 2H), 6.79-6.85 (m, 2H), 5.20 (s, 2H), 3.33-3.41 (m, 2H), 2.76 (dd, J1=5.2 Hz, J2=5.2 Hz, 1H), 2.74-2.79 (m, 1H), 1.82-1.91 (m, 1H), 0.89 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H17ClF5NO2S, 478.1 (M+H). found 478.1.
Reaction SMILES: [OH-].[Na+].C([NH:6][CH:7]([CH3:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:22])=[CH:16][C:17]([O:19][CH2:20]C)=[O:18])=[CH:11][CH:10]=1)(=O)C>O>[C:17]([CH:16]=[C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:7]([CH3:23])[NH2:6])=[CH:14][CH:13]=1)[CH3:22])([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)C=C(C)c1ccc(CC(C)NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C=C(C)c1ccc(CC(C)N)cc1
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide (6 g) in water (30 ml) was added to N-acetyl-2-{4-(2-carboethoxy-1-methylethenyl)phenyl}-1-methylethanamine (8.5 g) and the mixture stirred and heated under reflux for 8 hrs. The solution was cooled and evaporated to dryness. The residue was dissolved in methanol (30 ml) and made acid by addition of conc. HCl. The precipitated sodium chloride was removed by filtration, and the methanol solution dried over molecular sieves overnight. This solution was then added to a solution of thionyl chloride (8 ml) in dry methanol (10 ml) kept at -70° C. by Dry Ice/acetone. After warming to ambient temperature, the solution was stirred and heated under reflux for 1 hour. The solution was cooled, filtered and evaporated, the residue shaken with an aqueous solution of potassium carbonate and extracted with chloroform. The chloroform extract was dried (MgSO4) and evaporated to leave an oil, (2.8 g). τ(CDCl3) 8.9 (3H, d, J=8 Hz), 8.5 (2H, bs, exchangeable with D2O), 7.45 (3H, d, J=1.5 Hz). 7.2-7.4 (2H, m), 6.6-7.0 (1H, m), 6.3 (3H, s), 3.92 (1H, q, J=1.5 Hz), 2.5-3.0 (4H, m).
Reaction SMILES: C([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:20][S:17]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([OH:21])=[O:5])(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)c1ccc(S(C)(=O)=O)c(S(C)(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)O)cc1S(C)(=O)=O
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To 3,4-bis-methanesulfonyl-benzoic acid tert-butyl ester (0.366 g) in dichloromethane was added trifluoroacetic acid and the reaction mixture was stirred for 3 hours. The mixture was evaporated and trituration of the residue with diethyl ether gave the title compound (0.29 g; MS: APCI+(M+H) 279).
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1.N1C=CN=C1.CN(C)C=O>C(OCC)(=O)C>[Si:5]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.7 mL of t-butylchlorodiphenyl silane was added to the mixture of 5 g of 1-(4-hydroxyphenyl)-1-ethanone, 3 g of imidazole, and 70 mL of N,N-dimethylformamide, and stirred overnight at room temperature. The reaction mixture was added with 200 mL of ethyl acetate, washed with water and saturated brine in the subsequent order, and the obtained organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to obtain 11.7 g of 1-(4-{[t-butyl(diphenyl)silyl]oxy}phenyl)-1-ethanone [79-1] as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]3[CH2:18][CH2:17][CH2:16][C:11]3=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[O:24]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:20]=[CH:19][C:9]3[N:10]4[CH2:18][CH2:17][CH2:16][C:11]4=[N:12][S:13](=[O:15])(=[O:14])[C:8]=3[CH:7]=2)=[CH:25]1
Reactant: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(Br)c3)cc21
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(-c4ccoc4)c3)cc21
Temperature: 80 °C

Procedure:
A suspension of the product obtained in Step A of Example 16 (300 mg, 0.76 mmol), 111 mg (0.99 mmol) of 3-furanboronic acid, 137 mg (0.99 mmol) of K2CO3 and 45 mg (0.038 mmol) of tetrakistriphenylphosphine in a mixture of 6 ml of ethanol and 1.8 ml of water is heated at 80° C. for 3 hours under N2. The ethanol is evaporated off in vacuo and the residue is taken up in water and 1N HCl. The precipitate is filtered off to yield the title product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].[CH3:9]C(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[H-].[Na+]>CC(O)C.C(COC)OC.IC>[CH3:9][O:8][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: CC(C)[O-]
Reactant: Cc1ncsc1C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Solvent: CC(C)O
Product: COCc1scnc1C

Procedure:
4-Methyl-5-thiazolecarbaldehyde (J. Amer. Chem. Soc., 1982, 104, 4934-4943) was reduced using aluminium isopropoxide in 2-propanol. The resulting alcohol was treated with sodium hydride in dimethoxyethane and iodomethane was added. Distillation gave the title compound.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([NH:19][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and n-hexylamine comparable as in Example A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:14]=3)=[CH:11][C:10]([C:24]([O:26]CC)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F.C(#N)C.O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OCCOC)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Solvent: CC#N
Solvent: O
Solvent: O=CO
Product: COCCOc1cccc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 69A in analogy to the synthesis of the compound of Example 71A and with purification by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with the addition of 0.1% formic acid). 46 mg (100% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:33])=[CH:18][C:17]=1[CH3:35].Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:33])=[CH:18][C:17]=1[CH3:35]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4c(C)cccc4C)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4c(C)cccc4C)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylphenyl}-2-(2,6-dimethylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C1(=O)O[CH2:15][CH2:14][O:13]1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:15][CH2:14][OH:13])(=[O:3])[CH3:2]
Reactant: O=C1OCCO1
Reactant: CC(=O)Nc1cccc(O)c1
Product: CC(=O)Nc1cccc(OCCO)c1
Yield: 99 %

Procedure:
The title product was prepared according to the procedure described in Example 114, Step 1, starting from 3-acetamidophenol (2.10 g, 13.9 mmol) and ethylene carbonate (0.88 g, 10 mmol). The crude product was purified by column chromatography on silica using toluene/EtOAc/MeOH (49:49:2). Oil; yield 99%. MS m/z 195 (M)+.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)([O:3]C)=O.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C(O)(=O)C>O>[C:12]1([N:18]2[C:1](=[O:3])[C:5]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[NH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)C1CCCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2c([nH]n1-c1ccccc1)CCCC2

Procedure:
32.9 Parts of a mixture containing 60% 2-carboethoxyclohexanone and 40% of 2-carbomethoxycyclohexanone purchased from Aldrich Chemical Company, Milwaukee, Wisconsin 53233, and 21.6 parts of phenylhydrazine purchased from Eastman Organic Chemicals Company, Rochester, N. Y. 14650, were admixed in 200 parts of toluene containing 2.0 parts of acetic acid. The mixture was refluxed for two hours with water removal. The resulting yellow suspension was cooled to 0°. The solid was collected, washed with hexane and dried. The yield was 37.1 parts of white solid with m.p. 178°-181°.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6](S(C)(=O)=O)[CH:7]=[C:8]([C:10](=[N:20][NH2:21])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4].[CH:26](OCC)(OCC)OCC.C([O-])(O)=O.[Na+]>C(O)=O>[F:19][C:13]1[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[CH:26]=[N:21][N:20]=[C:10]1[C:8]1[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[NH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1cc(C(=NN)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: O=C(O)c1cc(-c2nncn2-c2cccc(F)c2F)c[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[N-(2,3-difluoro-phenyl)-N′-amino-carbamimidoyl]-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid methyl ester (200 mg, 0.54 mmol), CH(OEt)3 (4 mL), and HCOOH (0.8 mL) was stirred at room temperature for 2 hours and poured into 50 mL of aqueous NaHCO3 solution. The aqueous mixture was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered, and evaporated. The crude material was used for the next step without further purification. This crude product was dissolved in MeOH (5 mL) then 6N NaOH aqeous solution was added (1 mL) and the mixture was heated at 50° C. for 3 hours. The solvent was evaporated and the residue was acidified with 6N HCl to pH 3. The white precipitate was collected by filtration and washed with water. The crude product (150 mg, 96%) was dried on the pump for the next reaction. 1H NMR (500 MHz, DMSO-d6) δ12.61 (s, br, 1H), 12.20 (s, 1H), 8.78 (s, 1H), 7.75 (m, 1H), 7.55 (m, 1H), 7.47 (m, 1H), 6.96 (s, 1H), 6.58 (s, 1H) ppm. MS (ES+): m/e=291.1 (M+H); LC/Method A/2.46 min.
Reaction SMILES: [Br-:1].[K+].N[C@@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7].N([O-])=O.[Na+]>S(=O)(=O)(O)O>[Br:1][C@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:9]([OH:11])=[O:10]
Reactant: [Br-]
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)C[C@@H](Br)C(=O)O
Temperature: -10 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Potassium bromide (9.5 g., 80 mmol) was added to a stirred solution of D-leucine (3.0 g., 23 mmol) in 2.5N sulfuric acid (47 ml) at room temperature. The reaction mixture was cooled to -10° C. and solid sodium nitrite (2.4 g., 34 mmol) was added portionwise, maintaining the temperature between -10° and -5° C. After addition was complete, the reaction was stirred for 1 hour and then warmed to room temperature and stirred for another hour. The reaction mixture was then extracted twice with ether, the ether extracts were washed once with water, dried (magnesium sulfate), filtered and evaporated to give 2.7 g of crude title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C@H:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:22][CH2:21]4)[C:12]([CH3:33])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li+].[OH-].CO.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C@H:23]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:21]4)[C:12]([CH3:33])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(OC)cc4)ccc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(C)c(CCOc3ccc4c(c3)CC[C@H]4CC(=O)O)n2)cc1

Procedure:
Following the procedure described above (Example 472, step 2) and starting with ethyl ((1S)-5-{2-[6-(4-methoxyphenyl)-3-methyl-2-pyridinyl]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 481, 90 mg, 0.190 mmol) and LiOH (50 mg, 1.91 mmol) in a mixture of THF (4 mL), MeOH (5 mL), and water (2 mL), the title compound was obtained (0.052 g, 65%). 1H NMR (400 MHz, CD2Cl2) δ 7.96 (d, 2H), 7.52-7.45 (m, 2H), 7.09 (d, 1H), 6.96 (d, 2H), 6.83 (d, 1H), 6.74 (dd, 1H), 4.49 (t, 2H), 3.86 (s, 3H), 3.50 (qt, 1H), 3.31 (t, 2H), 2.96-2.75 (m, 3H), 2.52-2.35 (m, 5H), 1.82-1.73 (m, 1H); LC-MS: RT=2.48 min, (M+H)+ 418.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17]I.O>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
To a vigourosly stirred solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.07 g, 10.3 mmol) in DMF (25 mL) was added a 60% sodium hydride dispersion in mineral oil (500 mg, 12.5 mmol). After stirring for 20 min, methyl iodide (0.9 mL, 14.5 mmol) was added and the resulting mixture stirred for 48 h before being added to a mixture of water and brine (250 mL, 1:1). Extraction with ethyl acetate (4×50 mL), washing of the combined extracts with brine (100 mL) and drying (MgSO4) gave, after concentration, a residue which was purified via flash chromatography (silica gel, ethyl acetate/hexane, 1:1) to give the title compound as a colourless oil. δH (CDCl3): 1.50 (9H, s), 1.52, 1.88 (4H, 2m) 3.12 (2H, ddd), 3.18 (1H, m), 3.19 (3H, s), 3.77 (2H, m); Rf0.33 (ethyl acetate/hexane: 1/1).
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].[CH2:14]([Mg]Br)C>C(OCC)C>[CH3:14][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[OH:13]
Reactant: CC[Mg]Br
Reactant: COc1cccc2c1CCCC2=O
Solvent: CCOCC
Product: Cc1cccc2c(O)cccc12
Temperature: 0 °C

Procedure:
5-Methoxy-1-tetralone (5) (4 g, 22.6 mmol) was dissolved in 50 mL anhydrous diethyl ether, stirred, and cooled down on ice to 0° C. Ethylmagnesium bromide (19 mL, 56.8 mmol) was added dropwise to the solution, producing copious precipitation. The mixture was then heated to reflux and stirred for 10 h. After cooling, cold water was added slowly to the reaction mixture, which was then extracted with diethyl ether three times. The organic layer was evaporated to afford crude product 6. Without purification, zinc chloride (15 g, 114 mmol) was added to a solution of 6 in benzene (35 mL), then concentrated hydrochloride acid (12 mL) was added to the solution at room temperature. The reaction mixture was heated to reflux for 5 h, cooled, extracted with diethyl ether three times, and the organic layer was evaporated to afford crude product. Purification by column chromatography gave 7 (2 g). To a solution of 7 (2 g) in triglyme (15 mL) was added 10% Pd/C (2 g) and the mixture was heated to reflux for 3 days. After cooling, diethyl ether was added to the mixture and it was filtered on Celite, then washed with diethyl ether to provide compound 8.50% yield; 1H NMR δ1.37 (3H, t, J=7.8 Hz, CH3CH2—), 3.10 (2H, q, J=7.8 Hz, CH3CH2—), 4.01 (3H, s, OCH3), 6.82 (1H, d, J=7.8 Hz, H-2), 7.36-7.44 (3H, m, H-3, 6, 7), 7.64 (1H, d, J=8.7 Hz, H-4), 815 (1H, d, J=8.4 Hz, H-8).