Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[CH:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[O:19])=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc2c(c1)CCC2Oc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc3c(c2)CCC3Oc2ccccc2)c(O)n1
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a solution of 1-phenoxy-2,3-dihydro-1H-indene-5-carboxylic acid (100 mg, 0.39 mmol) in dichloromethane (50 mL) were added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol) and triethylamine (71 mg, 0.7 mmol). And then the mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (61 mg, 0.4 mmol) was added. The mixture was stirred at room temperature for 12 hours. The resultant mixture was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-1-phenoxy-2,3-dihydro-1H-indene-5-carboxamide (Compound I-45) (35 mg, 23%) as white solid. LRMS (M+H+) m/z: calcd 388.18. found 388. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.47 (s, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.41-7.29 (m, 3H), 7.05-6.93 (m, 3H), 5.89-5.86 (m, 2H), 4.30 (d, J=4.8 Hz, 2H), 3.10-2.84 (m, 2H), 2.64-2.56 (m, 1H), 2.16 (s, 3H), 2.11 (s, 3H), 2.09-1.98 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1.[CH:29](=O)[CH3:30].[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([CH2:29][CH3:30])[CH2:21][CH2:22]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCNCC2)CCO1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCN(CC)CC2)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.3 %

Procedure:
To a solution of 4-amino-5-chloro-2-ethoxy-N-[{4-(4-piperidinylmethyl)-2-morpholinyl}-methyl]benzamide (Example 22) (1.0 g) and TEA (0.49 g) in methanol (10 ml) was added acetaldehyde (0.21 g) under ice-cooling. The mixture was stirred at the same temperature for 2 hours, and then thereto was gradually added sodium borohydride (92 mg). After completion of addition, the mixture was stirred at the same temperature for 1 hour, and warmed to room temperature to stir overnight. The reaction solution was dried under reduced pressure to be solidified, and the residue was dissolved in chloroform, washed with water, then brine, and dried over anhydrous magnesium sulfate. Then, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (1.2 g) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]([F:35])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=3)[CH2:18][O:17][N:16]=2)=[C:11]([CH3:34])[CH:10]=1)[C:3]([O:5]CC)=[O:4].C(OC1C=CC(C2N=C(C3C=CC(CCC(OC)=O)=CC=3C)ON=2)=CC=1C(F)(F)F)(C)C>>[F:35][C:2]([F:1])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=3)[CH2:18][O:17][N:16]=2)=[C:11]([CH3:34])[CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)(F)Cc1ccc(C2=NOCN2c2ccc(OC(C)C)c(C(F)(F)F)c2)c(C)c1
Agent: COC(=O)CCc1ccc(-c2nc(-c3ccc(OC(C)C)c(C(F)(F)F)c3)no2)c(C)c1
Product: Cc1cc(CC(F)(F)C(=O)O)ccc1C1=NOCN1c1ccc(OC(C)C)c(C(F)(F)F)c1

Procedure:
The title compound was prepared using the procedure analogous to that described for EXAMPLE 75 substituting ethyl 2,2-difluoro-3-(4-(4-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from Step A) for methyl 3-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-methylphenyl)propanoate in Step E: 1H NMR (500 MHz, CD3OD) δ 1.41 (d, J=5.9, 6H), 2.64 (s, 3H), 3.45 (t, J=16.7, 2H), 4.92 (m, 1H), 7.29-7.32 (m, 2H), 7.43 (d, J=8.4, 1H), 8.01 (d, J=7.8, 1H), 8.38-8.40 (m, 2H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][NH:6][CH:7]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:8].C(N(CC)CC)C.[C:26]1([CH2:32][O:33][C:34]([NH:36][C@H:37]2[CH2:40][NH:39][C:38]2=[O:41])=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.ClCCl>[C:26]1([CH2:32][O:33][C:34]([NH:36][CH:37]2[CH2:40][N:39]([C:38]([N:6]([CH3:5])[C@H:7]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH3:8])=[O:41])[C:1]2=[O:2])=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CNC(C)C(=O)OCc1ccccc1
Reactant: O=C(Cl)Cl
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](C(=O)OCc1ccccc1)N(C)C(=O)N1CC(NC(=O)OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of phosgene in toluene (4.7 ml of a 20% solution, 9.36 mmol) was cooled to -25° C. under argon. While stirring, a solution (pre-cooled to 0° C.) of N-methyl-DL-alanine, benzyl ester (1.0 g, 5.2 mmol) and triethylamine (870 μl, 6.25 mmol) in dichloromethane (5 ml) was added over 5 minutes maintaining the temperature at -20° to -25° C. After stirring at -25° C. for 1 hour, solvent and excess phosgene were removed in vacuo. The residue was dissolved in dichloromethane (12 ml), cooled to 0° C. and then (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (1.15 g, 5.2 mmol), dimethylaminopyridine (63 mg, 0.52 mmol), and triethylamine (870 μl, 6.2 mmol) were added sequentially. Stirring was continued for 10 minutes at 0° C. and then overnight at room temperature. After refluxing for an additional 7 hours, the mixture was again stirred overnight at room temperature. The mixture was washed with water, dried (Na2SO4) and solvent was removed in vacuo. The resulting oil was chromatographed on silica gel eluting with a 4:6 ethyl acetate:hexane mixture. The desired product was obtained as an oil (580 mg).
Reaction SMILES: [C:1]([O-])([O-])=O.[Na+].[Na+].[I-].[NH2:8][N+:9]1C=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH3:16].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19]>CN(C=O)C>[CH2:15]([C:10]1[N:9]2[N:8]=[CH:1][C:18]([C:17]([O:21][CH2:22][CH3:23])=[O:20])=[C:19]2[CH:13]=[CH:12][CH:11]=1)[CH3:16]
Reactant: C#CC(=O)OCC
Reactant: O=C([O-])[O-]
Reactant: CCc1cccc[n+]1N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2c(CC)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
Next, 2.2 g (20.8 mmol) of Na2CO3 were added to a solution of 4.5 g (18.0 mmol) of 1-amino-2-ethylpyridinium iodide in 20 ml of DMF, followed by stirring at room temperature for 1 hour. Ethyl propiolate (3.6 g; 36.7 mmol) was added further, followed by stirring at room temperature for 20 hours. The solvent of the reaction mixture was distilled off. Water was added to the residue, followed by extraction with methylene chloride. After the methylene chloride layer was dried over Na2SO4, the solvent was distilled off and the residue was purified by chromatography on a silica gel column, whereby 0.93 g (4.3 mmol) of the title compound was obtained as crystals (yield: 24%-12% in two steps).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH:10]=[O:11].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O>CN(C)C=O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH:10]=[O:11])=[CH:15][C:14]=1[CH2:20][OH:21]
Reactant: OCc1cc(O)ccc1Br
Reactant: N#Cc1ccc(F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2ccc(Br)c(CO)c2)c(C=O)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of 4-fluoro-3-formylbenzonitrile (14.2 g, 96.0 mmol), 4-bromo-3-hydroxymethylphenol (19.4 g, 96 mmol), and potassium carbonate (15.2 g, 110 mmol) in N,N-dimethylformamide (200 mL) was stirred at 70° C. under nitrogen atmosphere for 2 h. The mixture was poured into ethyl acetate/water. The organic layer was washed with water twice and with brine, then dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (3:1 to 7:3 hexane/ethyl acetate) to give 4-[4-bromo-3-(hydroxymethyl)phenoxy]-3-formylbenzonitrile (26.0 g, 82%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C1OCCOCCOCCOCCOC1.[H-].[Na+].Br[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=2)=[C:36]([O:50][CH3:51])[CH:35]=1>CN(C=O)C.O>[CH3:51][O:50][C:36]1[CH:35]=[C:34]([CH2:33][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])[CH:39]=[CH:38][C:37]=1[C:40]1[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=1
Reactant: COC(=O)c1ccc(-c2ccc(CBr)cc2OC)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3=O)cc2OC)cc1
Temperature: 60 °C

Procedure:
A solution of Example 500B (328 mg, 1.64 mmol) in DMF (4 mL) at room temperature was treated with 15-crown-5 (361 mg, 1.64 mmol) and 60% sodium hydride in mineral oil (66 mg, 1.64 mmol). The mixture was treated with a solution of Example 500C (500 mg, 1.49 mmol) in DMF (2 mL), heated to 60° C. for 16 hours, cooled to room temperature, treated with water (20 mL), and extracted three times with ethyl acetate (50 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:1 ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:20][CH2:21][CH2:22][CH:23]([CH:25]1[CH2:30][CH2:29][C:28]([CH3:31])=[CH:27][CH2:26]1)[CH3:24])(=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>C(Cl)Cl>[C:12]([O:20][CH2:21][CH2:22][CH:23]([CH:25]1[CH2:30][CH2:29][C:28]2([O:9][CH:27]2[CH2:26]1)[CH3:31])[CH3:24])(=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCC(=O)OCCC(C)C1CC=C(C)CC1
Solvent: ClCCl
Product: COC(=O)CCC(=O)OCCC(C)C1CCC2(C)OC2C1
Reaction time: 8 h

Procedure:
An 8.2g (0.04 mole) portion of 85% m-chloroperbenzoic acid was added portionwise over 15 min. to a stirred, cooled (0° C.) solution of 11.3g (0.04 mole) of succinic acid, 3-(4-methyl-3-cyclohexenyl)butyl methyl ester in 250 ml of methylene chloride. The temperature rose to 10° C. during the addition and to ambient after the cooling bath was removed. The reaction mixture was stirred overnight. Sufficient 5% sodium hydroxide was added to dissolve the precipitated acid, and the organic layer was separated, washed with 5% sodium hydroxide and with brine, dried over magnesium sulfate and concentrated. Obtained was 10.6g of succinic acid 3-(3,4-epoxy-4-methylcyclohexyl) butyl methyl ester as a clear, colorless liquid. The analytical determinations indicated that the product was pure and did not require further purification (See Table I).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.O>CN(C)C=O>[ClH:1].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][S:5]([C:8]2[C:17]3[O:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=3[CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:36][CH2:35]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1c(-c2ccccc2)oc2c(S(=O)(=O)CCCCl)cccc2c1=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCS(=O)(=O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Product: Cl

Procedure:
A solution of 3.8 g of Intermediate XXXV and 4 g of 1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide was heated at 60° C. for 7 hours. After cooling to 20°-25° C., the reaction mixture was poured into 500 ml of water and extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate, and the solvent was then evaporated off in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate:petroleum ether (1:1). The base of the title compound was obtained. It was dissolved in ethanol and one equivalent of ethanolic hydrogen chloride was added to give 4.5 g of the title compound, m.p. (215) 226°-228C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]>C1(C)C=CC=CC=1.CO.[Pd]>[OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(O)c2c(-c3ccc(C#CCCCO)cc3)csc2[nH]c1=O
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#Cc1c(O)c2c(-c3ccc(CCCCCO)cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of Pd (BaSO4) (15 mg) in toluene (2 mL) and methanol (1 mL), was added 4-hydroxy-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (50 mg) in a single portion. The reaction was purged with hydrogen, and stirred under atmosphere hydrogen at rt for 24 h. The mixture was filtered through celite, and rinsed with methanol. The filtrate was concentrated and purified via reverse phase HPLC to afford the titled compound. MS (ESI) m/e 353 (M−H)+; 1H NMR (500 MHz, DMSO-d6): δ 1.31–1.47 (m, 4H), 1.55–1.61 (m, 2H), 1.94 (t, J=7.64 Hz, 2H), 2.58 (t, J=7.64 Hz, 2H), 6.91 (s, 1H), 7.15 (d, J=8.11 Hz, 2H), 7.31 (d, J=8.11 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].O[CH2:23][CH:24]1[O:28][C:27](=[O:29])[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25]1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:23][CH:24]1[O:28][C:27](=[O:29])[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25]1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1OC(CO)CC1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OC(COS(=O)(=O)C(F)(F)F)CC1(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride, 5.5 mL (32.5 mmol.), was added to 14 mL dry methylene chloride under argon at room temperature. The solution was cooled to -40° C. and 2.3 g (22 mmol.) of finely powdered, oven dried Na2CO3 was added. To the stirred mixture 6.7 g (25 mmol.) of 5-(hydroxymethyl)-4,5-dihydro-3,3-diphenyl-2(3H)furanone in 15 mL of methylene chloride was added dropwise, stirring 2 hours at -40° C. before warming to 0° C. for 0.5 hours. The reaction was quenched at 0° C. by adding 10 mL of water dropwise with vigorous stirring. The layers were separated, the organics washed with brine, dried (MgSO4), and evaporated at reduced pressure to a solid. This material was used as received and usually contained 5 to 15% of unreacted alcohol. 1H NMR (CDCl3)δ 2.77-2.83 (m, 1H), 3.05-3.14 (m, 1H), 4.51-4.71 (m, 2H), 4.7-4.75 (m, 1H), 7.25-7.45 (m, 10H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[CH2:4][CH2:5]CN=C=NCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:38]3[C:46]4[C:41](=[CH:42][C:43]([C:47]([OH:49])=[O:48])=[CH:44][CH:45]=4)[N:40]([CH3:50])[CH:39]=3)[C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=3[O:36][CH3:37])(=[O:28])=[O:27])=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1.CN(CCO)C>C(Cl)Cl.CN(C=O)C>[CH3:2][N:3]([CH3:12])[CH2:4][CH2:5][O:48][C:47]([C:43]1[CH:42]=[C:41]2[C:46]([C:38]([CH:22]([C:20]3[CH:19]=[CH:18][C:17]4[O:13][CH2:14][O:15][C:16]=4[CH:21]=3)[C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=3[O:36][CH3:37])(=[O:27])=[O:28])=[O:24])=[CH:39][N:40]2[CH3:50])=[CH:45][CH:44]=1)=[O:49]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)O)ccc12
Agent: CN(C)CCO
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)OCCN(C)C)ccc12

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (128 mg, 0.67 mmol) was added to a stirred solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolecarboxylic acid (the product of Example 17, 300 mg, 0.56 mmol), N,N-dimethylaminopyridine (75 mg, 0.61 mmol) and dimethylaminoethanol (0.17 ml, 1.67 mmol) in a mixture of CH2Cl2 (9 ml) and DMF (0.5 ml) at room temperature under a nitrogen atmosphere. After 12 h a fine white precipitate had formed. The product was removed by filtration and washed with cold methanol.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5](O)=[N:6][C:7]=1[CH3:8].[ClH:13]>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5]([Cl:13])=[N:6][C:7]=1[CH3:8]
Reactant: Cl
Reactant: Cc1nc(O)c(C#N)c(C)c1Br
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c(C#N)c(C)c1Br
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of 9.0 grams (0.040 mole) of 5-bromo-3-cyano-2-hydroxy-4,6-dimethylpyridine in 40 mL of phosphorus oxychloride is stirred, and one drop (catalyst) of N,N-dimethylformamide is added. The reaction mixture is then stirred at ambient temperature for about five hours, and then allowed to stand for about 72 hours. After this time, the reaction mixture is poured into 1000 mL of ice containing about one mL of concentrated hydrochloric acid. The mixture is stirred until the ice melts. The resultant precipitate is collected by filtration and washed with water. The solid is then dried under reduced pressure at about 60° C. An NMR spectrum of the solid indicates that it contains a large amount of starting material. The solid is then dissolved in 25 mL of phosphorus oxychloride, and two drops of N,N-dimethylformamide are added. The mixture is heated to reflux where it is stirred for about 18 hours. After this time, the reaction mixture is poured into 600 mL of ice containing about two mL of concentrated hydrochloric acid. The mixture is stirred until the ice melts. The resultant precipitate is collected by filtration, washed with water, and dried under reduced pressure at about 60 ° C., yielding 8.6 grams of 5-bromo-2-chloro-3-cyano-4,6-dimethylpyridine. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.P(Br)(Br)[Br:27]>C(Cl)Cl.C(OC)(C)(C)C>[Br:27][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CO)cc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1.20 g (3.57 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 3.1a) in 25 mL of DCM is added at 0° C. 0.24 mL (2.50 mmol) phosphorus tribromide. After warming to RT, the mixture is stirred 2 h at RT and is diluted with 30 mL tertbutylmethylether. The precipitate is collected and dried.
Reaction SMILES: COC(=O)C([C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:16])(=[O:15])=[O:14])=[C:9](OC)[CH:8]=1)(C)C.[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1C2C(=CC=CC=2)[CH2:27][CH2:26][C:25]1=[O:34].COC(=O)CN1C2C(=CC(S)=CC=2)CCC1=O>>[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:7]2[C:8](=[CH:9][C:10]([S:13]([Cl:16])(=[O:14])=[O:15])=[CH:11][CH:12]=2)[CH2:27][CH2:26][C:25]1=[O:34]
Reactant: COC(=O)CN1C(=O)CCc2ccccc21
Reactant: COC(=O)C(C)(C)c1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: COC(=O)CN1C(=O)CCc2cc(S)ccc21
Product: COC(=O)CN1C(=O)CCc2cc(S(=O)(=O)Cl)ccc21
Yield: 28 %

Procedure:
Compound 49B was prepared analogously to compound 21B using the product prepared from compound 49A. Yield was 28%. MS m/z 318 (M+1). Step 3. Preparation of (6-Mercapto-2-oxo-3,4-dihydro-2H-quinolin-1-yl}-acetic acid methyl ester (Compound 49C).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19].[CH3:22][N:23]=[C:24]=[O:25]>C(Cl)Cl>[Cl:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:24]([NH:23][CH3:22])=[O:25])(=[O:20])=[O:19]
Reactant: CN=C=O
Reactant: NS(=O)(=O)c1ccccc1OCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)NS(=O)(=O)c1ccccc1OCCCl
Temperature: 25 °C

Procedure:
5.9 g of triethylamine is added dropwise to a suspension of 11.0 g of 2-(2-cloroethoxy)-phenylsulfonamide, 50 ml of methylene chloride and 3.3 g of methyl isocyanate within 10 minutes at a temperature of 20°-25° C. The resulting clear solution is stirred for a further hour at room temperature and evaporated to dryness. The residue is solved in 5% aqueous sodium carbonate. After acidification of this solution with 10% hydrochloric acid 12.5 g of N-[2-(2-chloroethoxy)-phenylsulfonyl]-N'-methylurea precipitate therefrom, m.p. 218°-222° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10].[BH4-].[Na+]>[Co](Cl)Cl.CO>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=CC(CCCCCl)c1cccc(-c2cccnc2)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(CCCCCl)c1cccc(-c2cccnc2)c1
Reaction time: 0.5 h

Procedure:
To a mixture of 0.422 g (1.2 mmol) methyl 8-chloro-4-[m-(3-pyridyl)-phenyl]-oct-2-enoate, 0.097 g (0.41 mmol) cobalt (II) chloride and 8 ml methanol at 0° is added slowly 0.105 g (2.8 mmol) of sodium borohydride. The resulting black suspension is stirred at 0° for 30 min and then filtered through activated magnesium silicate (Florisil) and the filter cake is washed several times with methanol. The solvent is evaporated to obtain methyl 8-chloro-4-[m-(3-pyridyl)-phenyl]-octanoate; IR (CH2Cl2): 1732 cm-1.