Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][C@H:11]([CH2:13][S:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:10][C:9]1=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-:35].[Na+].Cl>CO.O>[OH:35][C@@H:11]([CH2:13][S:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][C@@H:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9]([OH:10])=[O:34]
Reactant: [OH-]
Reactant: CCCCCCC[C@@H]1C[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.72 g (7.88 mmol) of the product of Example 17 in 100 mL of methanol (1:1) at room temperature was added 16.7 mL of 1.0N NaOH solution. The reaction was stirred at room temperature for 1 h and then diluted with 100 mL of H2O and carefully acidified to pH 6 with 5% HCl solution. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue, 3.72 g (100%) of the crude hydroxy-acid was used in the next step (Example 25) without further purification. Electrospray Mass Spec: 489.4 (M-H)-.
Reaction SMILES: C[O:2][C:3]1[C:4]([C:21]([NH:23][CH3:24])=[O:22])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=1)[CH:7]=2.B(Br)(Br)Br>>[OH:2][C:3]1[C:4]([C:21]([NH:23][CH3:24])=[O:22])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)[CH:7]=2
Reactant: CNC(=O)c1cc2cc(-c3cccc(OC)c3)ccc2cc1OC
Agent: BrB(Br)Br
Product: CNC(=O)c1cc2cc(-c3cccc(O)c3)ccc2cc1O

Procedure:
The compound is prepared by reaction of 3-methoxy-7-(3-methoxyphenyl)-N-methyl-2-naphthamide (93 mg, 0.29 mol, 1 eq) with boron tribromide solution (5.5 ml, 5.5 mmol, 19 eq) according to method G. Purification was not necessary. The desired product was obtained in quantitative yield.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H]1([N:18]2[C:28]3[N:27]=[C:25]([NH2:26])[NH:24][C:22](=[O:23])[C:21]=3[N:20]=[CH:19]2)O[C@H](CO)[C@@H](O)[C@H]1O.[ClH:29].CO>CS(C)=O>[ClH:29].[CH2:1]([N:20]1[C:21]2[C:22](=[O:23])[NH:24][C:25]([NH2:26])=[N:27][C:28]=2[N:18]=[CH:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
40 ml (0.34 ml) of benzyl bromide were added dropwise to a suspension of 40 g (0.147 mol) of guanosine in 200 ml of dimethyl sulfoxide and the mixture was stirred at room temperature for 4 hours. It was treated with 100 ml of concentrated hydrochloric acid and stirred at room temperature for 30 minutes. It was then poured into 1200 ml of methanol, and the precipitate was filtered off with suction and washed with methanol.
Reaction SMILES: N[CH:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:37].Cl>C(N(CC)CC)C>[O:37]=[C:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18][CH:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nncs3)CS[C@H]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CSc2nncs2)CS[C@@H]2C(=O)C(=O)N12

Procedure:
Benzhydryl 7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give benzhydryl 7-oxo-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylate.
Reaction SMILES: Cl.[CH3:2][N:3]([N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-])=O.[OH-].[Na+]>O1CCCC1>[CH3:2][N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[CH:18][C:14]2=[CH:15][CH:16]=[CH:17][N:13]12
Reactant: CN(c1ccncc1[N+](=O)[O-])n1cccc1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1c2ccncc2N=Cc2cccn21
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
To cold, concentrated hydrochloric acid (200 ml) was added, in the following order, 100 g of stannous chloride dihydrate, 200 ml of tetrahydrofuran, and a solution of 28 g of 1-[N-methyl-N-(3-nitro-4-pyridinyl)amino]pyrrole-2-carboxaldehyde in 150 ml of tetrahydrofuran. Upon completion of the 1-[N-methyl-N-(3-nitro-4-pyridinyl)amino]pyrrole-2-carboxaldehyde addition, the reaction was poured into an aqueous solution of sodium hydroxide (200 g in 1 liter of water), stirred for five minutes, and then extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resultant oil was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to afford 10 g (38%) of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine as an oil, IR(CHCl3) C=N @ 1610 cm-1 ; MS(EI)M+ @ 199 (100%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:67]=[CH:66][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:42][CH2:41][CH2:40][C@H:39]2[C:43]([C:45]2[N:46]=[CH:47][N:48]3[CH:52]=[C:51]([Sn](CCCC)(CCCC)CCCC)[S:50][C:49]=23)=[O:44])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:51]3[S:50][C:49]4=[C:45]([C:43]([C@@H:39]5[CH2:40][CH2:41][CH2:42][N:38]5[C:36]([O:35][CH2:34][C:33]5[CH:66]=[CH:67][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=5)=[O:37])=[O:44])[N:46]=[CH:47][N:48]4[CH:52]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)[C@@H]3CCCN3C(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)[C@@H]5CCCN5C(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Yield: 73.6 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[(2S)-1-(4-nitrobenzyloxycarbonyl)-pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (1.40 g) was prepared in the same manner as in step a) of Example 1, except that 926 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.85 g of 7-[(2S)-1-(4-nitrobenzyloxycarbonyl)-pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [N:1]([C@@H:4]([CH3:20])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]([OH:19])[CH2:15][C:13]3=2)[CH:8]=[N:7]1)=[N+]=[N-]>CO>[NH2:1][C@@H:4]([CH3:20])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]([OH:19])[CH2:15][C:13]3=2)[CH:8]=[N:7]1
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)CC(O)CO3)N=[N+]=[N-]
Solvent: CO
Product: C[C@H](N)Cn1ncc2ccc3c(c21)CC(O)CO3
Yield: 88 %

Procedure:
A solution of the product from Step A in methanol was treated as described in Example 2, Step J to give the free base as an amorphous solid (0.36 g, 88%): mp 46-51° C.; GCMS(Cl+) m/z 248 (M+H). Analysis. Calculated for C13H17N3O2.0.1H2O: C, 62.68; H, 6.96; N, 16.97. Found: C, 62.55; H, 7.03; N, 16.64.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C.C(O)=O>CC1C=CC(S(N[C@@H]([C@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.C(N(CC)CC)C.CO>[OH:1][C@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: CO
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 128.4 %

Procedure:
Into 1 ml of methanol were dissolved 7 mg (0.01 mmol) of [RuCl2(p-cymene)]2 and 8 mg (0.02 mmol) of (R,R)-TsDPEN to prepare a solution, and to the solution was dropwise added 2 mg (0.02 mmol) of triethylamine, followed by stirring for 0.5 hour at room temperature. To the reaction solution were dropwise added a solution prepared by dissolving 396 mg (2.2 mmol) of 2-oxo-4-phenylbutanoic acid into 4 ml of methanol, and 1.2 ml (8.9 mmol) of triethylamine was furthermore dropwise added thereto. The bath was heated up to a temperature of 40° C., and then 0.25 ml (6.7 mmol) of formic acid was dropwise added over 1 hour, followed by stirring for 2 hours at a bath temperature of 40° C. Upon completion of the reaction, the solvent was distilled off under reduced pressure. Thereto was added 2 ml of water, and then concentrated hydrochloric acid was gradually dropwise added under ice cooling; thus, pH of the solution was adjusted to 2. Extraction was performed twice with 20 ml of ethyl acetate, and then the organic phase was washed with 2 ml of a saturated aqueous solution of sodium chloride, followed by concentration under reduced pressure. As a result, 509 mg (yield 99%, 85% ee) of (2R)-hydroxy-4-phenylbutanoic acid was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 7.28-7.14 (5H, m), 3.91-3.88 (1H, m), 2.66-2.62 (2H, m), 1.91-1.77 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])=O.[NH4+]>[Pd].C(O)(=O)C>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]([CH3:4])=[C:2]([OH:1])[CH:9]=1
Reactant: COc1ccc(C=O)c(O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(C)c(O)c1
Temperature: 110 °C

Procedure:
2-Hydroxy-4-methoxy-benzaldehyde (3 g, 19.7 mmol), ammonium formate (6.2 g, 99 mmol) and palladium/carbon (900 mg @ 10%) were added to 26 ml glacial acetic acid and heated at 110° C. for 1 h. The reaction was cooled, filtered, and diluted with water (100 ml). The crude product was extracted with chloroform (3×50 ml), washed with water, brine, and dried over anhydrous sodium sulfate. The resulting solution was concentrated and used for the next step without further purification. MS m/z 139 (M+1).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[F:32][C:33]([F:56])([F:55])[CH2:34][CH2:35][C@@H:36](OS(C(F)(F)F)(=O)=O)[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C1COCC1>[C:1]1([C@H:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:36]([CH2:35][CH2:34][C:33]([F:32])([F:55])[F:56])[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)[C@@H](CCC(F)(F)F)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](c1ccccc1)[C@@H](CCC(F)(F)F)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 37.1 %

Procedure:
A solution of tert-butyl 2-phenylacetate (8.5 g, 44.2 mmol) in THF (400 mL) in a 1 L round-bottomed flask was cooled in −78° C. bath and treated with a solution of KHMDS, 0.5M in toluene (97 mL, 48.6 mmol) via cannula over 10 minutes. After 10 minutes the mixture was removed from the bath and placed in a room temperature water bath and stirred for 15 minutes and then again cooled in −78° C. bath. After 15 minutes a solution of Preparation 4D (R)-benzyl 5,5,5-trifluoro-2-(((trifluoromethyl)sulfonyl)oxy)pentanoate (19.18 g, 48.6 mmol) in THF (50 mL) in a 100 ml, round bottom flask was added over 10 min via cannula with a 20 mL THF rinse. The reaction mixture turned cloudy. The reaction mixture was stirred at −78° C. for 1 hour and then quenched with saturated aqueous NH4Cl. The mixture was removed from −78° C. bath, diluted with 10% LiCl aq and extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated. The resulting light brown residue was dissolved in 100 mL CH2Cl2 and treated with charcoal and MgSO4. The mixture was filtered to give an almost colorless solution. The CH2Cl2 solution was concentrated and diluted with hexane and cooled in −20° C. freezer. The resulting solids were filtered and rinsed with cold hexane (containing 5% MTBE) and dried on a fitted filter funnel under a stream of nitrogen to give 8.16 g. The solid was triturated with 40 mL hexane and 4 mL MTBE stirring the white suspension at room temperature for 1 hour and then cooling at −20° C. for 3 hours before filtering the white solid and washing with cold solvent (10:1 hexane:MTBE) to give (2R,3R)-1-benzyl 4-tert-butyl 3-phenyl-2-(3,3,3-trifluoropropyl)succinate (7.16 g, 37% yield) as a white solid. 1H NMR (500 MHz, chloroform-d) δ 7.32-7.23 (m, 8H), 7.05-6.97 (m, 2H), 4.89-4.76 (m, 2H), 3.69 (d, J=11.4 Hz, 1H), 3.23 (ddd, J=11.2, 9.9, 3.9 Hz, 1H), 2.19-2.04 (m, 2H), 2.03-1.88 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[CH3:17][NH:18][S:19]([C:22]1[CH:23]=[C:24]([C:32](Cl)=[O:33])[C:25]2[O:30][CH2:29][CH2:28][O:27][C:26]=2[CH:31]=1)(=[O:21])=[O:20]>C(O)(=O)C.O>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][C:32]([C:24]3[C:25]4[O:30][CH2:29][CH2:28][O:27][C:26]=4[CH:31]=[C:22]([S:19](=[O:21])(=[O:20])[NH:18][CH3:17])[CH:23]=3)=[O:33])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Reactant: NC1CCN(C2CCCCC2)C1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CNS(=O)(=O)c1cc2c(c(C(=O)NC3CCN(C4CCCCC4)C3)c1)OCCO2
Yield: 61.3 %

Procedure:
84 g of 1-cyclohexyl-3-aminopyrrolidine, 430 ml of chloroform and 146 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were introduced into a balloon flask provided with an agitator and a thermometer. After agitation of the mixture, the base was extracted with methylene chloride and then the solvent was evaporated. The crystals formed were dissolved in boiling absolute alcohol and the resulting solution was filtered on carbon black. The crystals produced after cooling were dissolved in a solution of acetic acid in water and then the solution was filtered over carbon black and the base was reprecipitated by the addition of 20% ammonia. 129.5 g of N-(1-cyclohexyl-3-pyrrolidyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 160°-161° C.; yield: 61.2%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[NH:31][C:32](=[O:35])[CH2:33]Cl)[C:25]([OH:27])=[O:26].O>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][CH2:33][C:32]([NH:31][C:30]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[Cl:21])=[O:35])=[N:5][N:6]=1
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Reactant: O=C(CCl)Nc1ccc(C(=O)O)cc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nnc(SCC(=O)Nc2ccc(C(=O)O)cc2Cl)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
Compound 4 (789 mg, 2.79 mmol) and 3-chloro-4-(2-chloroacetamido)benzoic acid (5) (693 mg, 2.79 mmol) were dissolved in DMF (6 mL) and the mixture was stirred at 50° C. for 18 hours. Water was then added and the mixture extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to give 1.04 g, 75% yield of 4-(2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid (6).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([NH:20][CH2:21][CH2:22][OH:23])[N:13]=1)[CH:9]=[C:8]([C:24]([OH:26])=[O:25])[C:7]2=[O:27].[CH3:30][NH2:31]>C(O)(C)C>[Cl:1][C:2]1[C:3]([NH:31][CH3:30])=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([NH:20][CH2:21][CH2:22][OH:23])[N:13]=1)[CH:9]=[C:8]([C:24]([OH:26])=[O:25])[C:7]2=[O:27]
Reactant: CN
Reactant: O=C(O)c1cn(-c2nc(NCCO)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: CC(C)O
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(NCCO)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.3 %

Procedure:
8-Chloro-6,7-difluoro-1-[3,5-difluoro-6-(2-hydroxyethylamino)pyridin-2-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (250 mg) and an aqueous solution (about 40%; 3 g) of methylamine were added to isopropyl alcohol (4 ml), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (2 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (175 mg) as a pale brown powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([NH2:20])=O)[CH2:14][CH2:13]2)=[C:8]([F:21])[CH:7]=1)=[O:5])[CH3:2]>C1COCC1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]#[N:20])[CH2:16][CH2:17]2)=[C:8]([F:21])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(C(N)=O)CC2)c(F)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CCC(C#N)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.5 %

Procedure:
To a solution of 1.50 g of 1-(4-ethoxycarbonyl-2-fluorophenyl)piperidine-4-carboxamide in 20 ml of THF, 2.0 ml of triethylamine and 0.9 ml of trifluoroacetic acid anhydride were added at −78° C., and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, EtOAc was added, and then the organic layer was washed with water and brine, and dried over sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent: hexane-EtOAc=5:1˜4:1) to obtain 1.43 g of 4-(4-cyanopiperidino)-3-fluorobenzoic acid ethyl ester.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH2:28]([O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:28]([O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:9])=[N:15][CH:14]=2)=[CH:37][CH:38]=1)[CH3:29]
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(NCc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)cc1
Yield: 28.9 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg, 0.298 mmol), acetic acid (17 μL, 0.29 mmol), (4-amino-phenyl)-acetic acid ethyl ester (14 mg, 0.45 mmol) and sodium triacetoxyborohydride (101 mg, 0.48 mmol) to afford 43 mg (30%) of the desired product after purification.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:17])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=1)[NH2:7])[CH3:3].[N:18]1[S:22][N:21]=[C:20]2[C:23]([S:27]([NH:30][C:31]3[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[CH:36][C:32]=3[C:33](O)=[O:34])(=[O:29])=[O:28])=[CH:24][CH:25]=[CH:26][C:19]=12>>[CH2:2]([O:4][C:5](=[O:17])[C@@H:6]([NH:7][C:33](=[O:34])[C:32]1[CH:36]=[C:37]([Cl:41])[C:38]([Cl:40])=[CH:39][C:31]=1[NH:30][S:27]([C:23]1[C:20]2=[N:21][S:22][N:18]=[C:19]2[CH:26]=[CH:25][CH:24]=1)(=[O:29])=[O:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine ethyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid as in Example 1, Part C. HPLC: RT=10.96 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 676.36; m/z found, 673/675 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.20 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.23 (dd, J=8.8, 0.9, 1H), 7.86 (s, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.34 (s, 1H), 7.29 (dd, J=6.5, 1.9, 1H), 7.07-6.99 (m, 2H), 6.59 (d, J=7.0, 1H), 4.89 (q, J=5.8, 1H), 4.27 (q, J=7.1, 2H), 3.17 (d, J=5.8, 1H), 1.33 (t, J=7.2, 3H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[C:13](C(OCC)=O)[C:12]2=[O:29])=[CH:2]1>CN(C)C=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:29])[CH:13]=[C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(Cl)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Product: O=C1C=C(Nc2ccc(Cl)cc2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 17.8 %

Procedure:
A solution of the compound (0.050 g, 0.12 mmol) of Example 8 in N,N-dimethylformamide (1.0 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0072 g, y. 17%).
Reaction SMILES: O[N:2]=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C.[Zn]>[NH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(C=NO)c(Oc2ccccc2)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: N#Cc1ccc(CN)c(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 4-(hydroxyimino-methyl)-3-phenoxy-benzonitrile (200 mg) in acetic acid (1.2 ml) was stirred at 65° C. Zinc powder (500 mg) was added portionwise during 30 min. After stirring for a further 1 h, the reaction mixture was filtered and the filtrate was concentrated to near dryness. Water was added and the mixture was washed with diethyl ether. The organic phase was extracted (1×) with diluted acetic acid. The pH of the combined aqueous phases was adjusted to 11 using 2 N NaOH. The mixture was extracted with EtOAc. The organic phase was dried, filtered and concentrated to give 4-aminomethyl-3-phenoxy-benzonitrile (165 mg) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][Br:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc(Br)cc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccc(Br)cc2n1

Procedure:
A mixture of 220 g 7-bromoquinaldine, 180 g N-bromosuccinimide and 1 g dibenzoylperoxide in CCl4 (1 L) was illuminated with a 275 W sun lamp at reflux for 12 hours. The reaction mixture was cooled and directly chromatographed on 2 kg silica gel. Elution with toluene afforded the title compound which was used as is for the next step.