Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][C:6]1([C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12.[H-].[Na+].[CH3:43]I>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][C:6]1([C:29]([N:31]([CH3:43])[CH2:32][C:33]([F:36])([F:34])[F:35])=[O:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12
Reactant: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(=O)NCC(F)(F)F)ccc1-c1cnc(C)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(=O)N(C)CC(F)(F)F)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-N-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (200 mg) in DMF (2 mL) was added sodium hydride (60%, 7.8 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. Methyl iodide (0.012 mL) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and further recrystallized from ethyl acetate/methanol to give the title compound (25.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][N:13]1[CH:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]3[C:23]([CH3:37])=[CH:24][C:25]([NH:29]C(=O)OCCCC)=[N:26][C:27]=3[CH3:28])=[O:19])[CH:15]=[N:14]1)=[CH:7][CH:6]=2.C(Cl)Cl>CO>[NH2:29][C:25]1[N:26]=[C:27]([CH3:28])[C:22]([CH2:21][NH:20][C:18]([C:16]2[CH:15]=[N:14][N:13]([CH2:12][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[CH:3][C:2]([Cl:1])=[CH:11]4)[CH:17]=2)=[O:19])=[C:23]([CH3:37])[CH:24]=1
Reactant: CCCCOC(=O)Nc1cc(C)c(CNC(=O)c2cnn(Cc3ccc4ncc(Cl)cc4c3)c2)c(C)n1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccc3ncc(Cl)cc3c2)c1

Procedure:
To a solution of tent-Butyl 5-((1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-ylcarbamate (125 mg, 0.240 mmol) in DCM (1 ml) Tri fluoro acetic acid (0.092 ml, 1.200 mmol) was added at rt. The reaction was stirred for 2 h at II. The reaction mixture was concentrated under vacuum to afford crude title compound. The crude product was dissolved in MeOH and filtered over a PL-HCO3-cartridge (MP-resin, VARIAN) to afford pure title compound.
Reaction SMILES: O.[OH-].[Li+].[C:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([O:23]C(C)(C)C)=[O:22])[N:20]=3)=[CH:12][N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.O.CN(C=O)C>[C:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=3)=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.7 %

Procedure:
To a solution consisting of lithium hydroxide monohydrate (0.38 g, 9.0 mmol) dissolved in ethanol (20 mL)/water (10 mL) was added tert-butyl 2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxylate (Example 62, 705 mg, 3.0 mmol) in dry DMF (11 mL) and the mixture stirred at room temperature for 18 hours. Ethanol was removed under reduced pressure and the solution diluted with water and subsequently extracted with diethyl ether (2×30 mL). The aqueous phase was acidified with 2 N hydrochloric acid to pH2. The solid precipitate was filtered, washed with water and dried under high vacuum to give the title compound as an off-white solid (371 mg, 87% yield); Rf 0.15 with 9:1 v/v dichloromethane-methanol; 1H-NMR (300 MHz; DMSO-d6) δ 9.39 (s, 2H), 8.63 (s, 1H), 8.44 (dd, 2H), 7.55 (m, 3H); MS (ESI+) m/z 284 (M+1); H-PGDS FPBA IC50: 1.1 μM.
Reaction SMILES: C([NH:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28]OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH:24]=[CH:25][CH:26]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:42]([NH:49][CH2:50][C@@H:51]([C:60]1[CH:69]=[CH:68][C:67]([O:70][CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)=[C:66]2[C:61]=1[CH:62]=[CH:63][C:64](=[O:78])[NH:65]2)[O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)(O)[O-].[Na+].Cl>C(#N)C.CCOC(C)=O.O>[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][N:49]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:50][C@@H:51]([C:60]2[CH:69]=[CH:68][C:67]([O:70][CH2:71][C:72]3[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=3)=[C:66]3[C:61]=2[CH:62]=[CH:63][C:64](=[O:78])[NH:65]3)[O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[CH:24]=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OCCc2cccc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1cccc(N)c1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A stirred mixture of 4-nitrobenzenesulfonic acid 2-[3-(tritylamino)phenyl]ethyl ester (7.44 g, 13.2 mmol); 5-[(R)-2-benzylamino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-benzyloxy-1H-quinolin-2-one (5.42 g, 10.5 mmol) (see, e.g., U.S. Patent Publication No. 2006/0035931 A1, published Feb. 16, 2006) and sodium bicarbonate (3.32 g, 39.5 mmol) in acetonitrile (26.4 mL) was heated at 75° C. under nitrogen for 18 h. The mixture was cooled to room temperature and the pH was adjusted to pH <2 with aqueous hydrochloric acid (1 N, ˜40 mL). The mixture was stirred at room temperature for 1 h and then the pH of the mixture was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution (˜30 mL). Water (˜50 mL) and EtOAc (˜50 mL) were added and the layers were separated (a small amount of dilute aqueous sodium chloride solution was added to improve separation). The aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (30-60% of EtOAc in hexanes) to give the title compound (5.7 g, 68% yield) as a light yellow foamy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[N+:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[CH:7]=1)([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])ccn1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccn1
Temperature: 25 °C
Reaction time: 30 h
Yield: 101.2 %

Procedure:
To a solution of 2-amino-4-nitropyridine (3.0 g, 0.018 mol) in pyridine (40 mL) was added acetic anhydride (5.2 mL 0.055 mol). The reaction mixture was allowed to stir for 30 h at rt. Water was added to the solution and the resulting solid was collected and washed with water and dried under vacuum to give N-(4-nitropyridin-2-yl)acetamide as a brown solid (3.3 g, 99%). 1HNMR (300 MHz, CDCl3) δ: 8.90 (s, 1H), 8.50 (d, 1H), 8.30 (br s, 1H), 7.8 (dd, 1H), 2.3 (s, 3H); LCMS: (FA) ES+ 182.2.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][P:8]([CH3:12])(=[O:11])[O:9][CH3:10].C([O:15][C:16](=O)[C:17]([CH3:24])([CH3:23])[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])C.C(O)(=O)C>CCCCCC.O1CCCC1>[CH3:6][O:7][P:8]([CH2:12][C:16]([C:17]([CH3:24])([CH3:23])[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[O:15])(=[O:11])[O:9][CH3:10]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)C(C)(C)CC=C(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(C)(C)CC=C(C)C)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
Under argon at -60° C., 49.5 ml of a 2.02 N butyllithium solution in hexane was added dropwise to a solution of 13 g of methanephosphonic acid dimethyl ester in 160 ml of absolute tetrahydrofuran. After 15 minutes, a solution of 9.2 g of 2,2,5-trimethyl-4-hexenoic acid ethyl ester in 25 ml of absolute tetrahydrofuran was added dropwise thereto. After 2 hours at -60° C., the reaction mixture was allowed to warm up to room temperature within one hour, combined with 5.72 ml of glacial acetic acid, and then concentrated under vacuum. The residue, a white, gel-like mass, was distributed in a two-phase mixture of 35 ml of water and 165 ml of ether. The organic phase was dried over magnesium sulfate and concentrated on a forced circulation evaporator. After removing the volatile byproducts by distillation under 0.1 torr and at 60° C., the residue was purified by column chromatography on silica gel with hexane/50-100% ethyl acetate as the mobile phase, thus obtaining 8.6 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C@@H:9]1(N2C3N=CN=C(O)C=3N=C2)[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].P([O-])(O)(O)=O.[K+]>>[CH:5]1[N:1]([C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: NC(=O)c1nc[nH]n1
Agent: O=P([O-])(O)O
Agent: [K+]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 24 h

Procedure:
Each 10 ml of the above suspensions of the treated microbial cells and 10 ml of a suspension of untreated microbial cells obtained similarly as in Example 1 was admixed with each 10 ml of a reaction substrate solution (pH 7.0) containing 20 mM 1,2,4-triazole-3-carboxamide, 20 mM inosine and 25 mM monopotassium dihydrogen phosphate, and the reaction was carried out at 60° C. for 24 hours. Analysis of ribavirin yields gave the results as shown in Table 4.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].N12CCCN=C1CCC[CH2:16][CH2:15]2.ICC>CN(C)C=O.O>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:15][CH3:16])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2s1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCI
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)sc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 6-nitro-2-benzothiazolinone (2.5 g, 12.7 mmol) in anhydrous N,N-dimethylformamide (25 mL) under N2 is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.48 mL, 16.6 mmol) dropwise followed by iodoethane (1.22 mL, 15.3 mmol). Following a slight exotherm, the reaction mixture is stirred at ambient temperature for 21 h, diluted with water (20 mL) and filtered to give the title compound, mp 200–203° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C(Cl)CCl>[Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([NH:17][CH:14]3[CH2:16][CH2:15]3)=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc2nc(Cl)sc2c1
Solvent: ClCCCl
Product: O=C(NC1CC1)c1ccc2nc(Cl)sc2c1

Procedure:
2-chloro-N-cyclopropylbenzo[d]thiazole-6-carboxamide was prepared by EDC coupling of 2-chlorobenzo[d]thiazole-6-carboxylic acid and cyclopropylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:23]([OH:25])[CH:24]=1.[CH2:31](N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[C:23]([OH:25])[CH:24]=1
Reactant: CCN(CC)CC
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: COCCOc1ccc(CN)cc1O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
An amount of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.40 g, 1.42 mmol) in 5 mL of N,N′-dimethylformamide is added 5-(aminomethyl)-2-(2-methoxyethoxy)phenol (0.33 g, 1.70 mmol) and 0.44 mL (4.26 mmol) of triethylamine. The reaction mixture is heated at room temperature overnight under N2. Mass spectroscopy suggested the completion of reaction. Reaction mixture is subsequently evaporated under high-pressure vacuum to brown solid. The solid is stirred in 5 mL of methanol for 10 min, then filtered, and washed in turn with 100 mL of water, 100 mL of methanol, and ether and hexane to afford 0.48 g (76.2% yield) of tan solid: mp 179-180° C.; MS (ESI) m/z 447.0-449.0 (M+H)+1
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][N:4]1[C:8]([C:9]2[C:14]([CH2:15]O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:6]=[N:5]1.O=S(Cl)[Cl:21]>C(Cl)Cl>[ClH:21].[Cl:21][CH2:15][C:14]1[C:9]([C:8]2[N:4]([CH2:3][C:2]([F:18])([F:17])[F:1])[N:5]=[CH:6][CH:7]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCc1cccnc1-c1ccnn1CC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: FC(F)(F)Cn1nccc1-c1ncccc1CCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methanol (408 mg, 1.59 mmol) in DCM (5 mL) was added SOCl2 (1.5 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridine hydrochloride (498 mg) as an off-white solid, which was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:19][S:20][C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[N:22]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:15][CH2:14][CH2:13][O:12]1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CO>[CH3:1][C:2]1[C:3]([CH2:19][S:20]([C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[O:38])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:12][CH2:13][CH2:14][O:15]1
Reactant: CCCC1(CCOc2ccnc(CSc3nc4ccccc4[nH]3)c2C)OCCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCO1
Reaction time: 2 h
Yield: 64.3 %

Procedure:
The 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxolan-2-yl)ethoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole (482 mg, 1.17 mmol) obtained in the step (3f) was dissolved in a solvent mixture of toluene (30 ml) and methanol (3 ml). The mixture was cooled in a nitrogen atmosphere. To this mixture, a methanol solution (1.3 ml) of 3-chloroperbenzoic acid (311 mg, 1.17 mmol as the content was regarded as 65%) was added at an inner temperature of below −70° C. and stirred below −60° C. for 2 hours. To the reaction mixture, an aqueous solution of sodium hydrogen carbonate and ethyl acetate were added. The organic layer was separated and washed with a saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride and subjected to silica gel column chromatography using NH silica gel (elution solvent: methylene chloride/methanol=1/0→100/1→100/5) to obtain the title compound (323 mg, yield: 64.3%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu]>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 160 °C

Procedure:
A mixture of p-bromoacetophenone (3.98 g, 20 mmol), benzimidazole (4.72 g, 40 mmol), copper bronze (1.27 g, 20 mmol), anhydrous potassium carbonate (5.52 g, 40 mmol) and cuprous bromide (290 mg, 2 mmol) in dry N-methylpyrrolidinone (60 ml) was heated under nitrogen at 160° C. for 8 hours. Most of the solvent was removed by distillation under reduced pressure and the residue was diluted with dichloromethane (500 ml) and 2N sodium hydroxide (200 ml). The organic layer was washed with water (300 ml), dried (MgSO4) and concentrated to give a dark brown oil. Purification by flash chromatography (eluting with ethyl acetate gave 4'-(1-benzimidazolyl)acetophenone, 3.085 g as a pale yellow solid, m.p. 133°-135° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccccc1)C[C@@H](O)CCl
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOP(=O)(Cc1ccccc1)C[C@@H](O)CNCc1ccc(Cl)cc1

Procedure:
A mixture of 2.76 g of (2R)-3-chloro-2-hydroxypropyl(benzyl)phosphinic acid ethyl ester, 3.54 g of p-chlorobenzylamine, 3.25 g of N-ethyl-N,N-diisopropylamine and 20 ml of ethanol is heated under reflux for 48 hours. Removal of the solvent and chromatography yield (2S)-3-(p-chlorobenzylamino)-2-hydroxypropyl(benzyl)phosphinic acid ethyl ester; 1H-NMR spectrum (in CDCl3): δ=7.4-7.17 (9H,m); 4.14-3.83 (3H,m); 3.71 (2H,ABq); 3.20 (2H,d); 2.6-2.5 (2H,m); 1.96-1.62 (2H,m); 1.25 (3H,t); 31P-NMR spectrum (in CDCl3): δ=53.9; 52.7.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:46][O:47][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[CH2:56][CH:55]([NH:58][CH2:59][CH2:60][CH3:61])[CH2:54][CH2:53]2>CN(C=O)C>[CH3:46][O:47][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[CH2:56][CH:55]([N:58]([CH2:59][CH2:60][CH3:61])[C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:54][CH2:53]2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: Cc1ccc(C)c(CC(=O)O)c1
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: CCCN(C(=O)Cc1cc(C)ccc1C)C1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 340 mg (2.1 mmol) 2,5-dimethylphenylacetic acid (A3-4: W=OH, Cy=2,5-dimethylphenyl) and 0.70 mL diisopropylethylamine (DIPEA) (4.24 mmol) in 10 mL of dry DMF was cooled in an ice-bath. After addition of 950 mg (2.5 mmol) O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) in 5.0 mL dry DMF a solution of 640 mg (2.9 mmol) of the free base of N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1) in 8.0 mL dry DMF was added dropwise, the ice-bath was removed and the reaction mixture was stirred for 3 hrs at room temperature. The mixture was washed with a saturated solution of aqueous NaHCO3 for several times and the resulting aqueous layer was extracted with CH2Cl2. The organic layers were dried over MgSO4 and the solvent was evaporated in vacuo. Flash chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate 60/10 gave the product N-(8-methoxytetralin-2-yl)-N-propyl-2-(2,5-dimethylphenyl)acetamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:24](=[O:27])(=[O:26])[NH2:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.[N+](C1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(O)=O)([O-])=O>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:24](=[O:26])(=[O:27])[NH2:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1cccc(C(F)(F)F)c1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1cccc(C(F)(F)F)c1

Procedure:
By substituting 3-nitro-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid for the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid of Example 1 B, the above compound was obtained with a melting point of 270°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O-:25])=[O:24])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:12]([O-:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:37][C@H:38]2[C@H:42]([CH2:43][O:44][S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[O:41][C:40]([CH3:56])([CH3:55])[O:39]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O:25][C:11]([CH3:15])([CH3:12])[CH3:10])=[O:24])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:37][C@H:38]2[C@H:42]([CH2:43][O:44][S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[O:41][C:40]([CH3:56])([CH3:55])[O:39]2)=[CH:20][CH:21]=1)[C:12]([O:14][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2OC(C)(C)O[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)[O-])C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2OC(C)(C)O[C@H]2COc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 100 °C
Yield: 65.5 %

Procedure:
To 0.47 g (1 mmol) (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-L-glutamate and 0.47 g (1 mmol) [(4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl]dimethanediyl bis(4-methylbenzenesulfonate) in 15 mL DMF was added potassium carbonate (0.28 g, 2 mmol). The mixture was heated in a microwave for 2 h at 100° C. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (silica, 20% ethyl acetate in hexane) to afford 0.25 g (33%) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-{[(4S,5S)-2,2-dimethyl-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,3-dioxolan-4-yl]methoxy}benzyl)-L-glutamate.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[C:18](=O)([O-])[OH:19]>CN(C=O)C>[O:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][C:4]([CH:18]=[O:19])=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCOCC2)cc1
Reactant: O=C([O-])O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 22 h

Procedure:
N-Phenylmorpholine (77.2 g) was dissolved in DMF (150 ml) and phosphorus oxychloride (67.1 ml) was dropwise added in an ice bath. After the dropwise addition, the mixture was stirred at 60° C. for 22 hr. Ice water was added portionwise to the reaction mixture in an ice bath and the mixture was neutralized with a saturated aqueous hydrogencarbonate solution. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give the objective 4-morpholinobenzaldehyde (70.7 g), melting point 55° C.