Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7](=[CH2:11])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]#[N:13].[O:14]1CCCC1.B.OO.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11][OH:14])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]#[N:13]
Reactant: C1CCOC1
Reactant: C=C1CCc2c1ccc(F)c2C#N
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1c(F)ccc2c1CCC2CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Fluoro-1-methylidene-2,3-dihydro-1H-indene-4-carbonitrile (100 mg, 0.577 mmol) in THF (6 mL) at 0° C. was treated with borane tetrahydrofuran (1 M, 0.751 ml, 0.751 mmol). The resulting mixture was stirred for overnight at room temperature; LC analysis indicated consumption of starting material. To the mixture was added a combination of hydrogen peroxide (0.083 ml, 0.81 mmol) and 2M NaOH (0.404 ml, 0.808 mmol). The resulting mixture was then stirred for 2 hours. LC analysis indicated completion of the reaction. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was absorbed into silica gel and loaded into silica column for separation with the solvent systems of hexanes/EtOAc (1/1) to give the desired product 5-fluoro-1-(hydroxymethyl)-2,3-dihydro-1H-indene-4-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[NH2:38][C:39]1[S:40][CH2:41][CH2:42][N:43]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:38][C:39]3[S:40][CH2:41][CH2:42][N:43]=3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: NC1=NCCS1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1=NCCS1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 9.3 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3.5 hours with a stream of nitrogen bubbling through it. Solid 2-amino-2-thiazoline (2.67 g, 0.0261 mole) was added to the reaction mixture. The resulting suspension was allowed to stir at room temperature overnight. The solvent was evaporated under reduced pressure to give a white solid. The solid was triturated in water (200 ml), filtered, and the filter cake was rinsed twice more with water. The resulting solid was heated in boiling isopropyl alcohol to dissolve most of it, filtered while hot, and cooled to room temperature. A white precipitate formed. Water was added, and the white solid was filtered and rinsed once with isopropyl alcohol and twice with isopropyl ether. A 1.0-g sample of the resulting 3.3 g of white solid was dried at high vacuum to give 0.6 g (29%) of title compound, mp. 227°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([S:50]([C:53]2[CH:58]=[CH:57][C:56]([NH:59][C:60]3[N:65]=[CH:64][C:63]([NH2:66])=[CH:62][N:61]=3)=[CH:55][CH:54]=2)(=[O:52])=[O:51])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl>[C:37]([O:41][C:42]([N:44]1[CH2:45][CH2:46][CH:47]([S:50]([C:53]2[CH:54]=[CH:55][C:56]([NH:59][C:60]3[N:65]=[CH:64][C:63]([NH:66][C:4](=[O:6])[C:3]4[CH:7]=[C:8]([NH:11][C:12]([C:14]5[S:15][CH:16]=[CH:17][CH:18]=5)=[O:13])[CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:62][N:61]=3)=[CH:57][CH:58]=2)(=[O:51])=[O:52])[CH2:48][CH2:49]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccs1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5cccs5)ccc4Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
Intermediate 15 (Example 23) (0.124 g, 0.439 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.1 g, 32%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27]C)=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[CH:14]=2)[CH:7]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[CH:14]=2)[CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OC)cc12
Solvent: ClCCl
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3O)cc12
Reaction time: 16 h

Procedure:
To a stirred solution of (R)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (synthesized similar to that of Int-84 using intermediate 41) (1.2 g, 3.13 mmol) in 25 mL of DCM, 1.0M Borontribromide (15.6 ml, 39.2 g, 15.65 mmol) was added at −70° C. and stirred at −70° C. to room temperature during 16 h. Reaction mass was quenched with 5 mL of ice cooled water and stirred for 15 min. The reaction mixture was diluted with DCM (50 mL) and the organic layer was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford of the title compound (Int-76) as off white solid. MS (ESI): m/z 370.3 (M+H).
Reaction SMILES: [CH3:1]C(C)=O.[CH3:5]/[CH:6]=[C:7]1\[C:8]2[S:12][CH:11]=[C:10]([C:13]([NH:15][CH:16]([C:78]([OH:81])([CH3:80])[CH3:79])[C:17]3[S:21][CH:20]=[C:19]([C:22]([NH:24][CH:25]([CH:75]([OH:77])[CH3:76])[C:26]4[S:30][CH:29]=[C:28]([C:31]5[N:36]=[C:35]([C:37]6[S:41][CH:40]=[C:39]([C:42]7[S:46][CH:45]=[C:44]([C:47]([NH:49]/[C:50](/[C:53]([NH:55][CH2:56][CH:57]([OH:59])[CH3:58])=[O:54])=[CH:51]/[CH3:52])=[O:48])[N:43]=7)[N:38]=6)[CH:34]=[CH:33][C:32]=5[C:60]5[S:64][CH:63]=[C:62]([C:65]([NH:67][CH:68]([CH:72]([OH:74])[CH3:73])[C:69]([NH:71]\1)=[O:70])=[O:66])[N:61]=5)[N:27]=4)=[O:23])[N:18]=3)=[O:14])[N:9]=2>CO>[CH3:5]/[CH:6]=[C:7]1\[C:8]2[S:12][CH:11]=[C:10]([C:13]([NH:15][CH:16]([C:78]([OH:81])([CH3:80])[CH3:79])[C:17]3[S:21][CH:20]=[C:19]([C:22]([NH:24][CH:25]([CH:75]([O:77][CH3:1])[CH3:76])[C:26]4[S:30][CH:29]=[C:28]([C:31]5[N:36]=[C:35]([C:37]6[S:41][CH:40]=[C:39]([C:42]7[S:46][CH:45]=[C:44]([C:47]([NH:49]/[C:50](/[C:53]([NH:55][CH2:56][CH:57]([OH:59])[CH3:58])=[O:54])=[CH:51]/[CH3:52])=[O:48])[N:43]=7)[N:38]=6)[CH:34]=[CH:33][C:32]=5[C:60]5[S:64][CH:63]=[C:62]([C:65]([NH:67][CH:68]([CH:72]([OH:74])[CH3:73])[C:69]([NH:71]\1)=[O:70])=[O:66])[N:61]=5)[N:27]=4)=[O:23])[N:18]=3)=[O:14])[N:9]=2
Reactant: CC(C)=O
Reactant: C/C=C(/NC(=O)c1csc(-c2csc(-c3ccc4c(n3)-c3csc(n3)C(C(C)O)NC(=O)c3csc(n3)C(C(C)(C)O)NC(=O)c3csc(n3)/C(=C\C)NC(=O)C(C(C)O)NC(=O)c3csc-4n3)n2)n1)C(=O)NCC(C)O
Solvent: CO
Product: C/C=C(/NC(=O)c1csc(-c2csc(-c3ccc4c(n3)-c3csc(n3)C(C(C)OC)NC(=O)c3csc(n3)C(C(C)(C)O)NC(=O)c3csc(n3)/C(=C\C)NC(=O)C(C(C)O)NC(=O)c3csc-4n3)n2)n1)C(=O)NCC(C)O

Procedure:
Thus cultivated, 10 liters of the culture was controlled to have a pH of 7.0, to which was added 40 liters of acetone. The resulting extract was well stirred, and filtered, and acetone was removed from it under reduced pressure. 12 liters of ethyl acetate was added to it, and well stirred, and the ethyl acetate layer was concentrated under reduced pressure. Then, ethyl acetate was removed from it. The residue was subjected to column chromatography with Sephadex LH-20 (by Amersham Pharmacia Biotec, φ30 ×350 mm), and developed with N-hexane/dichloromethane/methanol (4/5/1) to obtain an active fraction. The active fraction was subjected to silica gel thin-layer chromatography (with Kieselgel 60F254, 20 mm×20 mm, by Merck), developed with chloroformlmethanol (15/1), and the active fraction was scraped out. The active fraction was then subjected to ODS column chromatography (φ20×250 mm, Develosilpack, by Nomura Chemical), and an active substance to give a peak was fractionated with an elution solvent of aqueous 70% methanol solution, at a flow rate of 9.0 ml/min and a detection wavelength of 210 nm. From it, the compounds of the invention, QN3323-A (5.0 mg) and QN3323-B (1.5 mg) were isolated. Similarly, known compounds, thiocillin I (11 mg) and thiocillin II (5.3 mg) were isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[C:27]([CH2:38][O:39][CH3:40])[CH:26]=3)[O:22][N:21]=2)[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]([CH3:15])[CH2:7][C:8]([O:10]C(C)(C)C)=[O:9].[ClH:41]>O1CCOCC1>[ClH:41].[CH3:1][O:2][C:3]1[CH:19]=[C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[C:27]([CH2:38][O:39][CH3:40])[CH:26]=3)[O:22][N:21]=2)[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]([CH3:15])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)OC(C)(C)C)c(OC)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)O)c(OC)c3)no2)ccc1-c1ccccc1C
Temperature: 70 °C
Yield: 78 %

Procedure:
To tert-butyl 2-((2-methoxy-4-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)(methyl)amino)acetate (52 mg, 0.09 mmol) was added a 4N solution of HCl in dioxane (3 mL) and the mixture was heated in a tube at 70° C. for 3 hours. The solvent was then removed in vacuo to give the title compound as a white solid (36 mg, 78%). 1H NMR (DMSO-d6, 400 MHz) δ 8.28 (1H, s), 8.16 (1, dd, J=7.9, 1.9 Hz), 7.72 (1H, dd, J=7.8, 1.5 Hz), 7.65-7.58 (2H, m), 7.40 (1H, d, J=7.9 Hz), 7.33 (2H, d, J=4.4 Hz), 7.30-7.25 (1H, m), 7.11 (1H, d, J=7.4 Hz), 4.20-4.11 (2H, m), 3.97 (2H, s), 3.91 (3H, s), 3.25-3.20 (5H, m), 2.48 (3H, s), 2.00 (3H, s). LC/MS (Method B): 488 (M+H)+. HPLC (Method F) Rt 3.15 min (Purity: 97.2%).
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]3=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(S(F)(F)[F:29])CC)C>C(Cl)Cl>[F:29][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]3=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: COCC1CN(c2ccc([C@H]3CC[C@H](O)CC3)cc2)C(=O)O1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COCC1CN(c2ccc([C@H]3CC[C@@H](F)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.5 g of (RS)3-[4-(trans-4-hydroxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one was dissolved in 10 ml of methylene chloride and treated at room temperature within 30 minutes with a mixture of 2.2 ml of diethylamino-sulfur trifluoride and 5 ml of methylene chloride. After stirring at room temperature for 2 hours the mixture was poured into 50 ml of ice-water and extracted twice with methylene chloride. The organic phase was washed with sodium chloride solution, sodium hydrogen carbonate solution and again with a sodium chloride solution, dried with magnesium sulfate and concentrated. The residue, 0.6 g of yellow honey, was chromatographed on a 30-fold amount of silica gel with methylene chloride-ethyl acetate (19:1) and yielded 80 mg of (RS)-3-[4-(cis-4-fluoro-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one as a colorless oil. 1H-NMR (CDCl3)ppm: 7.47 (d,2H), 7.24 (d,2H), 4.88 (bd,1H), 4.74 (m,1H), 4.04 (t, 1H), 3.91 (m,1H), 3.64 (d,2H), 3.43 (s,3H), 2.53 (m,1H), 2.16 (m,2H), 1.72 (m,6H).
Reaction SMILES: ClC1C=C(C=CC=1O)C=O.[Cl:11][C:12]1[CH:26]=[C:25]([CH:27]=[O:28])[CH:24]=[CH:23][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19]>>[Cl:11][C:12]1[CH:26]=[C:25]([CH:27]=[O:28])[CH:24]=[CH:23][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CCCOc1ccc(C=O)cc1Cl
Agent: O=Cc1ccc(O)c(Cl)c1
Product: O=Cc1ccc(OCCCC(=O)O)c(Cl)c1

Procedure:
Following the procedure of Preparation 3, 2.88 g (18.41 mmol) of 3-chloro-4-hydroxybenzaldehyde is alkylated as before. This produces 4.65 g (93%) of 4-(2-chloro-4-formylphenoxy)butanoic acid, ethyl ester as an orange oil: IR (neat) 1730, 1685 cm-1 ; 1HNMR (CDCl3) is consistent with the desired product; MS (CI) m/e 271 (M+ +H). Analysis calculated for C13H15O4Cl: C, 57.68; H, 5.58; Cl, 13.10; O, 23.64. Found: C, 58.05; H, 5.37; Cl, 12.43; O, 24.15.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([C:16](=[O:21])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([OH:21])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCn2c(CCc3ccccc3)nc3cccc1c32
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Fourteen grams of 4,5-dihydro-2-(2-phenylethyl)-6H-imidazo[4,5,1-ij]quinolin-6-one obtained in Example 1 was dissolved in dry methanol (140 mL); following the addition of sodium borohydride (0.76 g) under ice cooling and subsequent stirring at room temperature for 1 hr, the solvent was removed under reduced pressure and water was added to the residue, followed by extraction with dichloromethane. The organic layers were combined, washed with water and saturated brine successively, and dried over anhydrous sodium sulfate; thereafter, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluting solution: hexane/ethyl acetate) to yield the titled compound as colorless crystals (13.3 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5](O)=[O:6].S(Cl)(Cl)=O.[NH4+:16].[OH-].[Na+].[Cl-]>C1COCC1>[F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5]([NH2:16])=[O:6]
Reactant: [NH4+]
Reactant: CC(C)(CC(=O)O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)(CC(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A solution of 4,4,4-trifluoro-3,3-dimethylbutanoic acid [See: US2010/0240663](0.6 g, 3.53 mmol) in thionyl chloride (6 mL, 82 mmol) was heated at 60° C. for 2 h, cooled to RT and concentrated to dryness. The residue was dissolved in DCM (2 mL), added drop-wise to a mixture of THF (8 mL) and NH4OH (˜15M, 8 mL, ˜120 mmol) and stirred at RT overnight. Solid NaCl was added until saturated, the mixture extracted with 4:1 DCM/THF (3×) and the combined organics were washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford 4,4,4-trifluoro-3,3-dimethylbutanamide (240 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 7.46 (s, 1H), 6.93 (s, 1H), 2.20 (s, 2H), 1.18 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[O:6][CH2:7][CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:13][CH:12]=1)#[N:2].O.O.S.[Na].O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].CI.C([O-])(=O)C.[NH4+:52]>CN(C)C=O.CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[O:6][CH2:7][CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:15][CH:16]=1)(=[NH:52])[NH2:2]
Reactant: [NH4+]
Reactant: COc1ccc(C(=O)c2ccc(C(=O)NCCOc3cccc(C#N)c3)cc2)cc1OC
Agent: CC(=O)[O-]
Agent: S
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)c2ccc(C(=O)NCCOc3cccc(C(=N)N)c3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
0.5 g (1.16 mmol) of N-[2-(3-cyanophenoxy)ethyl]-4-(3,4-dimethoxybenzoyl)benzamide was dissolved in 10 ml of N,N-dimethylformamide (dehydrated). 0.21 g (2.32 mmol) of sodium hydrogensulfide dihydrate and 0.24 g (1.16 mmol) of magnesium chloride hexahydrate were added to the obtained solution under cooling with ice, and they were stirred at room temperature for 2.5 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained crude product was dissolved in 20 ml of acetone. 0.56 ml (9.0 mmol) of methyl iodide was added to the solution, and they were refluxed for 3 hours. The solvent was evaporated, and the obtained crude product was washed with ethyl acetate. After the filtration, the obtained crystals were dissolved in 10 ml of methanol. 155 mg (2.0 mmol) of ammonium acetate was added to the obtained solution, and they were stirred for 3 hours. The solvent was evaporated, and the residue was treated in the same manner as that in step 7 in Example 51 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH3:18][CH:19]([CH3:42])[CH:20]([NH:25][C:26]([C:28]1[S:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)=[CH:31][N:32]=1)=[O:27])[C:21]([O:23][CH3:24])=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:30]3[S:29][C:28]([C:26]([NH:25][CH:20]([CH:19]([CH3:42])[CH3:18])[C:21]([O:23][CH3:24])=[O:22])=[O:27])=[N:32][CH:31]=3)=[CH:34][CH:35]=2)=[C:4]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccccc1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3Oc3ccccc3)cc2)s1)C(C)C
Yield: 60 %

Procedure:
The title compound was synthesized analogous to Example 9, using 4-chloro-1-isocyanato-2-phenoxybenzene and intermediate 2. Yield: 60%; 1HNMR (DMSO-d6, 300 MHz): δ 9.61 (s, 1H), 8.73 (s, 1H), 8.71 (d, 1H), 8.4 (d, 1H), 8.36 (s, 1H), 7.74 (d, 2H), 7.54 (d, 2H), 7.44 (d, 2H), 7.2 (dd, 1H), 7.11 (d, 2H), 7.03 (dd, 1H), 6.86 (d, 1H), 4.33, (m, 1H), 3.68 (s, 3H), 2.26 (m, 1H), 0.95 (d, 6H); MS (ES+) m/z 579 (M+1).
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Cl:9][C:10]1[C:17](Cl)=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][CH3:13]>C(#N)C>[Cl:9][C:10]1[C:17]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][CH3:13]
Reactant: [S-]c1ccccc1
Reactant: CNc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Na+]
Solvent: CC#N
Product: CNc1c([N+](=O)[O-])ccc(Sc2ccccc2)c1Cl

Procedure:
An amount of 2.9 gm of sodium thiophenolate was added to a solution of 4.4 gm (0.02 mol) of 2,3-dichloro-6-nitro-N-methylaniline dissolved in 50 ml of acetonitrile. The mixture was refluxed for half an hour and subsequently evaporated, and the residue was taken up with chloroform and water. The chloroform layer was separated, dried, and evaporated. Six grams of brown oil, which crystallized with isopropanol, were obtained. The yield from the crystallization was 4 gm of product (67.5% of theory) in the form of yellow crystals, m.p. 79° C.
Reaction SMILES: C(O)(=O)C(O)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1>[OH-].[Na+]>[Cl:7][C:8]1[CH:9]=[C:10]([C@H:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: Clc1cc(Cl)cc(C2CCNC2)c1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc(Cl)cc([C@H]2CCNC2)c1
Yield: 97.8 %

Procedure:
3-(3,5-dichlorophenyl)pyrrolidine oxalate (471.6 g, 1.54 mol) was dissolved in 2 M aqueous NaOH solution (1000 mL) and extracted with ethyl acetate (3×350 mL). The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure to provide the free base of (R)-3-(3,5-dichlorophenyl)pyrrolidine (325.4 g, 98%) as a clear amber oil. A 5 L round bottom flask was fitted with a mechanical stirrer, a heating mantle, a J-Kem temperature probe/controller, a water cooled reflux condenser and a nitrogen inlet/outlet. The vessel was charged with 3-(3,5-dichlorophenyl)pyrrolidine (100 g, 0.46 mol) and 2-propanol (800 mL, 8 mL/g) under a nitrogen atmosphere at RT. (2R)-2-hydroxy-2-phenylacetic acid (70.4 g, 0.46 mol) was added as a solid in one portion, and the resulting solution was stirred for 5 min when a solid began to form. The suspension was heated at 85° C. for 5 min and then allowed to slowly cool to RT. The solid was filtered, washed with 2-propanol (2×250 mL) and dried under high vacuum. Repeated recrystallization of this salt (8×) in 2-propanol (1 mL/g) afforded (R)-3-(3,5-dichlorophenyl)pyrrolidine (R)-2-hydroxy-2-phenylacetate (30 g, 18%) in >96% ee. Absolute configuration was assigned based on X-ray analysis. 1H-NMR (400 MHz, DMSO-d6) δ 7.50 (t, J=1.8 Hz, 1H), 7.42-7.38 (m, 5H), 7.26-7.22 (m, 2H), 7.16 (dd, J=5.2, 9.3 Hz, 1H), 4.61 (s, 1H), 3.51 (dd, J=8.2, 10.9 Hz, 1H), 3.44-3.27 (m, 2H), 3.15-3.01 (m, 3H), 2.50 (t, J=1.8 Hz, 1H), 2.32-2.24 (m, 1H) and 1.91-1.81 (m, 1H) ppm. Chiral HPLC (Astec Chirobiotic, (25 cm×4.6 mm), 100% MeOH (0.1% TEA, 0.1% HOAc), 1.2 mL/min): tR=33.9 min (S), 34.9 min. (R).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].[CH3:16][CH:17]([CH3:29])[C:18](=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])[CH3:19]>C1COCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]([CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])([CH:17]([CH3:29])[CH3:16])[CH3:19])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C(=O)OC)=C(C)C(C)C
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(C)(c1ccc(Cl)cc1)C(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Under argon, 6.2 g (26 mmol) of 1-chloro-4-iodobenzene were dissolved in 50 ml of THF and cooled to −78° C. 24 ml (31.2 mmol) of a 1.3 M solution of isopropylmagnesium chloride×lithium chloride in THF were then slowly added dropwise. The reaction solution was then slowly warmed to −40° C. and stirred at this temperature for 2 h. The reaction solution was then warmed to −10° C., and 495 mg (2.6 mmol) of copper(I) iodide were added. 5 g (24.97 mmol) of dimethyl (3-methylbutan-2-ylidene)malonate, dissolved in 30 ml of THF, were then slowly added dropwise to the reaction solution. The resulting reaction mixture was slowly warmed to room temperature and stirred at this temperature for 1 h. The mixture was then cooled to 0° C., and ice-cold 1 M hydrochloric acid (pH˜2) was added carefully. The phases were separated, the aqueous phase was then extracted three more times with ethyl acetate and the combined organic phases were dried over magnesium sulphate, filtered and concentrated to dryness. The resulting crude product was initially pre-purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). The product was then re-purified by preparative RP-HPLC (mobile phase methanol/water). This gave 3.38 g (42% of theory) of the target compound.
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:12]1([CH3:27])[CH:17]=[CH:16][C:15]([C:18]2[N:22]=[C:21]([CH2:23][C:24](O)=[O:25])[O:20][N:19]=2)=[CH:14][CH:13]=1.N1CCCCC1>C(O)C>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:23]([C:21]3[O:20][N:19]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([CH3:27])=[CH:13][CH:14]=4)[N:22]=3)[C:24](=[O:25])[O:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: Cc1ccc(-c2noc(CC(=O)O)n2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2cc(-c3nc(-c4ccc(C)cc4)no3)c(=O)oc2c1

Procedure:
4.5 parts of 2-hydroxy-4-methoxy benzaldehyde and 7.38 parts of the ethyl ester of 3-p-tolyl-1,2,4-oxadiazol-5-acetic acid (melting point: 56° C) are dissolved in 80 parts of ethanol. 0.3 part of piperidine is added and the mixture is heated for 1 hour under reflux. After cooling, the crystalline precipitate obtained is filtered and washed in ethanol. Thus 8.5 parts of 7-methoxy-3-(3-p-tolyl-1,2,4-oxadiazol-5-yl) coumarin are obtained which melts at 227° C.