Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[C@H:7]([CH2:19][CH2:20][CH2:21][NH2:22])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(C)(C)C.[C:24]([O:31]C([O-])=O)(=O)[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([O:25][C:24](=[O:31])[C@H:21]([CH2:20][CH2:19][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[NH:22][C:24]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:31])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)[C@H](CCCN)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nδ -(Benzyloxycarbonyl-L-ornithine tert-butyl ester (7.50 g, 23.3 mmol) was dissolved in 27 ml of methylene chloride, and the solution was cooled to 0° C. To that solution was added dropwise tert-butyl pyrocarbonate (5.87 g, 26.9 mmol) in 10 ml of methylene chloride. The reaction mixture was stirred at 0° C. for 1 hour, and stirring was continued for 3 additional hours at room temperature. The solvent was evaporated at reduced pressure and the oily residue was chromatographed on a column of silica gel (25 cm×30 mm) using hexane:ethyl acetate (3:1) as solvent. Fractions of approximately 5 ml were collected, and those containing product were identified by thin layer chromatography (see below). Chromatographic fractions containing product were pooled and evaporated to a thick oil by rotary evaporation at reduced pressure. The yield was 8.63 gm (93.5%). 1H NMR (DCCl3) δ 1.44 (s,9H), 1.46 (s,9H), 1.5-1.9 (m,4H), 3.23 (t,2H), 4.17 (t, 1H), 4.88 (s,1H broad), 5.09 (s,2H and s,1H broad) 7.35 (s,5H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[N:13]1[C:17](=[O:18])[NH:16][C:15](=[O:19])[O:14]1)([O-:3])=[O:2].[CH2:20]=[O:21].O>CO.C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:20][OH:21])[C:15](=[O:19])[O:14]1)([O-:3])=[O:2]
Reactant: C=O
Reactant: O=c1[nH]c(=O)n(-c2c([N+](=O)[O-])cccc2[N+](=O)[O-])o1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=c1on(-c2c([N+](=O)[O-])cccc2[N+](=O)[O-])c(=O)n1CO
Reaction time: 2 h

Procedure:
2-(2,6-Dinitrophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(2,6-dinitrophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2Cl.O>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: N#CCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(C(C#N)c3ccc(Br)cc3)c2cc1OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
Commercially available 4-bromophenylacetonitrile (4.3 g) was dissolved in toluene (10 ml) and the temperature was lowered to 0° C., after which sodium hydride (1.0 g) was added, the temperature was raised to 50° C., and the admixture was then stirred for 1 hour. Next, 6,7-dimethoxy-4-chloroquinoline (2.2 g) was added, and the admixture was stirred for 15 hours, after which water was poured and the mixture was extracted with ethyl acetate. After drying with anhydrous sodium sulfate and removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1) to obtain 850 mg of the title compound (yield: 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][C:18]3[CH:35]=[CH:34][C:21]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:23])=[CH:20][CH:19]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:36][C:37]([F:49])([F:48])[O:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:42]3[CH:41]=[CH:40][C:39]([O:38][C:37]([F:36])([F:48])[F:49])=[CH:44][CH:43]=3)=[C:11]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[O:23])=[CH:34][CH:35]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(CCc2cc(-c3ccc(Cl)c(Cl)c3)ccc2O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(CCc2cc(-c3ccc(Cl)c(Cl)c3)ccc2Oc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
A DCM solution (1 mL) containing the intermediate from Step A (22 mg, 0.043 mmol), copper(II) acetate (8 mg, 0.043 mmol), 4-(trifluoromethoxy)phenyl boronic acid (18 mg, 0.086 mmol), triethylamine (0.03 mL, 0.215 mmol) and 4 Å molecular sieves (small spatula tip) was stirred under an air atmosphere. After stirring overnight the solution was filtered and concentrated to give tert-butyl N-[4-(2-{3′,4′-dichloro-4-[4-(trifluoromethoxy)phenoxy]biphenyl-3-yl}ethyl)benzoyl]-β-alaninate. LCMS1 4.85 min. (M+H)=674. The tert butyl group was cleaved as described in EXAMPLE 1 Step I to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.65 (d, J=8.2 Hz, 2H); 7.59 (d, J=2.2 Hz, 1H); 7.51 (d, J=8.3 Hz, 1H); 7.37-7.34 (m, 3H); 7.24 (d, J=8.3 Hz, 2H); 7.21 (d, J=8.4 Hz, 2H); 6.98-6.95 (m, 4H); 3.79 (q, J=5.9 Hz, 2H); 3.01 (s, 4H); 2.80 (t, J=5.8 Hz, 2H). LCMS1 4.43 min. (M+H)=618.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.ClCC(=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15].O1CCO[CH2:21][CH2:20]1>>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C:1]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[NH:9][CH:21]=[CH:20][S:8]1
Reactant: NC(=S)c1ccncc1
Reactant: C1COCCO1
Reactant: COC(=O)CC(=O)CCl
Product: COC(=O)CC1(c2ccncc2)NC=CS1
Temperature: 75 °C

Procedure:
In an oven-dried, 100-mL, round-bottomed flask was placed thioisonicotinamide (Pflaltz-Bauer) (2.9 g, 21 mmol) in 1,4-dioxane (60 mL). Methyl 4-chloroacetoacetate (Aldrich, 3.16 g, 2.4 mL, 21 mmol) was added at RT. The flask was purged with N2 and the solution was heated to 75° C. for 12 h. The mixture was cooled to RT, quenched with 2N NH3 in MeOH (10 mL), and concentrated. The material was purified by flash chromatography on silica gel (EtOAc/hexane, 50:50) to afford 2-(4-pyridyl)-thiazole acetic acid methyl ester as a light yellow solid. Mp: 78-79° C. MS m/z: 235 (M+1). Calc'd for C11H10N2O2S: 234.05.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11](O)=[O:12])[C:5]2[CH:24]=[CH:25][NH:26][C:4]=2[C:3]1=[O:27].C(Cl)(=O)C([Cl:31])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]([Cl:31])=[O:12])[C:5]2[CH:24]=[CH:25][NH:26][C:4]=2[C:3]1=[O:27]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc(-c2cc(C(=O)O)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(-c2cc(C(=O)Cl)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of Example 10 (0.24 g, 0.67 mmol) in dichloromethane (10 mL) was treated with oxalyl chloride (0.17 g, 1.33 mmol) and dimethylformamide (5 mg, 10 mol %). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to afford the title compound (0.25 g, quantitative).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[N:10]S(C1C=CC(C)=CC=1)(=O)=O)[N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:21][O:22][C:23]1[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=1[CH2:25][NH:26][C:27](=[NH:32])[NH:28][C:29](N)=[S:30]>>[Cl-:1].[NH:32]=[C:27]([NH:28][C:29]1[S:30][CH2:2][C:3](=[N+:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[N:10]=1)[NH:26][CH2:25][C:24]1[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=1[O:22][CH3:21]
Reactant: Cc1ccc(S(=O)(=O)N=C(CCl)N2CCCCC2)cc1
Reactant: COc1ccccc1CNC(=N)NC(N)=S
Product: COc1ccccc1CNC(=N)NC1=NC(=[N+]2CCCCC2)CS1
Product: [Cl-]
Yield: 8.3 %

Procedure:
Reaction of 100 mg (0.38 mmol) N-(2-chloro-1-piperidine-1-ylethylidene)-4-methylphenyl sulfonamide (preparation according to: Abdelaal, S.; Bauer, L. J. Het. Chem. 1988, 25 (6), 1849-1856) with 120 mg (0.38 mmol) N-[[(2-methoxybenzyl)amino](imino)-methyl]thiourea analogously to Example 3 yielded 12 mg of the desired product; ESI-MS [M+H+]=346.15. According to NMR, the compound exists as tautomeric mixture of 1-[2-({imino[(2-methoxybenzyl)amino]methyl}amino)-1,3-thiazole-4(5H)-ylidene]piperidine and N-(2-methoxybenzyl)-N′-(4-piperidine-1-yl-1,3-thiazole-2-yl)guanidine.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].[I:8][C:9]1([CH2:12][C@@H](O)CO)[CH2:11][CH2:10]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[I:8][C:9]1([CH2:12][C@@H:1]2[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]2)[CH2:11][CH2:10]1
Reactant: COC(C)(C)OC
Reactant: OC[C@H](O)CC1(I)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)OC[C@@H](CC2(I)CC2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
2,2-Dimethoxypropane (140 mg, 1.337 mmol) and pyridinium p-toluenesulfonate (PPTS, 6 mg) were added to a solution of crude (R)-3-(1-iodocyclopropyl)propane-1,2-diol (step F, 0.598 mmol) dissolved in dichloromethane (3 mL) and the mixture stirred at room temperature for 2 hours. Solvents were removed under reduced pressure and the crude product purified by flash chromatography using ethyl acetate/hexane (1:10) eluant to afford (R)-4-((1-iodocyclopropyl)methyl)-2,2-dimethyl-1,3-dioxolane (84 mg, 50%).
Reaction SMILES: [CH2:1]([C:14]1[C:15]2[S:24][C:23](CC)=[C:22]([Br:27])[C:16]=2[S:17][C:18]=1[C:19]([O-:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C1COCC1.[Li+].[OH-].Cl>O.CO>[CH2:1]([C:14]1[C:15]2[S:24][CH:23]=[C:22]([Br:27])[C:16]=2[S:17][C:18]=1[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCc1c(C(=O)[O-])sc2c(Br)c(CC)sc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCc1c(C(=O)O)sc2c(Br)csc12

Procedure:
3-Tridecyl-6-bromo-thieno[3,2-b]thiophene-2-carboxylic acid (154) was prepared using the following procedure. Compound 153 (71.0 g, 0.15 mol) was dissolved into a mixture of THF (400 mL), methanol (50 mL), and LiOH (72 mL, 10% solution). This mixture was refluxed overnight and poured into concentrated hydrochloric acid (300 mL). The acid mixture was then diluted to 1000 mL with water. Solid was filtrated and washed with water (3×500 mL). The light yellow solid was washed with methanol (300 mL) and dried under vacuum overnight (46.40 g. 69.5%). Mp: 88-90° C. 1H NMR (300 MHz, CD2Cl2) δ 7.55 (s, 1H), 3.17 (t, 2H), 1.75 (t, 2H), 1.26 (m, 20H), 0.87 (t, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C(O)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH:40][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[CH:25]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:18])[CH3:36]
Reactant: CCN(CC)CCN
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=NOC)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
Following the general method as outlined in Example 2, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, diphenylacetic acid, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained after column chromatography as an off-white solid as a mixture of E/Z-isomers.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[Cl:10][S:11]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([OH:9])=[O:8])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1
Product: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 120 °C

Procedure:
Benzoic acid (30.5 g, 0.25 mol) is treated with chlorosulfonic acid (10 ml/1.05 mol). The reaction mixture is heated to 120° C. in the course of 20 min with stirring. To complete the reaction, it is stirred for 45 min at 125° C. until the absence of the evolution of gas. The reaction mixture is cooled to room temperature (RT) and added to 300 ml of ice with stirring. The cream-colored precipitate is filtered off, thoroughly washed with ice water and dried. Yield: 40.8 g (74%)
Reaction SMILES: C(Cl)Cl.[OH:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:28].[C:29]1(=[O:39])[O:34][C:32](=[O:33])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12>CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[C:32]([C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[C:29]([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[C:20]([C:24]([F:25])([F:26])[F:27])=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:28])=[O:39])([OH:34])=[O:33]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc([C@H]2Cc3c(cccc3C(F)(F)F)NC(=O)[C@H]2O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([C@H]2Cc3c(cccc3C(F)(F)F)NC(=O)[C@H]2OC(=O)c2ccccc2C(=O)O)cc1
Temperature: 15 °C

Procedure:
Under argon, to dry methylene chloride (800 ml) and triethylamine (38 ml) was added DMAP (2.17 g) and (cis)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin -2-one (62.51 g). After stirring, the so-formed suspension was cooled to about 15° C. and phthalic anhydride (39.53 g) was added. The resulting solution was warmed to room temperature and stirred for 4 hours. Upon quenching with 500 ml of dilute hydrochloric acid the layers were separated and the crystallized product from the methylene chloride layer was filtered and washed and dried in vacuo to give 84.8 g (95.4%) of the title A compound as a white crystalline solid, m.p. 161°-162° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12]C2C=C3C(=CC=2)N(C2CC2)CCC3(C)C)=[CH:7][CH:6]=1)C.[CH3:29][O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=1.[CH2:41](N(CC)CC)[CH3:42]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:3][C:4]1([C:5]2[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][C:31]([O:30][CH3:29])=[O:40])=[CH:34][CH:35]=3)=[CH:9][CH:10]=2)[CH2:42][CH2:41]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCN3C2CC2)cc1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 120.0 mg, 0.56 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 154.0 mg, 0.56 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (35.0 mg, 0.19 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (130 mg, 0.19 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-8% EtOAc-hexanes) afforded 140.0 mg (78%) of the title compound as an orange solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27].[NH2:31][OH:32]>CS(C)=O>[OH:32][N:31]=[C:26]([C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:20](=[CH:21][C:11]3=4)[CH2:19][CH2:18][O:17]5)[C:2]2=[O:1])[CH:24]=1)[NH2:27]
Reactant: NO
Reactant: N#Cc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Solvent: CS(C)=O
Product: NC(=NO)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a solution of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (1.15 g, 2.92 mmol) in dimethyl sulfoxide (20 mL) was added hydroxylamine (50% wt in H2O, 2 mL, 32.67 mmol). The reaction was stirred at 80° C. for 3 h, and cooled to ambient temperature. The precipitate was collected by filtration, washed with water and diethyl ether, and dried in vacuo to afford N′-hydroxy-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H) yl)methyl]benzenecarboximidamide (0.85 g, 68%): 1H NMR (300 MHz, CDCl3) δ 7.96 (br s, 1H), 7.61 (s, 1H), 7.53-7.50 (m, 1H), 7.38-7.35 (m, 2H), 7.21-7.15 (m, 2H), 7.03-6.98 (m, 1H), 6.77-6.74 (m, 1H), 6.48 (s, 1H), 6.40 (s, 1H), 5.12-4.68 (m, 6H), 4.49 (t, J=8.6 Hz, 2H), 3.01-2.91 (m, 2H); MS (ES+) m/z 427.8 (M+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=2)[NH2:38])[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[C:37]([NH:38]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:39]=[CH:40][CH:41]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(Cc2cccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)c2)CC1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-(4-methylpiperazinomethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:3]([OH:22])[CH2:4][N:5]([O:17][CH:18]([CH2:20][CH3:21])[CH3:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[OH:30][C:31]1[C:32]([CH3:40])=[C:33]([CH:37]=[CH:38][CH:39]=1)C(O)=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:18]([O:17][N:5]([CH2:4][C@@H:3]([OH:22])[C@@H:2]([NH:1][C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([OH:30])[C:32]=1[CH3:40])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH2:20][CH3:21])[CH3:19]
Reactant: CCC(C)ON(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: Cc1c(O)cccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)ON(C[C@@H](O)[C@H](Cc1ccccc1)Nc1cccc(O)c1C)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 31.5 %

Procedure:
N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(sec-butoxy)-4-methoxybenzenesulfon-amide (Step 1, Example 67)(0.12 mmol, 50 mg), 3-hydroxy-2-methylbenzoic acid (0.12 mmol, 18 mg), 1-hydroxybenzotriazole hydrate (0.12 mmol, 16 mg), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.13 mmol, 25 mg), diisopropylethylamine (0.14 mmol, 0.025 mL) and anhydrous N,N-dimethylformamide (0.5 mL) were combined at room temperature and stirred for 18 hours. The crude reaction mixture was concentrated to a residue, dissolved in ethyl acetate, washed with 1N HCl, 5% aq. potassium carbonate solution, brine and dried over magnesium sulfate. The solution was concentrated to a residue, purified by RPHPLC (water/acetonitrile) and lyophylized providing 20 mg (30%) of a white solid. H1-NMR (CDCl3): δ 7.76-7.73(2H,m), 7.32-7.23 (5H,m), 7.00-6.97 (3H,m), 6.78-6.76 (1H,m), 6.56-6.53 (1H,m), 5.90 (1H,bs), 4.42-4.27 (2H,m), 4.09-3.95 (1H,m), 3.87 (3H,s), 3.25-2.27 (5H,m), 2.05-1.95 (3H,m), 1.77-1.58 (1H,m), 1.55-1.22 (1H,m), 1.24-1.20 (3H,m), 0.93-0.86 (3H,m); MS (ESI): M+H=557.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Sn](CCCC)(CCCC)CCCC)[CH:12]=2)=[CH:5][C:4]=1[CH2:30][OH:31].Br[C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=1[CH3:42].[Cl-].[NH4+].[C:45]1(C)C=CC=CC=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:31][CH2:30][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[CH2:2][OH:1])[CH2:9][S:10][C:11]1[CH:12]=[C:13]([C:33]2[CH:41]=[CH:40][C:36]([C:37]([O:39][CH3:45])=[O:38])=[CH:35][C:34]=2[CH3:42])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: Cc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(SCc2ccc(CO)c(CO)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cccc(SCc3ccc(CO)c(CO)c3)c2)c(C)c1
Reaction time: 24 h

Procedure:
1.67 g (3 mmol) of [2-hydroxymethyl-5-(3-tributylstannylphenylsulphanylmethyl)phenyl]methanol are dissolved in 30 mL of toluene and 5 mL of DME. 970 mg (4.5 mmol) of 4-bromo-3-methylbenzoic acid are added and the mixture is degassed with a stream of argon for 10 minutes. Pd(PPh3)4 (175 mg, 0.15 mmol) is then added and the reaction medium is brought to reflux and stirred for 24 h. The reaction medium is then treated with ammonium chloride solution and then extracted with ethyl acetate. The organic phases are combined, dried and then concentrated under reduced pressure. The residue is then dissolved in 50 mL of methanol, 1 mL of sulphuric acid is added and the mixture is then refluxed for 18 h. After cooling and treatment with water, the mixture is extracted with ethyl acetate. The organic phases are combined, dried and then concentrated under reduced pressure. The residue is then purified by chromatography on a column of silica. A colourless oil is obtained (m=180 mg, Y=15%).