Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH:1]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:18][CH2:19]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
The crude 2-[3-(4-benzhydryl-piperazin-1-yl)-propyl]-isoindole-1,3-dione (930 mg) was dissolved in ethanol (2 ml), followed by the addition of hydrazine hydrate (large excess, 2-3 ml). The solution was stirred at room temperature overnight. The white solid was precipitated. The white solid was filtered off and washed with small amount of ethanol. The filtrates were combined and concentrated. The resulted residue was dissolved in toluene (100 ml). The solution was washed with water (3×15 ml) and dried over anhydrous Na2SO4. After evaporated the solvent, the crude product 3-(4-benzhydryl-piperazin-1-yl)-propylamine was obtained (276 mg, 42.7% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([F:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13]C)[CH:8]=2)[N:3]=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([F:27])[CH:19]=1)([OH:17])=[O:16]>>[F:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[C:2]1[CH:11]=[C:10]([F:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[CH:8]=2)[N:3]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Reactant: COc1ccc2nc(Cl)cc(F)c2c1
Product: O=C(O)c1ccc(-c2cc(F)c3cc(O)ccc3n2)c(F)c1

Procedure:
The compound was prepared following Scheme 2, B conditions starting from 2-chloro-4-fluoro-6-methoxyquinoline (Intermediate 7) and 4-carboxy-2-fluorophenylboronic acid. Note: In step 2, after purification by prep HPLC, the collected fractions were immediately neutralized with sat.NaHCO3 to pH 6, followed by extraction with EtOAc/MeOH (v/v=10/1, 50 mL×3). Combined organics were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give the desired product. 1H NMR (MeOD 400 MHz): δ 8.10-8.00 (m, 2H), 7.98 (dd, J=8.0, 1.2 Hz, 1H), 7.85 (dd, J=11.6, 1.2 Hz, 1H), 7.62 (dd, J=11.6, 2.0 Hz, 1H), 7.45 (dd, J=9.2, 2.8 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H). MS (ESI): m/z 301.8 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[CH3:29][S:30]([CH2:33][CH2:34][NH2:35])(=[O:32])=[O:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:35][CH2:34][CH2:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with 2-(methylsulfonyl)ethanamine using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a light brown semisolid, MS (ESI−): m/z=479.1 [M−H]−.
Reaction SMILES: [C:1]1(=[CH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.[Pt]=O>[CH:1]1([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCC=C1CCCCCCCCCCC1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)CCCCC1CCCCCCCCCCC1
Reaction time: 3 h
Yield: 96.9 %

Procedure:
From Example 9Ci above, 0.276 g (0.001 mole) of 5-cyclododecylidene pentanoic acid was dissolved in 30 ml of glacial acetic acid. Platinum oxide (0.027 g) was added and the mixture was hydrogenated on a sloping-manifold hydrogenation apparatus for 3 hr at room temperature. The resultant mixture was then filtered through Celite (diatomaceous earth). The solvent was removed in vacuo to yield 0.26 g (93.8%) of 5-cyclododecylpentanoic acid having the following physical characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCN(C)CC4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(CCCOc2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 26.6 %

Procedure:
To a solution of methyl 6-chloro-5-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxyate (80 mg, 0.22 mmol) in methanol (8 mL) was added 1.0M aqueous NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (25 mg, 28% yield) as a white solid. MS (ES+) 428.1 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.41 (br. s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.56 (s, 1H), 7.34 (d, 2H), 6.98 (d, 2H), 4.12 (t, 2H), 3.20-2.75 (m, 10H), 2.70 (s, 3H), 2.10-2.01 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1Br.[H][H]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: [H][H]
Reactant: N#Cc1cc(C(O)CNC2CC2)cc(Br)c1N
Solvent: CO
Product: N#Cc1cc(C(O)CNC2CC2)ccc1N

Procedure:
4 gm of 1-(4'-amino-3'-bromo-5'-cyano-phenyl)-2-cyclopropylamino-ethanol was dissolved in methanol, and the solution was hydrogenated at room temperature at a hydrogen pressure of 3 to 5 atmospheres after addition of 1 gm of palladized coal (10%). After termination of hydrogen absorption, the catalyst was suction-filtered off, the filtrate was evaporated to dryness in vacuo, and the residue was distributed between dilute sodium hydroxide and chloroform. After evaporation of the chloroform phase, 1-(4'-amino-3'-cyano-phenyl)-2-cyclopropylamino-ethanol was obtained as an oil, which was purified chromatographically on silicagel (eluant: chloroform:methanol = 9:1). The dihydrochloride, obtained by addition of ethereal hydrochloric acid, was recrystallized from isopropanol. M.p. 148°-151° C. (decomp.).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)([CH3:34])[CH3:33]>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:32]([CH3:34])[CH3:33])[CH:24]=1
Reactant: CC(C)c1ccccc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 54.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-isopropylphenylboronic acid (30 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white, crystalline solid (30 mg, 55%). MS m/e 449.25 (M+H+)
Reaction SMILES: Cl.C([O:9][C:10]1[C:15](=[O:16])[CH:14]=[CH:13][N:12]([CH2:17][CH2:18]O)[C:11]=1[CH:20]([OH:28])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)C1C=CC=CC=1.[OH-].[Na+]>C(OCC)(=O)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH:20]2[C:11]3=[C:10]([OH:9])[C:15](=[O:16])[CH:14]=[CH:13][N:12]3[CH2:17][CH2:18][O:28]2)=[CH:26][CH:25]=1
Reactant: O=c1ccn(CCO)c(C(O)c2ccc(Cl)cc2)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=c1ccn2c(c1O)C(c1ccc(Cl)cc1)OCC2
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
2.5 ml of 37% conc. hydrochloric acid are added to 0.245 g of 3-benzyloxy-1-(2-hydroxy-ethyl)-2-[hydroxy-(4-chloro-phenyl)-methyl]-1H-pyridin-4-one (Example 34e) and the solution is heated with stirring at 110° C. for 45 minutes. After cooling, 5 g of ice are added. The reaction mixture is neutralised with sodium hydroxide solution to a pH of 6.5, then 5 ml of ethyl acetate are added and stirring is carried out for 4 hours in an ice-bath. The reaction mixture is filtered and washed with water and ethyl acetate. Drying yields 1-(4-chloro-phenyl)-9-hydroxy-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazin-8-one. Pink crystals, m.p.: 211°-214° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16]([CH2:18][NH2:19])[CH2:15][C:14]=2[CH:20]=1>>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][NH:19][CH2:18][CH:16]1[CH2:15][C:14]2[CH:20]=[C:10]([O:9][CH3:8])[CH:11]=[CH:12][C:13]=2[O:17]1)[CH3:7]
Reactant: COc1ccc2c(c1)CC(CN)O2
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCNCC1Cc2cc(OC)ccc2O1
Reaction time: 60 h

Procedure:
4.4 ml (0.04 mol) of ethyl acrylate are added to 6.5 g (0.04 mol) of 5-methoxy-2,3-dihydrobenzofuran-2-ylmethylamine and the reaction mixture is left to stand for 60 hours at room temperature, yielding 3-[N-(5-methoxy-2,3-dihydrobenzofuran-2-yl)methylamino]-propionic acid ethyl ester in the form of a yellowish oil.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>O.CO>[OH:1][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([OH:5])=[O:4]
Reactant: CCCCCCCCCCCCCC=CCC(O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCC=CCC(O)C(=O)O
Temperature: 25 °C

Procedure:
Methyl 2-hydroxy-4-octadecenoate (8.21 g, 0.026 mol, 1.0 eq) is heated under reflux with a large excess of sodium hydroxide (8.4 g, 0.21 mol, 8.1 eq) in water (20 ml) and methanol (20 ml) for 1 hour. After cooling down to room temperature, the mixture is washed with hexane (50 ml) and the organic phase separated. The clear aqueous layer is acidified to pH 1 with concentrated hydrochloric acid and the resultant mixture is extracted with diethylether (3×50 ml), the combined organic layers being washed with brine (50 ml) dried over anhydrous magnesium sulphate and evaporated to give a white solid. This is recrystallised from ethyl acetate/hexane to give the product acid (5) as white needles, 6.35 g (81%), mp 78-79.5° C.
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:18]=2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1nsc(=O)o1
Reactant: N#Cc1ccc(Cl)cc1
Product: CCOC(=O)c1nsc(-c2ccc(Cl)cc2)n1
Yield: 61.4 %

Procedure:
A sample of p-chlorobenzonitrile was distilled and then crystallized twice from methylcyclohexane to remove impurities that interfered in the following reaction. A solution of 8.76 g (0.050 mol) of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate and 68.8 g (0.50 mol, 10 equiv.) of purified p-chlorobenzonitrile was held at 190° C for 72 hours. The solution, which contained the product in 69% yield, was concentrated under vacuum to 150° C (about 2 torr). The residue was crystallized from heptane (charcoal) to give 8.25 g (61%) of gold crystals, mp 98°-99.5° C. A small sample was crystallized twice from heptane (charcoal) to give a white solid, mp 98°-99.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(-c2ccnc(Cl)c2)n(-c2cccc(F)c2)n1
Product: Cc1cc(-c2ccnc(NCc3ccccc3)c2)n(-c2cccc(F)c2)n1
Temperature: 180 °C
Yield: 90 %

Procedure:
A mixture of 2-chloro-4-[1-(3-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 47; 1.11 g, 0.0039 mol) and benzylamine (30 mL) was heated at 180° C. overnight (about eighteen hours). The excess benzylamine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 1.24 g (90% yield) of the titled compound as a clear oil, which solidified upon standing: mp: 94-96° C.; Anal. Calc'd. for C22H19FN4: C, 73.72; H, 5.34; N, 15.63. Found: C, 73.62; H, 5.62; N, 15.34.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[C:13]2[CH2:14][CH2:15][CH2:16][C:12]1=2.CO>[Pd].O1CCCC1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:15]1[CH2:16][CH:12]([OH:11])[CH:13]=[CH:14]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C1CC2=C(C1)O2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: OC1C=CC(n2cnc3c(Cl)ncnc32)C1
Yield: 25 %

Procedure:
Trimethylsilylated 6-chloropurine (prepared from 50 g (0.32 mol) of 6-chloropurine) is stirred with 5 mol % of the palladium(0) catalyst described above and an equivalent amount of epoxycyclopentene in tetrahydrofuran at room temperature for 24 hours. The reaction solution is heated with methanol for 1.5 hours, the precipitate formed is filtered off with suction, the resulting solution is concentrated and the residue is chromatographed over silica gel using methylene chloride/methanol 20/1. 18.9 g (25% of theory) of 6-chloro-9-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]purine (Example 1.5.1.) are obtained as yellowish crystals of melting point 118° C. 1H-NMR (270 MHz, d6 -DMSO), δ[ppm]: 8.80 (s, 1H), 8.62 (s, 1H), 6.25 (m, 1H), 6.08 (m, 1H), 5.60 (m, 1H), 5.31 (d, 1H), 4.76 (m, 1H), 2.95 (m, 1H), 1.81 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]([O-])(=[O:34])[CH2:32][OH:33].[Na+].[Na]>C(O)CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:33][CH2:32][CH2:31][OH:34])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])CO
Reactant: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [Na]
Solvent: OCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCO
Temperature: 95 °C
Reaction time: 4 h

Procedure:
886 mg of p-t-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide were added to a sodium glycolate solution from 3.0 g of ethylene glycol and 138 mg of sodium. The reaction mixture was stirred at 95° C. under argon for 4 hours. Thereafter, the ethylene glycol was distilled off and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase was dried and the solvent was distilled off. The residue was crystallized from diisopropyl ether. There were obtained 870 mg of p-t-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide. M.p. 143°-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([Cl:9])[CH:3]=1.[Br:10]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:10])=[C:4]([Cl:9])[CH:3]=1
Reactant: Cc1ccc(Br)cc1Cl
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Yield: 70.8 %

Procedure:
Dissolve 4-bromo-2-chloro-1-methyl-benzene (64.3 g, 312.9 mmol) in carbon tetrachloride (1 L). Add benzoyl peroxide (760 mg, 3.1 mmol) and N-bromosuccinamide (58.5 g, 329 mmol) and heat to 80° C. for 18 hours. Cool reaction to room temperature and filter. Concentrate the filtrate and purify by silica gel (hexanes) to yield 63 g (71%) of the title compound. NMR (CDCl3) δ 7.57 (d, 1H), 7.39 (dd, 1H), 7.31 (d, 1H), 4.53 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=S)[C:5]=3[CH:19]=[CH:20][CH:21]=2.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][N:24]=[CH:23]1.C(O)C>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[N:30][CH2:29][CH2:28][CH2:27][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)[C:5]=3[CH:19]=[CH:20][CH:21]=2
Reactant: NCCCn1ccnc1
Reactant: S=C1c2cccc3c(Cl)ccc(c23)N1Cc1ccccc1
Solvent: CCO
Solvent: CN(C)C=O
Product: Clc1ccc2c3c(cccc13)C(=NCCCn1ccnc1)N2Cc1ccccc1
Yield: 64.8 %

Procedure:
A mixture of 3.1 g of 6-chloro-1-(phenylmethyl)benz[cd]indole-2(1H)-thione (Cr), 1.4 g of 1H-imidazole-1-propanamine, 250 ml of ethanol, 75 ml of dimethylformamide, and 3.5 g of mercuric acetate is reacted as described in Example 3, giving 2.6 g of the desired product, mp 147°-149° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:18](=[O:19])[N:4]2[CH:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][S:7][C@H:3]12.COC(OC)OC.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>ClCCl.CO>[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[N:1][C@@H:2]2[C:18](=[O:19])[N:4]3[CH:5]([C:8]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:9])[CH2:6][S:7][C@H:3]23)=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)CS[C@H]12
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: ClCCl
Solvent: COC(OC)OC
Product: O=C(OCc1ccccc1)C1CS[C@@H]2[C@H](N=Cc3ccc([N+](=O)[O-])cc3)C(=O)N12

Procedure:
Benzyl 6β-aminopenam-3-carboxylate (1.11 g, 4 m mol) in dry dichloromethane (4 ml) with trimethylorthoformate (0.42 g, 0.44 ml, 4 m mol) was treated with 4-nitrobenzaldehyde (0.61 g, 0.4 m mol) in dry methanol (10 ml) at room temperature for 1.5 h. The mixture was then evaporated to dryness, triturated with ethanol and the solid material collected by filtration. Renystallisation from ethanol/ethylacetate gave almost colourless needles (1.2 g 74%); m.p. 95°-96° C.; νmax (CH2Cl2) 1795, 1750, 1530, 1360 cm-1 ; δ(CDCl3) 8.68 (1H, d, J 2 Hz, CH=N), 8.27 and 7.94 (4H, 2d, J 9 Hz), nitrophenyl), 7.38 (5H, s, phenyl), 5.51 (1H, d, J 4 Hz, 5-H), 5.45 (1H, dd, J 2 Hz and 4 Hz, 6-H), 5.23 (2H, s, CH2Ph), 4.93 (1H, t, J 5.5 Hz, 3-H) and 3.45 (2H, d, J 5.5 Hz, 2-H).
Reaction SMILES: I[CH3:2].[C:3]([O:7][C:8](=[O:25])[CH2:9][CH2:10][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:12][OH:13])([CH3:6])([CH3:5])[CH3:4]>C(#N)C.[Ag-]=O>[C:3]([O:7][C:8](=[O:25])[CH2:9][CH2:10][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:12][O:13][CH3:2])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)CC[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CI
Agent: O=[Ag-]
Solvent: CC#N
Product: COC[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.4 %

Procedure:
A solution of 4.82 ml (77.3 mmol) of iodomethane and 2.50 g (7.7 mmol) (S)-4-Benzyloxycarbonylamino-5-hydroxy-pentanoic acid tert-butyl ester in 25 ml of acetonitrile was cooled (0° C.) and treated with 2.72 g (11.8 mmol) of silver(I) oxide. The reaction mixture was stirred at RT for 3 days. The reaction was filtered and evaporated to yield after flash chromatography (SiO2, dichloromethane/ether 2.5%) 1.70 g (65%) of the titled compound as light yellow oil. MS: 360.18 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]([F:24])([F:23])[F:22])=[CH:11][C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:21]([F:23])([F:22])[F:24])=[CH:11][C:12]=2[S:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:25])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(Sc2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: O=S(c1ccc(Cl)cc1)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Yield: 65.6 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(p-chlorophenyl)thio]-5-(trifluoromethyl)pyrrole (2.57 g, 6.6 mmol) and 30% hydrogen peroxide solution (0.83 g, 7.3 mmol) in acetic acid is stirred at room temperature overnight and poured into water. The resultant aqueous mixture is filtered to obtain a solid. A solution of the solid in methylene chloride is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:3 ethyl acetate/hexanes solution gives the title product as a white solid (1.75 g, mp 174°-176° C.)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][NH:10][C:11]([O:13][CH2:14][CH2:15][Cl:16])=[O:12].[CH3:17][O:18][CH2:19][C:20](Cl)=[O:21].COCC(O)=O.S(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[CH3:17][O:18][CH2:19][C:20]([N:9]([C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[NH:10][C:11]([O:13][CH2:14][CH2:15][Cl:16])=[O:12])=[O:21]
Reactant: Cc1cccc(C)c1NNC(=O)OCCCl
Reactant: COCC(=O)Cl
Agent: COCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1C
Product: COCC(=O)N(NC(=O)OCCCl)c1c(C)cccc1C

Procedure:
200 g (0.825 mol) 2-Chloroethyl 2-(2,6-dimethylphenyl)-hydrazinecarboxylate in 500 ml xylene are warmed to 80°, and added to a warm (80°) solution of 2-methoxyacetylchloride in 250 ml xylene, prepared in situ by treating 73.5 g (0.826 mol) 2-methoxyacetic acid in 250 ml xylene with 107.1 g (0.9 mol) thionyl chloride at 80° for 2 hours. The mixture is heated for 30 minutes at 80°, then worked up as described in Example 1a.
Reaction SMILES: [C:1]1([CH:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:19])[CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)([Cl:22])=[O:21]>C1C=CC=CC=1>[Cl:22][C:20]([N:8]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:19])[CH2:9]1)=[O:21]
Reactant: O=C(Cl)Cl
Reactant: O=C1CNC(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: c1ccccc1
Product: O=C1CN(C(=O)Cl)C(c2ccccc2)c2cc(Cl)ccc2N1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
0.84 g. of dry, solid sodium hydrocarbonate are added to a suspension of 1.36 g. (5 mmoles) of 5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 60 ml. of absolute benzene, and 15 ml. of a 10% phosgene solution in benzene are added dropwise to the mixture at 10°-15° C. The mixture is stirred at 10°-15° C. for one hour and then at room temperature overnight. The inorganic salts are filtered off and washed with 50 ml. of acetone. The organic phase is evaporated, and the dry residue is recrystallized from benzene. 1.08 g. (64.5 %) of 4-chlorocarbonyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 181°-184° C., Rf2 = 0.82.