Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.Br[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:10][CH3:11])[C:4](=[O:8])[CH:3]=1
Reactant: CCBr
Reactant: Oc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1ccc(Br)cc1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 4-bromopyridin-2-ol (100 mg, 0.57 mmol), bromoethane (124 mg, 1.1 mmol) and potassium carbonate (238 mg, 1.7 mmol) in acetone (5 mL) was stirred at 60° C. for 3.0 h. The solution was allowed to cool to room temperature, filtered and the filter cake was washed with acetone (5 mL×2). The filtrate was collected and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE:EA=20:1) to afford the title compound as a white solid LC/MS m/z=402.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.14 (d, 1 H), 6.81 (d, 1 H), 6.33 (dd, 1 H), 3.95 (q, 2 H), 1.34 (t, 3 H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:23][O:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:28][CH2:27]1
Reactant: COCC1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: COCC1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 4-(methoxymethyl)piperidine to give 224. MS: (ESI+)=425.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:41]1([CH2:47][C:48]([NH2:50])=[O:49])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:44]3[CH2:45][CH2:46][N:41]([CH2:47][C:48]([NH2:50])=[O:49])[CH2:42][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 675.2 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1.S(=O)(=O)(O)O.[OH2:17].[OH2:18].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:18])=[O:17])[N:10]=2)[N:7]=1
Reactant: O
Reactant: Cc1nc2ccc(Cl)nn2n1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1nc2ccc(Cl)nn2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 82.7 %

Procedure:
10.0 g of 6-chloro-2-methyl[1,2,4]triazolo[1,5-b]pyridazine was added to 55 ml of concentrated sulfuric acid under ice cooling conditions; 19.4 g of sodium dichromate dihydrate was added little by little at constant temperature, followed by stirring at room temperature for 4 days. Under ice cooling conditions, about 200 ml of ice water was added; the crystal precipitated was collected by filtration, washed with water and ethyl ether and dried to yield 9.74 g of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]([O-:26])=O)[CH:22]=4)[CH:17]=[CH:16]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:29][OH:30]>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]([NH:29][OH:30])=[O:26])[CH:22]=4)[CH:17]=[CH:16]3)=[CH:27][CH:28]=2)[CH2:5][CH2:6]1
Reactant: NO
Reactant: O=C([O-])c1ccc2ccn(CCOc3ccc(CN4CCOCC4)cc3)c2c1
Product: O=C(NO)c1ccc2ccn(CCOc3ccc(CN4CCOCC4)cc3)c2c1

Procedure:
1-(2-(4-(morpholinomethyl)phenoxy)ethyl)-1H-indole-6-carboxylate was activated and coupled with NH2OH as described in Example 4, Step 3 to provide 1-(2-(4-(morpholinomethyl)phenoxy)ethyl)-N-hydroxy-1H-indole-6-carboxamide as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>>[Cl:13][CH2:14][CH2:15][NH:16][C:17](=[O:18])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCCCO)cc1
Reactant: O=C=NCCCl
Product: O=C(NCCCl)Nc1ccc(CCCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 4-(p-amino phenyl)butanol (2 g in 125 mL of ethyl ether) is added dropwise 1.25 g of 2-chloroethyl isocyanate. This solution is stirred for 3 h at room temperature, cooled at -20° C., and filtered. A white solid of 4-{p-[3-(2-chloroethyl)ureido]phenyl}butanol is separated and recrystallized from ethanol (white flakes), yield 55%, mp 123°-124° C., IR (KBr pellet): 3300 (NH), 1730 (C=O, ester), and 1640 cm-1 (C=O, ureido); 1H NMR (DMSO-d6): 8.65 (s, 1p, ArNH), 7.4-7.0 (dd, 4p, p-substituted Ar), 6.4 (broad t, 1p, NHCH2), 3.7-3.4 (m, 6p, ArCH2 and NHCH2CH2Cl), 2.85 (t, 2p, CH2OH), 2.3 (s, 1p, CH2OH), 1.85 (q, 2p CH2 CH2CH2), 1.45 (q, 2p, CH 2CH2OH)
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH:13]=[CH:14][OH:15])=[C:10]([Cl:16])[N:9]=[C:8]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.[C:23]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>C(Cl)(Cl)Cl.CCOCC>[C:26]([C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH:13]=[CH:14][OH:15])=[C:10]([Cl:16])[N:9]=[C:8]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:21][CH:22]=1)=[O:33])([OH:28])=[O:27]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc(N)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 95 mg of 3-[1-(4-aminobenzyl)-2-butyl-4-chloroimidazol-5-yl]propen-1-ol in 2 mL of CHCl3 was added 45 mg of phthalic anhydride and the mixture was stirred at room temperature for 1 hour. During this period of time the initially clear solution because turbid and produced solid. The reaction mixture was diluted with 2 mL of ether and the solid was collected by filtration and washed with ether. The desired product was obtained as a tan solid, 115 mg, m.p. 150°-151°; NMR (10% DMSO-d6CDCl3); δ 9.94 (s, 1h); 7.71 and 6.93 (d, 4H, J=8.3 Hz); 6.36 (m, 2H); 5.1 (s, 2H); 4.18 (d, 2H, J=3.9 Hz); 2.6 (t, 3H, J=7.4 Hz); 1.68 (m, 2H); 1.34 (m, 2H); 0.89 (t, 3H, J=7.4 Hz).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>O1CCCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Brc1nccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of 10.0 g of 2-bromothiazole under nitrogen in 50 ml of tetrahydrofuran while cooling in a dry ice-acetone bath is added dropwise 36.6 ml of a 1.6M solution of butyl lithium via syringe. Stirring is continued for 1 hour. To the reaction mixture is added dropwise 29.8 g of tributyltin chloride in 20 ml of tetrahydrofuran. Stirred 1 additional hour. The reaction mixture is quenched with 20 ml of water and 50 ml additional water is added. After stirring for 20 minutes the reaction mixture is extracted with chloroform (3×60 ml). The organic layer is dried (Na2SO4) and evaporated in vacuo to give 11.7 g of the desired product.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[N:3]=1.Cl.[Cl:13][C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)C(C)C)(C)C>>[Cl:13][C:14]1[C:15]([N:20]2[CH2:21][CH2:22][N:23]([C:2]3[NH:6][C:5]4[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=4[N:3]=3)[CH2:24][CH2:25]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc2nc(Cl)[nH]c2c1
Reactant: Clc1cccnc1N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2c1

Procedure:
The reaction of 2-chloro-6-methyl-1H-benzoimidazole (0.202 g, 1.59 mmol, Example 14b), 1-(3-chloropyridin-2-yl)piperazine hydrochloride (0.373 g, 1.22 mmol, Example 3b) and N,N-diisopropylethylamine (0.56 mL, 3.2 mmol, Aldrich) under the conditions of Example 3c afforded the title compound as a white solid. M.p. 258-259° C. MS (ESI, pos. ion) m/z: 328 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].Br[C:15]1[CH:23]=[C:22]([CH3:24])[C:21]2[N:20]([CH3:25])[C:19]3[CH2:26][CH:27]4[NH:31][CH:30]([C:18]=3[C:17]=2[C:16]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]4>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:15]2[CH:23]=[C:22]([CH3:24])[C:21]3[N:20]([CH3:25])[C:19]4[CH2:26][CH:27]5[NH:31][CH:30]([C:18]=4[C:17]=3[C:16]=2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]5)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)[O-])cc1
Reactant: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Yield: 6 %

Procedure:
Intermediate 12 was coupled to the product of Example 71, step C following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(4-nitro-phenyl)sulfonyl-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (44 mg, 6%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.86-8.33 (m, 2H), 8.08-8.16 (m, 2H), 8.03 (s, 1H), 7.34 (s, 1H), 5.23 (br s, 1H), 4.71 (br s, 1H), 3.85 (s, 3H), 3.36 (br s, 1H), 2.76 (s, 3H), 2.46 (d, J=16.2 Hz, 1H), 2.11-2.39 (m, 2H), 1.85-1.97 (m, 1H), 1.53-1.67 (m, 1H), 1.36 (br s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.[O-]CC.[Na+].[Na].C(O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@H](N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1

Procedure:
Ethyl 4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate (method F, step a, 0.97 g) was added to a solution of sodium ethoxide prepared from sodium (1.28 g) and ethanol (100 ml). The resultant solution was heated under reflux for 18 h. Acetic acid (0.1 ml) was added and the solvent was evaporated. Ethyl acetate, water and sodium hydroxide were added to the residue and separated. The aqueous phase was extracted twice with ethyl acetate-methanol mixtures and the combined organic phases were washed with brine, dried (MgSO4), filtered and evaporated to give the subtitle compound as an oil.
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[C:5]([NH:13]C(=O)C)[C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.C>C(O)C>[CH2:9]1[C:10]2[C:6](=[C:5]([NH2:13])[C:4]3[CH2:3][CH2:2][CH2:1][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CC(=O)Nc1c2c(cc3c1CCC3)CCC2
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Nc1c2c(cc3c1CCC3)CCC2
Temperature: 0 °C
Yield: 90.4 %

Procedure:
A slurry of N-(1,2,3,5,6,7-hexahydro-s-indacen-4yl)-acetamide (110 grams) in YY mL of 25% sulfuric acid was treated with enough ethanol to make a solution (ca YY mL). The resulting solution was heated to reflux for a period of 2 days. The resulting black solution was treated with charcoal at reflux, filtered hot and cooled to 0° C. The solution was then cautiously neutralized with 20% sodium hydroxide solution. The resulting slurry was then filtered and washed with water until the filtrate ran neutral. The tan solid was then isolated and dried in vacuo to give 80 grams of the title compound, m.p. 94.5-96.6° C., which was used without further purification. If necessary, the title compound can be recrystallized from methanol to afford a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])[CH:8]=[CH:9]C(O)=O)([CH3:4])([CH3:3])[CH3:2].O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH2:9])[CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 90.1 %

Procedure:
A solution of 3,5-di-tert-butyl-4-hydroxycinnamic acid (2.77 g, 10 mmol) in dry DMF (20 mL) was refluxed at 150° C. under N2 for 2 h with stirring. The resulting mixture was then poured into water (200 mL) and extracted with chloroform (100 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with hexane, to give 2.094 g (90.2%) of the title compound as a colorless solid: mp 51-51.5° C.; 1H NMR (400 MHz, CDCl3): δ 7.248 (s, 2H), 6.666 (d×d, 1H, J1=10.8 Hz, J2=17.6 Hz), 5.587 (d, 1H, J=16.8 Hz), 5.241 (s, 1H), 5.094 (d, 1H, J=10.8 Hz), 1.456 (s, 18H); 13C NMR (100 MHz, CDCl3): δ 153.980, 137.529, 136.055, 129.040, 123.216, 110.996, 34.565, 30.507; Anal. Calcd. for C16H24O: C, 82.70; H, 10.41. Found; C, 83.08; H, 10.37.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C@H:20]2[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]2)=[CH:16][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]=[CH:9][C:8]2=[O:15].CO>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C@H:20]2[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]2)=[CH:16][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH2:9][C:8]2=[O:15]
Reactant: O=c1ccoc2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCOc2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc21
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a stirred solution of 6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chromen-4-one (0.10 g, 0.2315 mmol) in ethyl acetate (2.5 mL) was added 10% Palladium on C (20 mg, 20% w/w) followed by methanol (2.5 mL). After stirring for 18 h under hydrogen atmosphere, the reaction mixture was filtered through celite and concentrated to furnish the crude product, which was further purified by Preparative HPLC to yield the title compound (41 mg)
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].O.[C:19](OCC)(=O)[CH3:20]>C1COCC1>[OH:2][CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)[CH2:19][CH3:20]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1ccc(-c2ccc(-c3cccs3)s2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
3.5 g of 5-formyl-2,2':5',2"-terthiophene was dissolved in 200 ml of anhydrous THF under nitrogen stream. 7.9 ml of ethyl Grignard reagent was dropped in slowly under ice bath temperature and stirred at 0° C. for 1 hour. The reaction mixture was then heated to 70° C. in oil bath for 4 hours. The solution was monitored by thin layer chromatography to determine whether the reaction was completed. 50 ml of water and 300 ml of ethyl acetate were added and the ethyl acetate extract was purified by column chromatography. From the eluate of ethyl acetate/n-hexane (1/9) fraction, yellow solid was obtained and recrystallized to give granulate crystal. The melting point of the product was 89°-90° C. and the yield was about 70%.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:29])[C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([NH:23][C:24](=[O:26])[CH3:25])=[CH:18][C:17]=3[O:27][CH3:28])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30]O>C(O)(=O)C>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH+:14]([O-:30])[C:15](=[O:29])[C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([NH:23][C:24](=[O:26])[CH3:25])=[CH:18][C:17]=3[O:27][CH3:28])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OO
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)[NH+]([O-])C1CCN(CC2CCCCC2)CC1

Procedure:
To a solution of N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide (10 g; 0.023 moles) in glacial acetic acid (50 ml) a 30% hydrogen peroxide solution (6 ml) was added. The mixture was heated for 8 hours at a temperature between 70° and 80° C. Afterwards the solvent was evaporated in vacuo, and N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide N-oxide was obtained as a viscous liquid. After recrystallisation from a mixture of acetone and diethyl ether, there was obtained 7.3 g of the N-oxide, melting at 206°-208° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([NH:22]C(=O)OCC4C=CC=CC=4)[CH:20]=3)[N:15]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:14]=2)=[N:5][C:6]([NH:9][CH:10]([CH3:12])[CH3:11])=[N:7][CH:8]=1)#[N:2].C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:22][C:19]1[CH:20]=[C:21]2[C:13]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][N:7]=[C:6]([NH:9][CH:10]([CH3:11])[CH3:12])[N:5]=3)=[CH:14][N:15]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:34])=[O:35])[C:16]2=[N:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(NC(=O)OCc4ccccc4)cnc32)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(N)cnc32)cc1

Procedure:
Benzyl 3-(5-cyano-2-(isopropylamino)pyrimidin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (0.199 g, 0.342 mmol) in EtOH (15 mL) was charged with ammonium formate (0.129 g, 2.055 mmol, 6.0 Eq) and 10% Pd/C (0.040 g, 0.2 Eq) and heated at reflux for 3 hours.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([OH:15])[C:12]([F:16])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[CH2:18][O:15][C:13]1[C:12]([F:16])=[CH:11][C:3]([C:4]([NH:6][S:7]([CH3:10])(=[O:8])=[O:9])=[O:5])=[C:2]([F:1])[CH:14]=1
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(O)cc1F
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(OCc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 2,5-Difluoro-4-hydroxy-N-(methylsulfonyl)benzamide (Preparation 18 10.6 g, 42.2 mmol) in DMSO (53 mL) was added 4-(bromomethyl)-1,2-dichlorobenzene (10.63 g, 44.3 mmol) and potassium carbonate (11.66 g, 84.4 mmol) and the reaction stirred at ambient temperature for 18 hours. The reaction was quenched with aqueous hydrogen chloride solution (1 M, 100 mL) and water (100 mL). The resulting off-white precipitate was stirred at room temperature for 1 hour, filtered and washed with water (3×100 mL). The resulting pale yellow solid was suspended in acetone (106 mL) and heated at reflux for 1 hour. The suspension was then cooled to room temperature and filtered to yield the first crop of the crude title compound as a white solid (11.6 g, 67%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH:18]=O)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1.N1CCCC1>CO>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1/[CH:18]=[C:26]1\[C:27](=[O:31])[NH:28][C:29]2[C:25]\1=[CH:24][CH:23]=[C:22]([Cl:21])[CH:30]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 131.9 %

Procedure:
In a manner similar to the method described in Example 227b, [2-(4-chloro-2-formyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester (8 g, 27 mmol) was reacted with 6-Chlorooxindole (4.5 g, 27 mmol) and pyrrolidine (2.1 g, 30 mmol) in methanol to give title compound as a yellow solid (16 g).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[CH3:17][Si:16]([CH3:19])([CH3:18])[O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(O)CCCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(CCCC)O[Si](C)(C)C
Reaction time: 60 h

Procedure:
To a cold solution of 166 g of 4-hydroxy-1-octyne [Prostaglandins, 10, 289 (1975)], and 240 g of imidazole in one liter of dimethylformamide is added dropwise 202 g of chlorotrimethylsilane. The mixture is allowed to stand at room temperature for 2 to 3 days. The mixture is partitioned with water and hexane. The hexane layer is washed with brine dried over magnesium sulfate, and concentrated. Distillation of the residue gives a colorless liquid, bp 38° C. (0.2 mm).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3/[C:7](=[CH:16]\[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])/[C:6]=2[CH:22]=1.O1CCCC1.C([Li])CCC.[C:33](=[O:35])=[O:34]>CCCCCC>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17]/[CH:16]=[C:7]1\[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[O:10][CH2:11][C:5]2[CH:4]=[CH:3][C:2]([C:33]([OH:35])=[O:34])=[CH:22][C:6]\1=2
Reactant: O=C=O
Reactant: CN(C)CC/C=C1/c2cc(Br)ccc2COc2ccccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CC/C=C1/c2cc(C(=O)O)ccc2COc2ccccc21

Procedure:
Pure (Z)-3-(9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine (0.78 g., 2.2 mmole), in cold (-70° C.) dry tetrahydrofuran (50 mL), was treated with 2.4 mmole n-butyl lithium in hexane followed by gaseous carbon dioxide by the procedure of Example I, Step c. This provided the desired carboxylic acid which was recrystallized from water to yield 0.15 g. pure Z-isomer, m.p. >205° C. (decomp.) with melting at 210° C. pmr (CDCl3 /D2O) δ: 7.84 (d, J=1.8 Hz, 1H, H10), 7.81 (dd, J=6.4, 1.8 Hz, 1H, H8), 6.94-7.35 (m, 5H, aromatic), 5.78 (t, J=6.9 Hz, 1H, CH=), 5.25 (s, 2H, CH2O), 3.20 (m, 2H, NCH2), 2.80 (s, 6H, NMe2), 2.50-2.90 (m, 2H, CH2).