Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].O(C)[Li].C(OC(C)=O)(C)C.Cl>O.CN(C=O)C.CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cccs2)cc1C=O
Agent: Cl
Agent: [Li]OC
Solvent: O
Solvent: CO
Solvent: CC(=O)OC(C)C
Product: COc1cc(OC)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Reaction time: 5 h
Yield: 75 %

Procedure:
2,4-Dimethoxy-5-thiophen-2-yl-benzaldehyde from Ex-6A (7.81 g), 4-acetylbenzoic acid (4.9 g), MeOH (60 mL) and DMF (150 mL) were sequentially charged into a clean reaction vessel fitted with a stir bar and nitrogen inlet adapter. After complete dissolution LiOMe (4.60 g) was added and the resulting solution was aged for 5 h. The reaction was diluted with H2O (200 mL) and transferred to a separatory funnel containing iPrOAc (100 mL). The layers were cut and the aqueous layer was acidified to a pH of 1 with 3 N HCl. The resulting precipitate was filtered and then dried on the filter funnel under a stream of N2. The crude product was then dissolved in THF (60 mL) and crystallized with the addition of heptane (60 mL). The product was filtered and then dried to a constant weight in the vacuum oven affording 8.9 g (75% yield) of the title compound as a yellow solid, m.p. 213–216° C. 1H-NMR (300 MHz, CDCl3): 8.20 (d, 2H, J=8.5 Hz), 8.09 (d, 1H, J=16.1 Hz), 8.06 (d, 2H, J=8.5 Hz), 7.85 (s, 1H), 7.52 (d, 1H, J=16.1 Hz), 7.40 (m, 1H), 7.30 (dd, 1H, J=5.2 and 1.7 Hz), 7.08 (dd, 1H, J=5.2 and 3.6 Hz), 6.53 (s, 1H), 3.98 (s, 3H), 3.97 (s, 3H); EIMS m/z=394 (M+). Anal. calc. for C22H18O5S: C, 66.99; H, 4.60; S, 8.13; found: C, 66.71; H, 4.59; S, 8.10.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].N1C=CC=CC=1>CN(C)C=O>[O:1]([CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2)[Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.25 h

Procedure:
19-Hydroxy-4-androstene-3,17-dione, t-butyldimethyl-silylchloride and pyridine are mixed in dry dimethylformamide and heated on a steam bath overnight. The reaction mixture is poured onto water and stirred well for 15 minutes. The resulting solid is filtered and dissolved in methylenechloride, dried over magnesium sulfate and the solvent removed by evaporation. The residue which remains is crystallized from an acetone-hexane solution to yield 19-t-butyldimethylsiloxy-4-androstene-3,17-dione.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][O:11][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Yield: 60.7 %

Procedure:
(2-Hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (400 mg, 2.28 mmol), TBDPS chloride (593 μL, 2.28 mmol) and imidazole (342 mg, 5.02 mmol) in DMF (2 mL) were stirred at RT for 12 h. The reaction mixture was diluted with brine and extracted with CH2Cl2. The combined organics were passed through a phase separation cartridge and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 50% EtOAc/isohexane to obtain [2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-methyl-carbamic acid tert-butyl ester as a colourless oil (572 mg, 61%).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.CCCCCC.[N+](C1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25](=[CH2:32])[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2C1)#[C-].C([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[N+:4]([C:5]1([CH3:7])[C:23]2[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=2[C:25](=[CH2:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[CH2:6]1)#[C-:1]
Reactant: [C-]#[N+]C1Cc2ccccc2C(=C)c2ccccc21
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: [C-]#[N+]C1(C)Cc2ccccc2C(=C)c2ccccc21
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
Diisoproylamine (1.1 g, 10.9 mmole) in 25 ml of dry tetrahydrofuran was stirred in a dry ice/acetone bath. Under a nitrogen blanket, this solution was treated with n-butyllithium/hexane (5.0 ml of 2.2 M solution) added dropwise over 10 minutes. After 5 minutes, a solution of 10-isocyano-5-methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.4 g, 10.4 mmole) in 25 ml of dry tetrahydrofuran was added dropwise (over 45 minutes) to the lithium diisopropylamide solution. The resulting deep red solution was stirred in the cold for 15 minutes then treated with methyliodide (4.56 g, 32 mmole) added all at once. The mixture was stirred 2 hours in the cold and an additional 1 hour at room temperature. The solvent was removed in vacuo and the residue chromatographed on 75 g of silica gel, eluted with methylene chloride. The combined product fractions were evaporated in vacuo to give 2.2 g (86%) solid. Recrystallization from ether gave, m.p. 146°-147.5° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([O:14]C)=[O:13])=[N:11][C:4]=2[NH:3]1.O.[OH-].[Na+]>O1CCOCC1>[O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[N:11][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(n1)NC(=O)CS2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CSc2ccc(C(=O)O)nc2N1
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A solution of Methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (788 mg) in dioxan (120 ml)/water (30 mL) was treated dropwise over 2 hours with 0.5M NaOH solution (8 mL) and stirred overnight. After evaporation to approx. 3 ml, water (5 mL) was added and 2M HCl to pH4. The precipitated solid was filtered off, washed with a small volume of water and dried under vacuum to give a solid (636 mg); MS (APCI−) m/z 209 ([M−H]−, 5%), 165([M-COOH]−, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=2)=[CH:5][C:4]=1[N+:24]([O-])=O>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:22])[CH:14]=2)=[CH:5][C:4]=1[NH2:24]
Reactant: COc1ccc(NC(=O)/C=C/c2ccc([N+](=O)[O-])c(F)c2)cc1[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(NC(=O)/C=C/c2ccc(N)c(F)c2)cc1N
Yield: 47 %

Procedure:
A solution of N-(4-methoxy-3-nitrophenyl)-3-(3-fluoro-4-nitropheny)-2-propenamide (Example 8) (1.3 mmol) in acetone-water (10:5) was reacted according to the procedure as described in the Example 6. The title compound, melting point 170-172° C., was thereby obtained in 47% yield.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.F[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: Fc1ccccn1
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](Nc2ccccn2)CC1
Temperature: 165 °C
Reaction time: 2 h

Procedure:
A mixture of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (100 mg, 0.23 mmol), 2-fluoropyridine (0.5 mL) and diisopropylethyl (0.2 mL) was placed in a microwave tube and heated to 150° C. in the Personal Chemistry Microwave for 1 h, 165° C. for 1 h, then 185° C. for another 2 h. The reaction mixture was concentrated and the resulting residue was diluted with ethyl acetate. The organic phase was washed with 10% citric acid and brine. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 29 mg of the title compound, m/z 518.9 [M+1]+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[O:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:13]([C:24](=[O:37])[C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)[CH2:12]1)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+].[CH3:43][S:44](Cl)(=[O:46])=[O:45].Cl>C(O)(=O)C.O1CCCC1.O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CCCCCC>[CH3:43][S:44]([O:8][CH2:9][CH2:10][C@H:11]1[O:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:13]([C:24](=[O:37])[C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)[CH2:12]1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2C[C@@H](CCO[Si](C)(C)C(C)(C)C)OC2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C(=O)N2C[C@@H](CCOS(C)(=O)=O)OC2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
3.95 g (6.92 mmole) of 2-[(5R)-(3,4-dichlorophenyl)-3-(3,4,5-trimethoxybenzoyl)oxazolidin-5-yl]ethanol t-butyldimethylsilyl ether [prepared as described in step (f) above] were dissolved in 70 ml of a 3:3:1 by volume mixture of acetic acid, tetrahydrofuran and water. The mixture was then heated under a nitrogen atmosphere at 80° C. for 8 hours. At the end of this time, the solution was neutralised by the addition of a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 30 ml of pyridine. 70 mg (0.57 mmole) of 4-dimethylaminopyridine and 0.66 ml (8.53 mmole) of methanesulfonyl chloride were added, whilst ice-cooling, to the resulting solution, and the mixture was then stirred under a nitrogen atmosphere at 0° C. for 2 hours. At the end of this time, the reaction mixture was poured into 200 ml of ice-cooled 10% w/v aqueous hydrochloric acid and then extracted three times, each time with 100 ml of ethyl acetate. The combined organic extracts were washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 5:1 to 1:1 by volume as the eluent, to obtain 3.02 g (yield 82%) of the title compound as a white amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1.[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>CN(C)C(=O)C>[Cl:11][CH2:12][CH2:13][C:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1)=[O:15]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc2ncnn2n1
Solvent: CC(=O)N(C)C
Product: O=C(CCCl)Nc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Amino[1,2,4]triazolo[1,5-b]pyridazine (0.80 g) was dissolved in N,N-dimethylacetamide (7 ml), followed by addition of 3-chloropropionyl chloride (0.68 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour and poured into ice-water, followed by extraction with a mixture of ethyl acetate and tetrahydrofuran (1:1). The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. Ethyl ether was added to the residue. The resulting crystals were collected by filtration and dried to yield the title compound (0.875 g).
Reaction SMILES: OC1C=CC(C(OCC)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C1(Br)CC1.[CH:25]1([O:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([O:35]CC)=[O:34])=[CH:31][CH:30]=2)[CH2:27][CH2:26]1>CN(C)C=O>[CH:25]1([O:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1ccc(OC2CC2)cc1
Agent: BrC1CC1
Agent: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OC2CC2)cc1

Procedure:
The intermediate 4-cyclopropyloxybenzoic acid was prepared as follows: A 66.5 g. portion of ethyl 4-hydroxybenzoate was dissolved in 800 ml. of dimethylformamide and to the solution was added 83.0 g. of anhydrous potassium carbonate and 5 g. of potassium iodide. To the resulting stirred suspension was added 60.5 g. of cyclopropyl bromide. The stirred reaction mixture was refluxed for 6 days and the hot reaction mixture was filtered to remove the inorganic solids which were washed well with dimethylformamide. The combined filtrate and dimethylformamide washings were evaporated in vacuo and the remaining liquid-solid residue was taken up in a mixture of 500 ml. of water and 500 ml. of ether. The resulting mixture was shaken well and the layers were separated. The aqueous layer was extracted with 200 ml. of ether. The combined ether solutions were washed successively with two 250 ml. portions of aqueous potassium hydroxide solution, next with 200 ml. 0.5N hydrochloric acid and then with two 100 ml. portions of water. The ether solution was dried over anhydrous magnesium sulfate and the ether removed in vacuo to yield, as an amber liquid, 36.2 g. of ethyl 4-cyclopropyloxy-benzoate.
Reaction SMILES: [OH-].[Li+].O.[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:14]=2[C:15]([O:17]CC2C=CC(F)=CC=2)=[O:16])=[CH:7][CH:6]=1>O1CCCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:14]=2[C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1
Reactant: O=C(OCc1ccc(F)cc1)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1

Procedure:
Lithium hydroxide (0.70 g, 29.1 mmol) and water (20 ml) were added to a solution of (4-fluorophenyl)methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-(trifluoromethyl)benzoate (may be prepared as described in Description 118; 4.1 g, 9.71 mmol) in tetrahydrofuran (100 ml) and the mixture was heated to reflux for 2 hours. The mixture was evaporated under reduced pressure on a buchi. Water (100) ml was added and the mixture was acidified to pH=1 using 2M aqueous hydrochloric acid. The precipitate was filtered and washed with water (2×50 ml). The solid was dried in air, under vacuum to yield the title compound as a white solid. 2.39 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27]>CO.CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:16][CH:17]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:27])[F:28]
Reactant: O=C(/C=C/c1ccc(Cc2ccncc2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(CCc1ccc(Cc2ccncc2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 18 h

Procedure:
To a solution of (2E)-N-[4-chloro-3-(trifluoromethyl)phenyl]-3-[4-(pyridin-4-ylmethyl)phenyl]acrylamide (70 mg, 0.17 mmol) in MeOH (2 mL) and EtOAc (2 mL) was added Pd/C (10 wt %, 20 mg). The mixture was stirred under hydrogen (60 psi) for 18 h and then filtrated through Celite. The filtrate was concentrated and purified by column chromatography to give A-84 (28 mg, 41%). 1H NMR (300 MHz, CD3OD) δ: 8.35 (d, 2H), 8.03 (d, 1H), 7.70 (dd, 1H), 7.48 (d, 1H), 7.10-7.24 (m, 6H), 3.96 (s, 2H), 2.97 (dd, 2H), and 2.65 (dd, 2H). LCMS: (FA) ES+ 419.2 (M+1), ES− 417.2 (M−1).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:22])[NH:13][C:14]2[S:15][C:16]([S:19]([CH3:21])=[O:20])=[CH:17][N:18]=2)[CH:7]=1)(=O)C>O1CCCC1>[OH:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[C:12]([NH:13][C:14]1[S:15][C:16]([S:19]([CH3:21])=[O:20])=[CH:17][N:18]=1)=[O:22]
Reactant: CC(=O)Oc1cccc(C(=O)Nc2ncc(S(C)=O)s2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)c1cnc(NC(=O)c2cccc(O)c2)s1
Temperature: 25 °C

Procedure:
2 M hydrochloric acid (40.0 mL) is added to a suspension of 8 (0.370 g, 1.13 mmol) in tetrahydrofuran (17.0 mL), and the reaction is warmed to reflux. The reaction becomes homogeneous upon heating. After refluxing for 4 hours, the reaction is allowed to cool to room temperature, and is concentrated in vacuo. The residue is suspended in water and filtered. The filter pad is washed with water, air dried, and then re-dissolved in a minimum amount of warm THF. Water is added to the warm THF solution until the solution turns turbid, and the resulting mixture is allowed to cool to room temperature. Additional water is added, and a white solid forms on standing. The crystalline product is filtered, and the filter pad is washed with water, and dried in vacuo at 70° C. and gives 10 as a white crystalline solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([N+:13]([O-])=O)[S:12][C:6]=2[CH:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:4]1.[C:22](O)(=[O:24])[CH3:23]>[Pd].C(OC(=O)C)(=O)C>[C:22]([NH:13][C:11]1[S:12][C:6]2[CH:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:4][N:3]([CH3:2])[CH2:9][CH2:8][C:7]=2[CH:10]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)O
Reactant: CN1CCc2cc([N+](=O)[O-])sc2C(c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2c(s1)C(c1ccccc1)CN(C)CC2
Reaction time: 24 h

Procedure:
A suspension of 6-methyl-2-nitro-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine hydrochloride (0.20 g) and 10% palladium on carbon (20 mg) in acetic acid (18 ml), acetic anhydride (2 ml) was hydrogenated on a Parr apparatus for 24 hours at 70 psi. The mixture was filtered and the filtrate evaporated. The residue was dissolved in water (30 ml), basified to pH~11 with ammonia solution and extracted with dichloromethane (2×50 ml). The extracts were dried filtered and evaporated to a yellow viscous oil. Crystallisation from toluene gave the title product (m.p. 180°).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:11]1(NC2CCCCC2)CCCC[CH2:12]1.C([Si](C)(C)C)#C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[C:11]([C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)#[CH:12]
Reactant: Brc1cnc2ccccn12
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: O
Solvent: CC#N
Product: C#Cc1cnc2ccccn12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 3-bromoimidazo[1,2-a]pyridine (5 g, 0.0254 mol) in acetonitrile (50 mL) in a sealed tube was added bis(triphenylphosphine) palladium(II) dichloride (0.445 g, 0.634 mmol), CuI (0.17 g, 0.89 mmol), dicyclohexylamine (5.6 mL, 0.028 mol) and ethynyltrimethylsilane (7.2 mL, 0.051 mol). The solution was purged with argon for 15 minutes, sealed and heated at 80° C. for 3 h. At this point the HPLC did not show any starting bromide. The solvents were concentrated and to the residue was added water and dichloromethane (25 mL each). The organic layer was separated and the aqueous layer was repeatedly extracted with dichloromethane (3×20 mL). The combined extracts were dried (Na2SO4), and concentrated (Rf, 0.47 in 1/1 hexanes/ethyl acetate). The resulting residue was dissolved in THF (100 mL) and treated with tetrabutyl ammonium fluoride monohydrate (8.3 g, 0.032 mol) in water (5 mL) and the mixture was stirred at rt for 2 h. The solvents were concentrated and the resuting residue was partitioned between water (25 mL) and dichloromethane (150 mL). The aquesous layer was extracted with dichloromethane (2×30 mL). The combined extracts were dried (Na2SO4), and concentrated. The resulting residue was purified by combiflash on silica gel using hexanes/ethyl acetate. The desired product was eluted with 50/50 hexane/ethyl acetate and isolted as an off-white solid: MS (M+H)+200.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]3[S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.CC([O-])(C)C.[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[C:13]3[S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:24][CH:23]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1ccc(Nc2cccc3c2sc2ccccc23)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Product: Brc1ccc(N(c2ccccc2)c2cccc3c2sc2ccccc23)cc1
Yield: 80.1 %

Procedure:
Toluene (125 mL) was bubbled with nitrogen gas for 15 minutes, and subsequently 1,1′-Bis(diphenylphosphino)ferrocene (0.2 g, 0.4 mmol) and Pd2(dba)3 (0.1 g, 0.1 mmol) were added. The mixture was bubbled with nitrogen gas for 15 minutes, then N-phenyldibenzo[b,d]thiophen-4-amine (3.2 g, 11.6 mmol), 1-bromo-4-iodobenzene (4.5 g, 15.9 mmol), NaOtBu (1.5 g, 15.6 mmol) were added. The mixture was bubbled with nitrogen gas for 15 minutes and refluxed for 12 hours. After cooling, the reaction mixture was filtered through a silica pad and washed with 50% CH2Cl2/hexane. The solvent was removed in vacuo and the residue was purified by flash chromatography using 10-15% CH2Cl2/hexane to afford N-(4-bromophenyl)-N-phenyldibenzo[b,d]thiophen-4-amine (4.0 g, 80% yield) as a white solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][NH2:26]>>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([NH:26][CH3:25])=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Reactant: CN
Product: CNC(=O)C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Yield: 34 %

Procedure:
The compound (97 mg, 0.28 mmol) prepared in Example 42 and methylamine instead of ethylamine were reacted according to the same procedure as Example 89 to give the title compound (34 mg, Yield 34%).