Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH2:22]([O:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Reactant: BrCCCOCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCc2ccc(OCCCOCc3ccccc3)cc2O1
Yield: 66 %

Procedure:
To a 200 ml acetone solution of ethyl 7-hydroxychromane-2-carboxylate (9.18 g, 41.3 mmol) was added benzyl 3-bromopropyl ether (14.2 g, 62.0 mmol), powdered potassium carbonate (11.4 g, 82.5 mmol), and tetrabutylammonium iodide (1.53 g, 4 mmol). The resulting suspension was heated to reflux overnight. Acetone was removed under reduced pressure, diluted with AcOEt and sat. NH4Claq. The organic layer was separated. The aqueous layer was extracted with AcOEt twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on slica gel eluting with 10% AcOEt/hexanes to give the title compound 10.1 g (66%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH2:32]([NH:34][CH2:35][CH2:36][OH:37])[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[CH2:25][N:34]([CH2:32][CH3:33])[CH2:35][CH2:36][OH:37])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccc(F)cc3C=O)ccc2n1
Reactant: CCNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN(CCO)Cc1cc(F)ccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
114 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-5-fluorobenzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 57 μl of 2-(ethylamino)ethanol and 28 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 216 mg of sodium triacetoxyborohydride are added, and the mixture is stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([S:12][CH3:13])[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.C([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1B(O)O)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O.C(OCC)(=O)C.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:2]1[N:3]=[C:4]([S:12][CH3:13])[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12
Reactant: CSc1nc(I)c2c(N)nccn12
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CSc1nc(-c2cc3ccccc3[nH]2)c2c(N)nccn12
Temperature: 100 °C

Procedure:
To a suspension of 1-iodo-3-methylsulfanyl-imidazo[1,5-a]pyrazin-8-ylamine (612 mg, 0.00200 mol) in 1,4-dioxane (20 mL) and water (5 mL) were added 1-Boc-indole-2-boronic acid (570 mg, 0.0022 mol), potassium carbonate (830 mg, 0.0060 mol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (80 mg, 0.0001 mol). The flask was evacuated and refilled with nitrogen (3×). The mixture was heated at 100° C. overnight. LC-MS showed the reaction to be incomplete. Another 80 mg of PdCl2(dppf) was added and the mixture was heated at 100° C. overnight. LC-MS showed the reaction was complete. The mixture was diluted with ethyl acetate (100 mL) and methanol (5 mL); the insoluble solid was filtered off through a pad of celite. The filtrate was washed with brine (20 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (Hex:EtOAc=30:70→EtOAc:MeOH=98:2) to give the title compound as a yellow solid. LC-MS (ES, Pos.): 296 [MH+]; 1H-NMR (DMSO-d6): δ 2.64 (s, 3H), 6.58 (br s, 2H), 6.70 (d, J=1.5 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 7.13 (m, 1H), 7.18 (d, J=4.8 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.53 (d, J=4.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 11.60 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[C:25]([F:28])([F:27])[F:26]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Fc1cccc2c1CCNC2C(F)(F)F
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2c(F)cccc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:16]C(=O)OC(C)(C)C)[C:11]([CH2:14][CH3:15])=[CH:12][CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H](NC(=O)OC(C)(C)C)/C(/CC)=C/C)(C(C)(C)C)(C)C>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[Si:1]([O:8][CH2:9][C@@H:10]([NH2:16])[C:11]([CH2:14][CH3:15])=[CH:12][CH3:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC=C(CC)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: C/C=C(\CC)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC=C(CC)[C@H](N)CO[Si](C)(C)C(C)(C)C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-ethylpent-3-en-2-ylcarbamate (Intermediate 203, 17.2 g, 50.06 mmol) in DCM (300 mL) at room temperature was added zinc bromide (45.1 g, 200.25 mmol). The reaction mixture was stirred for 2 days. The reaction mixture was filtered through fitted funnel and washed with saturated sodium bicarbonate. The aqueous layer was extracted two more times with DCM and the organics were combined, dried over magnesium sulfate, filtered and concentrated to afford the title compound (12.19 g, 100%) as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1.C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>O.CN1C(=O)CCC1>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCc2ccc(O)cc2C1
Temperature: 180 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Combine 7-methoxy-2-tetralone (5.00 g, 28.3 mmol), thiophenol (3.39 g, 30.8 mmol), K2CO3 (213 mg, 1.54 mmol), and NMP (15 ml) in a round bottom flask equipped with nitrogen inlet. Heat at 180° C. for six hours and then stir at ambient temperature overnight. Treat reaction mixture with 1N aq. NaOH (20 ml) and water (20 ml) before extracting with Et2O. Adjust the alkaline mixture to pH 4 with 1N aq. HCl and extract with Et2O (3×). Dry (MgSO4) the ethereal layer and concentrate to a yellow solid. Purify the crude material on silica gel, eluting with 5% EtOAc/DCM, to obtain 7-hydroxy-2-tetralone (1.88 g) as a light red solid. 1HNMR (CDCl3): 7.09 (d, 1H), 6.69 (d, 1H), 6.62 (s, 1H), 4.86 (s, 1H), 3.53 (s, 2H), 2.99 (t, 2H), 2.54 (t, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:41]=[CH:40][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:22](OS(C(F)(F)F)(=O)=O)=[N:21]2)=[CH:17][CH:16]=1.[F:42][C:43]([F:54])([F:53])[C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].Cl>O1CCCC1.C(O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:22]([C:47]3[CH:48]=[CH:49][C:44]([C:43]([F:54])([F:53])[F:42])=[CH:45][CH:46]=3)=[N:21]2)=[CH:40][CH:41]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccc(C(F)(F)F)cc3)n2)cc1
Yield: 22 %

Procedure:
Tetrakis(triphenolphosphine)palladium (120 mg) was added to a mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-trifluoromethanesulfonyloxy-1H-pyrazol-4-yl]propionate (1.20 g), 4-trifluoromethylphenylboronic acid (0.46 g), 2N aqueous sodium carbonate solution (2.6 ml), ethanol (3 ml), and toluene (50 ml). This mixture was refluxed under an argon atmosphere for 13 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the oily substance obtained, 1N aqueous sodium hydroxide solution (5 ml), ethanol (5 ml) and tetrahydrofuran (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(4-trifluoromethylphenyl)-1H-pyrazol-4-yl]propionic acid (250 mg, yield: 22%). This was recrystallized from ethyl acetate-hexane. Melting point: 149–150° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)=[C:9]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)=[C:9]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
To a solution of ethyl(1RS)-1-(4-fluorophenyl)-1-hydroxy-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in CH2Cl2 (3 ml) at 0° C. was added triethylsilane (38 μl, 0.24 mmol), followed by boron trifluoride etherate (121 μl, 0.98 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (40 mg, 90%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[C:12](OC)(=[O:15])[CH:13]=[CH2:14].C([O-])(=O)C>>[O:7]1[C:1]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][C:12]1=[O:15]
Reactant: C=CC(=O)OC
Reactant: Oc1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1ccc2ccccc2o1
Temperature: 90 °C

Procedure:
In another example, 282 grams (3.0 moles) of phenol, 182 grams (3.04 moles) of acetic acid, 52.0 grams (0.604 moles) of methyl acrylate, 2.4 grams (0.012 moles) of cupric acetate monohydrate, 1.4 grams (0.0062 moles) of pallidium acetate, and 6 grams of a finely divided inert diatomaceous earth known in the trade as Celite were placed in a stainless steel autoclave. The autoclave was sealed and pressured to 250 pounds per square inch with air; this pressure being maintained as the mixture was stirred and air was bubbled through it at a rate of two cubic feet per hour (measured at atmospheric pressure). The mixture was heated to 90°C. for 3.5 hours while maintaining the stirring and the air flow, hereinbefore described. The catalyst did not precipitate out on the walls of the autoclave, while the methyl esters of o- and p-hydroxycinnamic acids and coumarin were obtained in a good yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:28][NH:27][C:25](=[O:26])[C:24]1[CH:29]=[CH:30][C:21]([O:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:22][CH:23]=1)=[O:5]
Reactant: O=C(Cl)c1cc(Br)ccc1Br
Reactant: CCCCCCCCOc1ccc(C(=O)NN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Br)ccc2Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 126.5 %

Procedure:
Under a blanket of nitrogen, 2,5-dibromobenzoyl chloride (57.43 g, 0.11925 mol) was added to a solution of 4-octyloxybenzoic acid hydrazide (50.88 g, 0.1925 mol) and triethylamine (27 mL, 19.48 g, 0.1925 mol) in 800 mL of methylene chloride. The reaction mixture was stirred for 5 hours at room temperature. The precipitated solid was filtered off and re-crystallized from hot DMF/water gave 79.38 g (78% yield) 2,5-dibromo-N′-[4-(octyloxy)benzoyl]benzohydrazide.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1>ClC(Cl)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[CH:16]=[CH:15][N:14]([CH:1]3[CH2:3][CH2:2]3)[C:11]2=[N:12][CH:13]=1
Reactant: OB(O)C1CC1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Product: Brc1cnc2c(ccn2C2CC2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
Cyclopropylboronic acid (0.872 g, 10.15 mmol) was added to a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5.08 mmol), Na2CO3 (1.076 g, 10.15 mmol), copper(II)acetate (0.922 g, 5.08 mmol) and 2,2′-bipyridine (0.793 g, 5.08 mmol) in dichloroethane (20 mL), and the mixture was stirred at 110° C. for 8 h. The reaction mixture was concentrated, and then diluted with ethyl acetate and water. Organic layer was separated, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in reduced pressure and purified by flash chromatography using 10% ethyl acetate in pet ether to afford title compound (0.38 g, 31.3%) as oil. 1H NMR (300 MHz, CDCl3): δ 8.38 (d, J=2.1 Hz, 1H), 7.99 (d, J=2.1 Hz, 1H), 7.20 (d, J=3.3 Hz, 1H), 6.34 (d, J=3.6 Hz, 1H), 3.5 (m, 1H), 1.15 (m, 2H), 1.03 (m, 2H).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21]C#N)=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].SC[C@@H]([C@@H](CS)O)O.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>>[C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCN1CCOCC1
Reactant: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCOCC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)morpholine
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N+:7]([O-])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=1[CH3:20].C[Si]([C:30]#[N:31])(C)C.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][C:11]([C:30]#[N:31])=[CH:12][CH:13]=[C:8]2[N:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=1[CH3:20]
Reactant: CCOC(=O)[N+]1([O-])C(C)=C(Cc2ccc(Cl)cc2Cl)c2ncccc21
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)n1c(C)c(Cc2ccc(Cl)cc2Cl)c2nc(C#N)ccc21
Yield: 48.1 %

Procedure:
To a suspension of ethyl 3-(2,4-dichlorobenzyl)-2-methylpyrrolo[3,2-b]pyridine-1-carboxylate N-oxide (414 mg) in anhydrous triethylamine (4 ml) was added trimethylsilylcyanide (704 mg) at room temperature in a nitrogen atmosphere, and the mixture was refluxed with heating overnight. The reaction mixture was cooled and a saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was subjected to flash silica gel chromatography (silica gel, 80 ml, eluted with hexane-ethyl acetate=5-1) and crystallized from isopropyl ether to give the objective compound (204 mg) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:9][C:8]=2[CH:23]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:32])C=1.O.C(=O)([O-])O.[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]3([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])[O:32][CH:9]3[C:8]=2[CH:23]=1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C=C1CNC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C2OC21CNC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-2H-1-benzopyran (0.5 g, 1.52 mmol) in dichloromethane (10 ml) at 0° C. was treated with m-chloroperbenzoic acid (70%, 0.45 g, 1.52 mmol). After stirring for sixteen hours at room temperature, water and sodium hydrogen carbonate were added and the organic phase separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/acetone (95/5), to give 0.43 g of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran 1NMR (CDCl3): δ1.4 (s, 3H), 1.6 (s, 3H), 3.7 (dd,1H), 3.85 (s, 1H), 4.15 (dd, 1H), 6.70 (br.s, 1H), 6.95 (d, 1H), 8.2 (d, 1H), 8.30 (s, 1H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]=O)=[CH:22][CH:21]=[CH:20][CH:19]=2>>[CH3:15][C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]=[C:8]1[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=3)[NH:10][C:9]1=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1[nH]c2ccccc2c1C=O
Product: Cc1[nH]c2ccccc2c1C=C1C(=O)Nc2ccc(S(N)(=O)=O)cc21

Procedure:
5-Aminosulfonyl-2-oxindole was condensed with 2-methylindole-3-carboxaldehyde to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[N:8]=[C:9]([S:13][CH3:14])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(SC)=NC1c1cccc(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(C)nc(SC)nc1-c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2.09 g (6.43 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-1,4-dihydropyrimidine-5-carboxylic acid ethylester was dissolved in 30 ml of chloroform. 8.39 g (96.5 mmol) of manganese dioxide was added at room temperature and stirred at 80° C. for 2 hours. After filtration of insoluble matters, the obtained filtrate was concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=1[CH3:22].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=2[CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(/C=C/C#N)cc(C)c1N
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Cl)n1
Temperature: 145 °C
Yield: 78.5 %

Procedure:
To a mixture of 2,4-dichloropyrimidine (25 gm) and (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (28 gm) was added N,N-diisopropylethylamine (250 ml) under stirring. The mixture was then heated to 140 to 150° C. and stirred for 55 to 60 hours. The solution was then cooled to room temperature and the solvent was distilled off under reduced pressure to provide a residual solid. To the residual solid was added ethyl acetate (1500 ml) and water (1000 ml). The reaction mass was stirred for 30 minutes at room temperature and then the layers were separated. The organic layer was dried with sodium sulfate and then concentrates to provide 30 gm of (E)-3-(4-(2-chloropyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[CH2:23]([N:35]([CH2:53][CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH:47]([OH:52])[C:48]([F:51])([F:50])[F:49])=[CH:41][CH:40]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:23]([N:35]([CH2:53][CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:36][CH2:37][O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][C:47](=[O:52])[C:48]([F:49])([F:50])[F:51])=[CH:43][CH:44]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(O)C(F)(F)F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
A suspension of 1,1, 1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane, 1.7 g, 4.0 mmol) in dichloromethane (20 ml) was treated with 4-[N-dodecyl-N-2-[4-[4,4,4-trifluoro-3-hydroxybutyl]phenoxy]ethylamino]butanoic acid, ethyl ester (430 mg, 0.79 mmol) dissolved in dichloromethane (5 ml). The mixture was stirred at 22° C. for 4 h, poured into a saturated aqueous sodium bicarbonate and sodium thiosulfate (100 ml) and extracted with ethyl acetate (2×100 ml). The combined oganic layers were washed with sat. sodium bicarbonate (2×60 ml), brine (60 ml), dried over sodium sulfate and concentrated in vacuo . The residue was chromatographed on silica gel (hexane/ethyl acetate 2:1 to 1.5:1) to afford the title compound (333 mg, 77%) as a colorless oil.