Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:16]1([NH:19][C:20]([C:22]2[S:35][C:25]3=[N:26][C:27](S(C)=O)=[C:28]([Cl:31])[C:29]([CH3:30])=[C:24]3[C:23]=2[NH2:36])=[O:21])[CH2:18][CH2:17]1>C1COCC1>[CH:16]1([NH:19][C:20]([C:22]2[S:35][C:25]3=[N:26][C:27]([O:4][CH2:3][CH2:2][CH2:1][OH:5])=[C:28]([Cl:31])[C:29]([CH3:30])=[C:24]3[C:23]=2[NH2:36])=[O:21])[CH2:18][CH2:17]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCCO)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a solution of 1,3-propanediol (1.053 g, 13.84 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. for 1 hour, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.240 g, 67%). Mass (m/z): 356.2 (M++1), 354.1 (M+−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][CH2:12][CH2:13]Cl)=[N:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[Na]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:11][CH2:12][CH2:13][O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=C(SCCCl)c1cccc(F)c1
Agent: [Na]
Solvent: CCO
Product: Fc1cccc(C2=NOCCS2)c1

Procedure:
Cyclisation of 2-chloroethyl 3-fluoro-N-hydroxybenzenecarboximidothioate was accomplished as described in Example 2 using sodium (4.6 g) in ethanol (300 ml) to give 3-(3-fluorophenyl)-5,6-dihydro-1,4,2-oxathiazine, mp 47°-9° C. (Found: C, 54.66; H, 4.13; N, 7.07. C9H8FNOS requires C, 54.81; H, 4.09; N, 7.10).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7][CH3:8].[CH3:25][N:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][C:27]1=[O:41].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.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].C(Cl)Cl>[CH3:8][O:7][C:6]1[N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[N:4]=[CH:3][C:2]=1[C:29]1[CH:30]=[CH:31][N:26]([CH3:25])[C:27](=[O:41])[CH:28]=1
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)cc1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1c(-c2ccn(C)c(=O)c2)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Temperature: 110 °C
Yield: 90 %

Procedure:
Combined 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (25 mg, 0.063 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (29.7 mg, 0.127 mmol), PdCl2(dppf)-CH2Cl2 adduct (4.13 mg, 5.06 μmol) and sodium bicarbonate (26.6 mg, 0.316 mmol) in dioxane (0.2 mL) and water (0.05 mL) and heated at 110° C. for 1 h in the microwave. More PdCl2(dppf)-CH2Cl2 adduct (ca. 3 mg), sodium bicarbonate (10 mg) and water (100 uL) was added and the mixture was heated at 110° C. for 1 h in the microwave. The reaction was concentrated onto Celite® purified on 12 g NH silica gel column eluted with 0 to 5% MeOH in methylene chloride to give 6-(5-methoxy-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide as a brown oil (24 mg). MS m/z 424 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C@@H:10]([NH:14][C:15]([C@H:17]2[CH2:19][C@@H:18]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH2:11][O:12][CH3:13])=[CH:6][CH:5]=1)[CH3:2]>C(Cl)(Cl)Cl>[CH3:13][O:12][CH2:11][C@H:10]([NH:14][C:15]([C@H:17]1[CH2:19][C@@H:18]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:16])[C:7]1[CH:8]=[N:9][C:4]([O:3][CH:1]2[CH2:2][CH2:1][O:3][CH2:4][CH2:2]2)=[CH:5][CH:6]=1
Reactant: CCOc1ccc([C@H](COC)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Solvent: ClC(Cl)Cl
Product: COC[C@H](NC(=O)[C@H]1C[C@@H]1c1ccccc1)c1ccc(OC2CCOCC2)nc1

Procedure:
Prepared analogously to Compound 46 using Compound 45. Yield=343 mg (20%) as a solid. 1H NMR (400 MHz, COCl3): δ8.10-8.11 (d, J=2.4 Hz, 1H), 7.54-7.57 (m, 1H), 7.25-7.29 (m, 2H), 7.18-7.21 (m, 1H), 7.05-7.07 (m, 2H), 6.66-6.88 (t, J=4.2 Hz, 1H), 6.38-4.40 (d, J=7.2 Hz, 1H), 5.20-5.21 (m, 1H), 5.10-5.12 (m, 1H), 3.94-3.99 (m, 2H), 3.57-3.69 (m, 4H), 3.37 (s, 3H), 2.42-2.49 (m, 1H), 2.02-2.08 (m, 2H), 1.61-1.79 (m, 4H), 1.25-1.28 (m, 1H) [α]D20=159.3 (c=0.198 g/100 mL, CHCl3). LC-MS (m/z) 383.15 (MH+), tR=0.54 min (method B).
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:9][CH:8]1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[H][H]>[Ru].ClCCl.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[OH:6][C@H:7]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:9][C@@H:8]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: [H][H]
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Agent: Cl[Ru]Cl
Agent: [Ru]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 99.5 °C
Reaction time: 0.17 h

Procedure:
90 mL of dehydrated N,N-dimethylformamide was added to 2.58 g of benzene ruthenium (II) chloride dimer (5.15 mmol) and 6.73 g of (S)-(−)-2,2,′-bis(diphenylphosphino)-1,1-binaphthyl (S-BINAP) (10.8 mmol). The mixture was stirred for 10 minutes in an oil bath at an external temperature of 97 to 102° C. in an argon atmosphere. Subsequently, the mixture was stood to be cooled at room temperature. Volatile materials were evaporated under reduced pressure in an oil bath at an external temperature of 50 to 60° C. to give a catalyst. 300 g of 1-benzyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (1.03 mol) and 500 mL of dehydrated dichloromethane were placed in an autoclave and the ruthenium catalyst dissolved in 850 mL of dehydrated dichloromethane was added. The mixture was stirred for 6 hours under a hydrogen pressure of 5 MPa at an external temperature of 50 to 62° C. Hydrogen was released and the reaction mixture was concentrated under reduced pressure. This gave 320 g of the title compound as a green oil. This product was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]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.COCCOC[O:29][C:30]1[CH:31]=[C:32]([CH:43]=[CH:44][CH:45]=[CH:46][C:47](N2CCSC2=S)=[O:48])[CH:33]=[CH:34][C:35]=1[O:36]COCCOC.C(Cl)(Cl)Cl.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.COCCOCOC1C=C(C=CC=CC(N2CCN(CCOC(C3C=CC=CC=3)C3C=CC=CC=3)CC2)=O)C=CC=1OCOCCOC.CO>[OH:29][C:30]1[CH:31]=[C:32]([CH:43]=[CH:44][CH:45]=[CH:46][C:47]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:22][CH2:21]2)=[O:48])[CH:33]=[CH:34][C:35]=1[OH:36]
Reactant: COCCOCOc1ccc(C=CC=CC(=O)N2CCSC2=S)cc1OCOCCOC
Reactant: c1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Agent: COCCOCOc1ccc(C=CC=CC(=O)N2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)cc1OCOCCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(C=CC=Cc1ccc(O)c(O)c1)N1CCN(CCOC(c2ccccc2)c2ccccc2)CC1
Yield: 38.9 %

Procedure:
To a solution of 690 mg (2.33 mmol) of N-(2- benzhydroxyethyl)piperazine in dry dimethylformamide (2 ml) was added 1.75 g (3.26 mmol) of N-[5-[3,4-bis(βmethoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidine-2-thione, and the mixture was reacted at room temperature 18 hours under argon atmosphere. The reaction mixture was concentrated by evaporation under reduced pressure and the residue was subjected to silica gel column chromatography. There was obtained from fractions eluted with chloroform - methanol (100:1) 856 mg (1.30 mmol) of N-[5-[3,4-bis(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]-N'-(2-benzhydroxyethyl)piperazine. To a solution of 856 mg (1.30 mmol) of the amide compound in methanol (17 ml) was added 257 mg (1.35 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 4 hours. A saturated aqueous solution of sodium chloride was added to the reaction mixture, which was adjusted to a pH value of 10 by the addition of an aqueous solution of sodium carbonate, and then extracted with ethyl acetate. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was subjected to Sephadex column chromatography, eluted with methanol, to give 439 mg (0.906 mmol) of N-[5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl]--N'-(2-benzhydroxyethyl)piperazine. Spectrophotometric data of the product support the structure shown below. ##STR97##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.F[B-](F)(F)F.ClC1C=CC([N+]#N)=CN=1.OO.FC(F)(F)C(O)=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N+:3]=1[O-:28]
Reactant: Fc1ccc(Cl)nc1
Reactant: O=C(O)C(F)(F)F
Agent: F[B-](F)(F)F
Agent: N#[N+]c1ccc(Cl)nc1
Agent: OO
Product: [O-][n+]1cc(F)ccc1Cl
Yield: 70 %

Procedure:
2-Chloro-5-fluoropyridine (9), a highly volatile substance, was synthesized from thermolysis of 2-chloro-5-pyridinediazonium tetrafluoroborate (8). Hand, E. S.; Baker, D. C. Synthesis 1989, 905-908. The isolation of 9 by the literature procedure was very complicated, in that it included repeated extractions, repeated distillations, treatment with sulfuric acid and sodium hydroxide, and steam distillation. In our hands, the reported yield of 70% was difficult to obtain after these operations. To improve upon these complicated procedures, following the thermolysis of compound 8, the reaction mixture was directly treated with 50% hydrogen peroxide and trifluoroacetic acid to give 2-chloro-5-fluoropyridine-N-oxide (10), which was easily isolated, with a total yield of 73%. Nitration of 10, followed by catalytic hydrogenation of the resulting 2-chloro-5-fluoro-4-nitropyridine-1-oxide (11) removed the N-oxide function, as well as reduced the nitro group to give the desired 4-amino-2-chloro-5-fluoropyridine (12). N-Oxidation of commercially available 2,5-dichloropyridine (13), followed by nitration and reduction yielded 4-amino-2,5-dichloropyridine (16).
Reaction SMILES: [CH3:1][N:2]([CH3:24])/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[CH:10]=[CH:11][C:12]=1[OH:13])=[O:6].[Cl:25][C:26]1[C:27](F)=[CH:28][C:29]([F:52])=[C:30]([S:32]([N:35]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=2[O:50][CH3:51])[C:36]2[S:37][CH:38]=[N:39][N:40]=2)(=[O:34])=[O:33])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CS(C)=O>[Cl:25][C:26]1[C:27]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:22])([F:21])[F:23])=[CH:8][C:7]=2[C:5](=[O:6])/[CH:4]=[CH:3]/[N:2]([CH3:1])[CH3:24])=[CH:28][C:29]([F:52])=[C:30]([S:32]([N:35]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=2[O:50][CH3:51])[C:36]2[S:37][CH:38]=[N:39][N:40]=2)(=[O:33])=[O:34])[CH:31]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: CN(C)/C=C/C(=O)c1cc(-c2ccccc2C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccccc4C(F)(F)F)cc3C(=O)/C=C/N(C)C)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.5 %

Procedure:
To a suspension of (2E)-3-(Dimethylamino)-1-[4-hydroxy-2′-(trifluoromethyl)biphenyl-3-yl]prop-2-en-1-one (Preparation 43, 809 mg, 2.41 mmol) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 16, 1.10 g, 2.39 mmol) in dimethylsulfoxide (10.0 mL) was added potassium carbonate (859 mg, 6.22 mmol). The reaction mixture was stirred for 18 hours at room temperature under an atmosphere of nitrogen. The reaction was poured into a saturated solution of aqueous ammonium chloride (20 mL) and extracted with dichloromethane (3×40 mL). The combined organic phase was washed with brine (3×40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a yellow solid (1.96 g). The solid was purified by silica gel column chromatography (40%-75% ethyl acetate in heptane gradient elution) to afford the title compound as a clear glass (563 mg, 30%)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10].[C:11]1([CH2:17][CH2:18][OH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:19][CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCCCCCCCBr
Reactant: OCCc1ccccc1
Product: BrCCCCCCCCOCCc1ccccc1

Procedure:
(4.3 g), T.l.c. [B] Rf 0.3, from 1,8-dibromooctane (13.4 g) and benzeneethanol (20 g).
Reaction SMILES: [Mg].II.Br[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[Br-].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1>C1COCC1>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:21])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)CBr
Agent: II
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
Magnesium (5.2 g, 199 mmol) is suspended in anhydrous THF (60 mL) under nitrogen. A small crystal of iodine is added. 1-Bromo-2,2-dimethylpropane (25 g, 165 mmol) is dissolved in anhydrous THF (90 mL) and a portion of the solution is added to the magnesium. The mixture is heated to reflux temperature to initiate the reaction. The rest of the bromide solution is added dropwise. After the addition is complete the mixture is refluxed for 4 h. The Grignard reagent is allowed to cool to room temperature and added dropwise to a solution of methyl-4-formylbenzoate (15 g, 91.5 mmol) in THF which has been cooled in an ice bath. After the addition is complete the resulting solution is stirred at room temperature for 2 h. The reaction is quenched with MeOH, worked up and concentrated to give 8.07 g (37%) of the titled compound as a yellow oil. 1H NMR.
Reaction SMILES: [CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])[N:41]=[C:40]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:62]>ClCCl>[CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH2:46][CH2:47][S:48]([CH3:51])(=[O:49])=[O:50])[N+:41]([O-:62])=[C:40]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCS(C)(=O)=O)n1
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCS(C)(=O)=O)[n+]1[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a dichloromethane solution (0.06 M) of tert-butyl (3-[cyclopropyl({2-(3-methoxypropyl)-6-[3-(methylsulfonyl)propoxy]pyridin-4-yl]methyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 101, Step 1 (1 eq.) was added 3-chloroperoxybenzoic acid (3.6 eq.). The resulting solution was stirred at RT for 18 h. The reaction was quenched with sat. aq. NaHCO3 and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 90:10 (v/v) CH2Cl2:EtOH→85:15 (v/v) CH2Cl2:EtOH) afforded the title compound.
Reaction SMILES: [O-]O.[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C(C)C)C=CC=CC=1.C(C1C=CC=CC=1)(=[O:23])C>O>[CH3:10][C:9]([OH:23])([CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: [O-]O
Solvent: O
Product: CC(C)(O)c1ccccc1

Procedure:
In the manufacture of cumene hydroperoxide (CHP) wherein cumene is oxidized to CHP, the improvement comprising refining the cumene hydroperoxide product stream containing, in weight percents, about 80 to about 89 CHP, about 0.6 to about 1.6 water, about 0.5 to about 2.0 acetophenone, about 2 to about 15 cumene, and about 5 to about 9 dimethylbenzyl alcohol to obtain a product substantially reduced in color, water, acetophenone, and dimethylbenzyl alcohol, by subjecting said product stream to a first evaporation step at a temperature of 150° to 210° F. and pressure of 2 to 10 mm Hg, passing the residue therefrom to a second evaporation step at a temperature of about 135° to about 210° F. and a pressure of about 0.5 to about 8 mm Hg, and condensing the vapors therefrom to recover a refined cumene hydroperoxide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:20]([O:21][CH2:22]C)=[CH:19][CH:18]=[C:17](C[N+]([O-])=O)[C:10]=1[CH:11]=[CH:12][CH2:13][N+]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OC)=CC=C(C[N+]([O-])=O)C=1C=CC[N+:41]([O-])=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]2[C:10]=1[CH:11]=[C:12]([CH3:13])[NH:41]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C[N+](=O)[O-])c(C=CC[N+](=O)[O-])c1OCc1ccccc1
Reactant: COc1ccc(C[N+](=O)[O-])c(C=CC[N+](=O)[O-])c1OCc1ccccc1
Product: COc1ccc2[nH]c(C)cc2c1OCc1ccccc1

Procedure:
This compound is obtained according to the operating method described in Example 2b, in which the 2-benzyloxy-3-ethoxy-6,β-dinitromethylstyrene is replaced with 2-benzyloxy-3-methoxy-6,β-dinitromethylstyrene. A pale yellow powder (yield =40%, m.p. =74°-75° C.) is obtained.
Reaction SMILES: CO.[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:4]=1.C=O.[CH:20]([O-])=O.[NH4+]>O>[CH3:20][NH:16][C:15]1[C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH3:17])[CH:8]=[CH:7][CH:6]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C[O-]
Reactant: Cc1cccc(Nc2ncccc2N)c1
Agent: C=O
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CNc1cccnc1Nc1cccc(C)c1
Reaction time: 3 h

Procedure:
600 mL of methanol and 24 mL water were added to a 3-neck 2 L round bottom flask. Nitrogen was bubbled directly into the solution. Palladium on carbon was added (10%, 10.35 g, 9.73 mmol) while bubbling continued. Next, N2-(m-tolyl)pyridine-2,3-diamine (19.38 g, 97 mmol) and formaldehyde (37%, 14.48 mL, 195 mmol) were added. The reaction mixture was stirred under nitrogen for 3 h. Next, nitrogen was bubbled into the solution and ammonium formate (123 g, 1945 mmol) was added slowly. The reaction mixture was stirred under nitrogen overnight at room temperature. The reaction mixture was filtered through Celite® and the Celite® was washed with dichloromethane. The filtrate was washed with water twice, and the organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified using column chromatography eluting with 30% ethyl acetate/hexanes to isolate the desired product. The product was combined with material from other reactions and purified by column chromatography eluting with 30% ethyl acetate/hexanes. A dark reddish-brown solid was obtained. The solid was recrystallized from boiling hexanes with a small amount of ethyl acetate to dissolve the solid. The product was filtered off as needles with some reddish color which were washed with hexanes, obtained 15.1 g.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH:50]1([NH2:53])[CH2:52][CH2:51]1.Cl>CN(C)C=O>[CH:50]1([NH:53][C:26]([C:24]2[CH:23]=[CH:22][C:20]3[CH:21]=[C:17]([C:15]([NH:14][CH:3]([C:4]4[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:11])[F:13])[CH:5]=4)[C:2]([F:30])([F:1])[F:29])=[O:16])[O:18][C:19]=3[CH:25]=2)=[O:27])[CH2:52][CH2:51]1
Reactant: O=C(O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Reactant: NC1CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 2-({2,2,2-trifluoro-1-[3-(trifluormethyl)phenyl]ethyl}carbamoyl)-1-benzofuran-6-carboxylic acid (100 mg, 0.21 mmol) in N,N-dimethylformamide (1 ml) was admixed with 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (100 mg, 0.46 mmol) and cyclopropylamine (36 mg, 0.63 mmol), and stirred in a closed vessel at 50° C. overnight. The cooled reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with sat, sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue was chromatographed on a preparative HPLC with water/acetonitrile as the eluent (gradient=43 min from 10%, acetonitrile in water to 100% acetonitrile).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>CC#N>[C:18]1([O:17][C:15](=[O:16])[NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cccnc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1cccnc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a solution consisting of pyridin-3-yl amine (9.49 g, 101 mmol) and pyridine (8.77 g, 111 mmol) in CH3CN (80 mL) at 0° C. was added phenyl chloroformate (15.8 g, 101 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with H2O (200 mL) and the resulting precipitate was filtered and dried under vacuum to provide the title compound as a tan solid (17.34 g, 80%). MS (ESI+): calcd for C12H10N2O2 m/z 214.07, found 215.3 (M+H)+. 1H NMR (500 MHz, d6-DMSO): 10.46 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.27 (dd, J=4.7, 1.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.37 (dd, J=8.4, 4.7 Hz, 1H), 7.31-7.22 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>S1(CCCC1)(=O)=O>[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 150 °C
Yield: 99.7 %

Procedure:
A mixture of 23.6 g (0.150 mole) of 4-nitrochlorobenzene, 23.1 g (0.165 mole) of 4-(methylthio)phenol, 22.8 g (0.165 mole) of anhydrous K2CO3 and 150 ml of sulfolane was heated at 150° C. for 6 hrs. The product was recovered (39.1 g, 99.7% yield) as described in Example 1 and recrystallized from ethanol, which gave purified 1-(methylthio)-4-(4-nitrophenoxy)benzene, mp 59°-61° C.