Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](Cl)([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]CC.[CH3:12][C:13]([CH3:21])=[CH:14][CH2:15][CH2:16][C:17]([CH:19]=[CH2:20])=[CH2:18].Cl.[C:23]([O-:26])(=[O:25])[CH3:24].[Na+].C([O-])(=O)C.[OH-].[Na+]>>[OH:25][CH2:20]/[CH:19]=[C:17](/[CH3:18])\[CH2:16][CH2:15][CH:14]=[C:13]([CH3:21])[CH3:12].[CH3:1][C:2](=[CH:3][CH2:4][CH2:5]/[C:6](=[CH:24]/[CH2:23][OH:26])/[CH3:7])[CH3:10]
Reactant: CCCCCCCC(C)(C)Cl
Reactant: CC(=O)[O-]
Reactant: C=CC(=C)CCC=C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=CCC/C(C)=C/CO
Product: CC(C)=CCC/C(C)=C\CO

Procedure:
The dimethyloctyl chloride is then obtained by reacting the myrcene hydrochloride (neryl/geranyl chloride) with sodium acetate and saponifying the acetate with sodium hydroxide to produce nerol/geraniol. This is then hydrogenated to produce dimethyloctanol, which is treated with HCl in the presence of zinc chloride to produce the dimethyloctyl chloride.
Reaction SMILES: C([Li])CCC.[CH3:6][S:7][CH:8]([S:11][CH3:12])[S:9][CH3:10].[Si:13]([N:20]1[C@H:23]([CH2:24]I)[CH2:22][C:21]1=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[Si:13]([N:20]1[C@H:23]([CH2:24][C:8]([S:11][CH3:12])([S:9][CH3:10])[S:7][CH3:6])[CH2:22][C:21]1=[O:26])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CSC(SC)SC
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1CI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSC(C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
n-Butyllithium (19.4 ml of 2.5 M hexane solution, 48.5 mmol) is added slowly by syringe to a solution of tri(methylthio)methane (7.47 g, 48.5 mmol) in 150 ml of freshly distilled THF at -78° C. The resulting solution is stirred at -78° C. for 30 min. prior to the addition of a solution of (4S)-1-(tert-butyldimethylsilyl)-4-iodomethylazetidin-2-one (15.0 g, 46.15 mmol) in 50 ml of THF. This solution is stirred at -78° C. for 30 min., then quenched by addition of saturated aqueous ammonium chloride solution. The reaction mixture is allowed to warm to room temperature, then poured into ether (250 ml), washed with water (2×100 ml) brine (100 ml) and dried over magnesium sulfate. Removal of solvents in vacuo gives an oil which is crystallized from petroleum ether to give 13.3 g (82%) of (4S)-1-(t-butyldimethylsilyl)-4-(2,2,2-tri(methylthio)ethyl)azetidin-2-one as colorless prisms. m.p. 61°-62° C. IR(CHCl3,CM-1) 2918, 2850, 1730; n.m.r. (CDCl3) δ4.0(m,l), δ3.35(dd,l,J=5.5,16), δ2,83(dd,l,J=3,16) δ2,5(ABq,2) δ2,15(s,9), δ0.98(s,9), δ0.25(s,6).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([Cl:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)(=[O:4])=[O:3].[F-:14].[K+].C(OCC)(=O)C>O1CCOCC1.O>[F:14][S:2]([C:5]1[S:6][C:7]([Cl:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)F)sc1Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2--Chlorosulphonyl-4-nitro-5-chlorothiophene (20.1 parts) were stirred in p-dioxane (80 parts) at room temperature. Potassium fluoride (5.2 parts) in water (20 parts) was added and the mixture heated to 50° C. Stirred under these conditions for 4 hours, then cooled and poured onto ice/water. Ethyl acetate was then added to extract the product and separated. Dried over magnessium sulphate then screened and concentrated to yield the product 2-fluorosulphonyl-4-nitro-5-chloro thiophene (20.4 parts).
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC(F)(F)C[C@@H]1c1ccnn1C
Yield: 97.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (80.0 mg, 0.13 mmol) prepared in Example 126a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (61.0 mg, 99%) as a colorless solid.
Reaction SMILES: [C@H]1(NCC2C=C(C(C)(C)C)C=C(C(C)(C)C)C=2O)CCCC[C@@H]1NCC1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1[OH:23].[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[CH:46]([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2.C(OO)(C)(C)C>C1(C)C=CC=CC=1.CC(C)[O-].[Zr+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[C:46]([OH:23])([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Reactant: CC(C)(C)c1cc(CN[C@H]2CCCC[C@@H]2NCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: [Zr+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 55 °C

Procedure:
A chiral zirconium complex was prepared by stirring zirconium(IV) isopropoxide (0.560 g, 1.44 mmol) with 2,2′-[(1S,2S)-1,2-cyclohexanediylbis(iminomethylene)]bis[4,6-bis(1,1-dimethylethyl)phenol] (Formula IIIa wherein R6 is C(CH3)3, 1.00 g, 1.82 mmol) for 30 minutes in toluene (25 mL) at ambient temperature. The homogeneous solution was evaporated to dryness in vacuo, and the residue redissolved in toluene (8.70 g, 10 mL). A toluene solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (1.53 g of a 21.55% by weight toluene solution, 1.47 mmol of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate) was added to the toluene solution of the chiral zirconium complex and the reaction mixture was heated to 55° C. Over the next 47 minutes, a toluene solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (36.71 g of a 21.55% by weight toluene solution, 35.2 mmol of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate) and, simultaneously, an aqueous solution of tert-butyl hydroperoxide (70%, 4.69 g, 36.4 mmol) were co-fed to the reaction mixture at 55° C. After the two solutions were added, the reaction mixture was heated at 55° C. for an additional 6 hours, cooled to 25° C., and then filtered. After drying, 4.64 g (52.5%) of the S-enantiomer of methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate was obtained as a white solid in 98% enantiomeric excess. Quantitative HPLC analysis of the filtrate and solids showed that the overall reaction proceeded with 85% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 74% yield (87% chemoselectivity) and 75% enantiomeric excess of the S-enantiomer.
Reaction SMILES: B(F)(F)F.CCOCC.[I:10][C:11]1[CH:30]=[CH:29][C:14]([C:15]([O:17][CH:18]([C:27]#[N:28])[C:19]2([CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH2:22][O:21][CH2:20]2)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:27]([CH:18]1[C:19]2([CH:23]3[CH2:24][CH2:25][CH2:26]3)[CH2:22][O:21][C:15]([C:14]3[CH:13]=[CH:12][C:11]([I:10])=[CH:30][CH:29]=3)([O:16][CH2:20]2)[O:17]1)#[N:28]
Reactant: N#CC(OC(=O)c1ccc(I)cc1)C1(C2CCC2)COC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC1OC2(c3ccc(I)cc3)OCC1(C1CCC1)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
Boron trifluoride etherate (1 ml) was added to a stirred solution of 1-cyano-1(3-cyclobutyloxetan-3-yl)methyl 4-iodobenzoate (2.3 g, 5.8 mmol) in dry dichloromethane (30 ml) at -70° C. under a nitrogen atmosphere. The solution was allowed to warm to room temperature and was stirred overnight. Triethylamine (1 ml) was added, the solution was evaporated to dryness to leave a gum which was partitioned between water and dichloromethane. The organic layer was separated, dried over anhydrous potassium carbonate and evaporated. The residue was chromatographed on basic alumina, eluting with hexane:dichloromethane (4:1 v/v) to give 3-cyano-4-cyclobutyl-1(4-iodophenyl)-2,6,7-trioxabicyclo[2.2.2]octane as a white solid (1.05 g, 46%).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][NH:8][S:9]([C:12]1[S:13][C:14]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:16]=1)(=[O:11])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]([NH:18][CH2:17][C:14]2[S:13][C:12]([S:9]([NH:8][CH2:7][C:6]([OH:28])=[O:5])(=[O:10])=[O:11])=[CH:16][CH:15]=2)=[O:20])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNS(=O)(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of 1c (400 mg, 0.9 mmole) in CH2Cl2 (10 ml) at 0° C. is added TFA (10 ml) and the reaction is stirred for 1 h at 0° C. and a further hour at room temperature. Evaporating the solvents to dryness gave 1d (300 mg, 86%) as a white solid. 1H NMR (d6-DMSO) δ 9.34 (t, J=5.65 Hz, 1H), 8.20 (t, J=6.03 Hz, 1H), 7.89 (d, J=8.67 Hz, 2H), 7.56 (d, J=8.67 Hz, 2H), 7.43 (d, J=3.77 Hz, 1H), 7.05 (d, J=3.77 Hz, 1H), 4.63 (d, J=5.65 Hz, 2H), 3.59 (d, J=6.03 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=NO)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].[H][H].ClCC#N.CN(C)C=[O:27]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: [H][H]
Reactant: ON=C(c1ccccc1)c1ccncc1
Agent: N#CCCl
Agent: [H-]
Agent: [Na+]
Product: O=C(c1ccccc1)c1ccncc1
Reaction time: 1 h

Procedure:
Phenyl 4-pyridinyl ketone oxime (5.4 g) was stirred in 50 ml of dimethyl formamide containing 1.5 g of a 50% dispersion of sodium hydride in oil, for 0.5 hours at room temperature. After the hydrogen evolution was completed, chloroacetonitrile (2.5 g) was added. The reaction mixture was stirred for 1 hour. The greater part of the dimethyl formamide was evaporated at reduced pressure, and then the residue was treated with ether and water. The ether layer was separated and dried over magnesium sulphate. The product was recrystallized from a mixture of ether and petroleum ether (40°-60° C.), yielding pure phenyl 4-pyridinyl ketone, O-cyanomethyl oxime (4.9 g, m.p. 101.5°-103° C.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]1([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]1)=[O:15].Cl.[F:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:20][NH:29][CH2:28][CH2:27][F:26])([OH:19])[C:21]([F:23])([F:22])[F:24])=[O:15]
Reactant: NCCF
Reactant: Nc1c(C(=O)NCC2(C(F)(F)F)CO2)cnn1-c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(C(=O)NCC(O)(CNCCF)C(F)(F)F)cnn1-c1ccc(F)cc1
Reaction time: 96 h
Yield: 128.5 %

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-pyrazole-4-carboxamide (1.03 g, 3 mmol) in anhydrous acetonitrile (10 ml) was added 2-fluoroethylamine hydrochloride (650 mg, 6 mmol, ca. 90% purity) and triethylamine (0.98 ml, 7 mmol) and the resulting suspension was shaken for 4 days. It was partitioned between ethyl acetate (70 ml) and water (20 ml), washed with saturated brine (20 ml), dried over sodium sulphate and evaporated to give a gum (1.57 g). This was purified on 100 g SiO2 using the Flashmaster 2 with 0-100°/0 ethyl acetate in cyclohexane 60 minute gradient as eluent. This gave the title compound (924 mg).
Reaction SMILES: [S:1]([Cl:4])(Cl)=[O:2].[Na+].[F:6][C:7]([F:14])=[CH:8][CH2:9][CH2:10]S([O-])=O>CCCCCC>[F:6][C:7]([F:14])=[CH:8][CH2:9][CH2:10][S:1]([Cl:4])=[O:2]
Reactant: O=S([O-])CCC=C(F)F
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CCCCCC
Product: O=S(Cl)CCC=C(F)F
Temperature: 25 °C

Procedure:
Thionyl chloride (200 ml) in dry n-hexane (400 ml) was stirred at ambient temperature and 4,4-difluorobut-3-enyl-sulfinic acid sodium salt ( 44 g) was added in portions. On complete addition the mixture was heated to reflux under nitrogen for 4.5 hours, cooled to ambient temperature then filtered. The filtrate was evaporated under reduced pressure to give a liquid which was distilled and the fraction collected at bp 50-60° C. at 0.1 mm Hg to yield
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][O:11]C(Cl)Cl.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1
Reactant: COC(Cl)Cl
Reactant: BrCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1ccc(CCBr)cc1
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
To a solution of (2-bromoethyl)benzene (100 mmol, 18.5 g) in methylene chloride (185 ml) at 0° C. was added dropwise titanium tetrachloride (200 mmol, 22 ml). The mixture was stirred for 10 minutes and alpha,alpha-dichloromethyl methyl ether (100 mmol, 9 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and poured into saturated NaHCO3 (1 liter). Ethyl acetate (750 ml) was added and the solution was filtered through diatomaceous earth, the organic layer separated, dried (Na2SO4) and solvent removed in vacuo. The residue was triturated with hexane to afford 8.7 g of title product; m.p. 49°-52° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][C:6]([OH:8])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.C([Li])CCC.[CH2:37]1[O:42][C:40](=[O:41])[NH:39][C@@H:38]1[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][C:6]([N:39]1[CH:38]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:37][O:42][C:40]1=[O:41])=[O:8]
Reactant: COC(=O)C(CCc1ccccc1)CC(=O)O
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(CCc1ccccc1)CC(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of the compound of example 49 (2.51 g, 10.62 mmol) in anhydrous THF (60 mL) and containing triethyl amine (1.8 mL, 12.74 mmol) at −70° C. was added drop wise trimethylacetyl chloride. After 15 minutes, the reaction mixture was placed in an ice bath and stirred for 45 minutes after which time, the reaction mixture was cooled to −78° C. In a separate flask, n-butyl lithium (2.5 M in hexanes, 43 mL, 10.62 mmol) was added to a solution of R-4-benzyl-2-oxazolidinone in anhydrous THF at −78° C. After 15 minutes of stirring, this mixture was transferred by cannula to the former solution. The resultant mixture was stirred for 20 minutes at −78° C. followed by an additional 2 h in an ice bath. The reaction was quenched by the addition of a saturated solution of ammonium chloride. The mixture was extracted several times using ethyl acetate. The recombined organic layer was extracted with brine, saturated sodium hydrogen carbonate, brine, and water, respectively. The solvent was evaporated following drying over sodium sulfate and filtration. The resultant crude material was flashed using 30% ethyl acetate in hexanes to give the product as a white solid. 1H-NMR(CDCl3, 300 MHz: 1.89(m, 1H); 2.05(m, 1H); 2.75(m, 3H); 3.00(m, 1H); 3.68(m, 3H); 3.75(s, 3H); 4.18(m, 2H); 4.65(m, 1H); 7.21(m, 5H), 7.33(m, 5H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:18]([N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A mixture of ethyl 4-bromobutyrate (2.0 g, 10.25 mmol), dibenzylamine (2.02 g, 10.25 mmol) and potassium carbonate (2.83 g, 20.5 mmol) in N,N-dimethylformamide (20 mL) was heated with stirring at 100° C. overnight. The resulting mixture was diluted with water (80 mL) and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (80 mL×2), and then dried over Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc:PE=1:4) to afford ethyl 4-(dibenzylamino)butanoate as a white solid (2.0 g, yield: 64%).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:18][CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:19]([C@@H:21]([OH:24])[CH2:22][CH2:23][C@@:9]34[OH:25])[O:20][C:4]([C:5]=25)=[C:3]([OH:26])[CH:2]=1.C(N(CC)CC)C.[C:34]([O:38]C(=O)CC)(=[O:37])[CH2:35][CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:18][CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:19]([C@@H:21]([OH:24])[CH2:22][CH2:23][C@@:9]34[OH:25])[O:20][C:4]([C:5]=25)=[C:3]([OH:26])[CH:2]=1.[C:34]([O-:38])(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)OC(=O)CC
Agent: O=C([O-])[O-]
Agent: Oc1ccc2c3c1O[C@H]1[C@@H](O)CC[C@@]4(O)[C@@H](C2)N(CC2CCC2)CC[C@]314
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)[O-]

Procedure:
75 ml of methylene chloride and 3.57 g(0.01 mole) of Nalbuphine were added to a 250 ml round-bottomed flask. The flask was placed in an ice bath to keep it cool. The content was stirred then gradually 0.16 mole of triethylamine was added. With rapid stirring, another 20 ml of dichloromethane solution containing 0.011 mole of propionic anhydride was added drop by drop. Afterward, the mixture was stirred at room temperature for 1 hour. 20 ml of 10% sodium carbonate solution was added to neutralize the residual acid and remove the water soluble impurities. Sodium sulfate was used to dehydrate the solution. After drying under vacuum, a Nalbuphine propionate solid was obtained. The product was purified by column chromatography.
Reaction SMILES: O[Li].O.[CH:4]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:17])=[CH:14][C:15]=2[F:16])=[CH:8][C:7]([C:18]([OH:20])=[O:19])=[C:6]([OH:21])[CH:5]=1.[CH2:22]1COCC1.Cl>CO.O>[F:16][C:15]1[CH:14]=[C:13]([F:17])[CH:12]=[CH:11][C:10]=1[C:9]1[CH:4]=[CH:5][C:6]([O:21][CH3:22])=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc(F)cc2F)cc1C(=O)O
Yield: 93 %

Procedure:
LiOH.H2O (60 mg, 1.43 mmol) was added to a solution of fully methylated diflunisal (140 mg, 0.50 mmol) in MeOH:THF:H2O (4.5 mL 1:1:1), and stirred at rt for 4 h. Upon completion, the reaction was acidified with 30% HCl, extracted with ethyl acetate (3×5 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (2:1 ethyl acetate:hexane, 1% acetic acid) to afford 33 (122 mg, 93%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 10.77 (br s, 1H), 8.31 (dd, 1H, J=2.5, 0.9 Hz), 7.75 (dt, 1H, J=8.6, 2.1 Hz), 7.41 (dt, 1H, J=8.9, 6.6 Hz), 7.15 (d, 1H, J=8.8 Hz), 6.94 (m, 1H), 4.13 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 177.7, 161.4, 158.2, 135.7, 133.9, 131.4, 129.0, 123.5, 118.1, 112.2, 112.0, 104.6, 56.9. HRESIMS calculated for C14H10F2O3 (M−H) 263.0520. found 263.0514. Normal phase HPLC retention time: 21.6 min. Reverse phase HPLC retention time: 11.9 min. >99% pure.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(#N)C.O>[Br:19][C:7]1[S:6][C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[C:8]=1[CH3:9]
Reactant: Cc1csc2ccc(F)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: Cc1c(Br)sc2ccc(F)cc12
Temperature: 40 °C
Reaction time: 0.58 h

Procedure:
A mechanically-stirred solution of 5-fluoro-3-methylbenzo[b]thiophene (50.32 g, 0.303 mol, 1.0 equiv) in acetonitrile (350 mL) is treated with NBS (56.32 g, 0.318 mol, 1.05 equiv). An initial endotherm reduces the reaction temperature to 17° C. A subsequent exotherm then increases the reaction temperature to 40° C. over a 10 min. period, at which time the reaction is cooled to 18-20° C. by application of an ice water bath. The reaction is stirred at RT for an additional 35 min. and the resultant slurry is slowly diluted with water (350 mL). The slurry is stirred for 10 min and the product is filtered, washed with 50:50 acetonitrile:water (100 mL) and dried to a colorless crystalline solid (65.56 g, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27]C1C=C2C(=CC=1)OC(C1C=CC=CC=1)CC2=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][C:14]3=[O:27])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CC(c2ccccc2)Oc2ccc(O)cc21
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=C1CC(c2ccccc2)Oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc21

Procedure:
6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4one was prepared as described for 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 200 mg of 6-hydroxyflavanone. 1H NMR (400 MHz, d6-DMSO) δ: 9.03 (bs, 1H), 8.64 (d, 1H, J 9.0 Hz), 7.59-7.41 (m, 7H), 7.31 (d, 1H, J 9.0 Hz), 7.23 (d, 1H, 8.8 Hz), 5.75 (dd, 1H, J 12.3, 2.9 Hz), 3.30 (dd, 1H, −16.3, 12.3 Hz), 2.87 (dd, 1H, −16.3, 2.9 Hz).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7]O)[N:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=1.S(Cl)([Cl:15])=O>ClCCl>[ClH:15].[Br:1][C:2]1[N:6]([CH2:7][Cl:15])[N:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1nc(Br)n(CO)n1
Solvent: ClCCl
Product: CC(C)(C)c1nc(Br)n(CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.88 g of 5-bromo-3-t-butyl-1H-1,2,4-triazole 1-ylmethanol was dissolved to 100 ml of dichloromethane. 4.2 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Chloroform was added to the residue and filtered. The filtrate was concentrated under reduced pressure to obtain 2.03 g of 5-bromo-3-t-butyl-1-(chloromethyl)-1H-1,2,4-triazole hydrochloride.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>C(O)C>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: COCCN
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCCOC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 38, reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.41 g) and methoxyethylamine (1.04 g) in ethanol (15 ml) for 48 hours yielded the title compound, 0.38 g. m.p. 193-4° C. (recrystallized twice from methanol).