Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:19][CH2:18]1)[C:10]([F:17])([F:16])[C:11]([O:13]CC)=[O:12].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:19][CH2:18]1)[C:10]([F:17])([F:16])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(F)(F)C1(c2ccc(F)cc2F)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)C(F)(F)C1(c2ccc(F)cc2F)CO1
Yield: 100.1 %

Procedure:
In 11 ml of ethanol was dissolved 1.1 g of ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutyrate. To the resulting solution was dropwise added 4.7 ml of a 1N aqueous sodium hydroxide solution at 5°-10° C. The solution was subjected to reaction at the same temperature for 10 minutes. The reaction mixture was introduced into a mixed solvent consisting of 50 ml of ethyl acetate and 50 ml of water. The resulting solution was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 0.99 g of oily 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutyric acid.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:52]=[CH:51][C:42]([C:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][CH3:48])=[O:44])=[C:41]([S:53]([CH:56]([CH3:58])[CH3:57])(=[O:55])=[O:54])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:52]=[CH:51][C:42]([C:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][CH3:48])=[O:44])=[C:41]([S:53]([CH:56]([CH3:58])[CH3:57])(=[O:54])=[O:55])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCN(CC)C(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CCCN(CC)C(=O)c1ccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1S(=O)(=O)C(C)C

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-N-ethyl-2-(isopropylsulfonyl)-N-propylbenzamide (Intermediate 259), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:13][CH3:14])(=[O:12])/[CH:7]=[CH:8]\[C:9]([O-:11])=O.[Cl:15][C:16]1[CH:24]=[C:20]([C:21](O)=[O:22])[C:19]([NH2:25])=[CH:18][CH:17]=1>O.N1C=CC=CC=1.C(#N)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:25]=[C:9](/[CH:8]=[CH:7]/[C:6]([O:13][CH3:14])=[O:12])[O:11][C:21](=[O:22])[C:20]=2[CH:24]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COC(=O)/C=C\C(=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)/C=C/c1nc2ccc(Cl)cc2c(=O)o1
Reaction time: 0.08 h
Yield: 68.3 %

Procedure:
A mixed solution comprising 1.49 g of methanesulfonyl chloride and 10 ml of acetonitrile was cooled with ice, and 10 ml of an acetonitrile solution comprising 1.3 g of monomethyl maleate and 1.34 g of pyridine was dropwise added thereto under cooling with ice over a period of 5 minutes, followed by stirring for 5 minutes at the same temperature. 10 ml of an acetonitrile solution comprising 1.72 g of 5-chloroanthranilic acid and 2.77 g of pyridine was added under cooling with ice over a period of 2 minutes, followed by rinsing with 5 ml of acetonitrile and stirring for 20 minutes at the same temperature. 1.49 g of methanesulfonyl chloride was added over a period of 2 minutes under cooling with ice, followed by rinsing with 2 ml of acetonitrile and stirring for 30 minutes, and then the temperature was returned to room temperature, followed by reaction for 4 hours. The reaction liquid was poured to 20 ml of water, followed by stirring for 30 minutes. The resulting crystals were collected by filtration, washed with water and a mixed liquid of acetonitrile:water (2:1), and dried to obtain 1.82 g of the brown desired product (melting point: 162 to 164° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:15][C:16]1([CH3:19])[CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+].O.P([O-])(O)(O)=O.[Na+]>C(#N)C.O>[OH:17][C:16]([CH3:19])([CH3:18])[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(OCC(C)(C)O)ccc1[N+](=O)[O-]
Yield: 29.2 %

Procedure:
A mixture of methyl 5-hydroxy-2-nitrobenzoate (0.5 g, 2.54 mmol), 2,2-dimethyloxirane (6.86 ml, 7.61 mmol), potassium carbonate (351 mg, 2.54 mmol) and sodium dihydrogen phosphate monohydrate (350 mg, 2.54 mmol) in acetonitrile (4 ml) and water (0.6 ml) was stirred at 140° (5 bar) in a steel bomb for 6 hr. After cooling to r.t, the mixture was diluted with water, extracted with AcOEt, dried over MgSO4, filtered and evaporated. The crude product was purified by silica gel chromatography using a methylenechloride/MeOH gradient to obtain the title compound (200 mg, 29%) as light yellow viscous oil.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.ClC(OC)=O.[NH2:33][C:34]1[CH:50]=[CH:49][C:37]([CH2:38][S:39]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(=[O:41])=[O:40])=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([CH2:38][S:39]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(=[O:41])=[O:40])=[CH:49][CH:50]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCS(=O)(=O)Cc1ccc(N)cc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCS(=O)(=O)Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 130 mg; 0.47 mmol) in DCM was treated with diisopropylamine (90 mL; 0.52 mmol) and methyl chloroformate (40 mL; 0.52 mmol). After stirring at 0° C. for 15 minutes, ethyl 3-(4-aminobenzylsulfonyl)propanoate (Intermediate 42, 130 mg; 0.48 mmol) was added. After stirring at 0° C. for 30 minutes and RT for 1 hour, saturated sodium bicarbonate solution was added and the mixture stirred for 15 minutes. DCM was added and the layers separated. The organic extract was filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:18])[O:17][CH2:16][CH2:15][O:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:37](O)CCO.CC1C=CC(S(O)(=O)=O)=CC=1>>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:18])[O:17][CH2:16][CH2:37][CH2:15][O:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: OCCCO
Reactant: CC1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OCCCO1

Procedure:
The title compound was prepared from 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-acetyl-2-cyclohex-1-enyl-phenyl)-amide (as prepared in Example 1, step (h), 0.58 mmol), 1,3-propanediol (882 mg, 11.6 mmol) and catalytic PTSA according to the procedure in Example 1, step (h) (147 mg, 49%). Mass spectrum (ESI, m/z): Calcd. for C28H38N4O4Si, 523.2 (M+H). found 523.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][NH:7][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[Cl:11])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NCCc1cccc(Br)c1
Solvent: ClCCl
Solvent: O
Product: O=C(NCCc1cccc(Br)c1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromophenethylamine (10.0 g, 50 mmol) in DCM (100 ml) containing TEA (8.36 g, 60 mmol, 1.2 eq.) cooled to 0° C. is added 2-chlorobenzoylchloride (8.75 g, 50 mmol, 1.0 eq.) portionwise. The resulting mixture is stirred at rt for 1 hr. Water (100 ml) is added to quench the reaction. The organic layer is collected, washed with water and brine, dried over sodium sulfate, and concentrated to give the title compound.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N+]([O-])([O-])=[O:15].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:15])[N:7]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1nccc(-c2ccccn2)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1nc(-c2ccccn2)cc[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 2-amino-4-(2-pyridyl)pyrimidine (10.10 g, 58.66 mmol) in 5% aqueous sulfuric acid (200 mL) was added sodium nitrate (20.24 g, 293.3 mmol) portionwise over 10 min. The solution was stirred at room temperature for 2 h and was then adjusted to pH 10 by addition of 6N aq. NaOH. The resulting mixture was then extracted with 30% i-PrOH in CHCl3 (10×300 mL), and the combined organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was triturated with hexanes and collected by vacuum filtration to afford 6.89 g of 4-(2-pyridyl)pyrimid-2-one (68%) as a beige solid. A mixture of 4-(2-pyridyl)pyrimid-2-one (6.89 g, 39.8 mmol) in phosphorus oxychloride (30 mL) was heated at 110° C. for 90 min in a sealed tube. The dark brown solution was then cooled to room temperature and poured over cracked ice and water (500 mL). The mixture was vigorously stirred at 0° C. for 1 h, and was then adjusted to pH 14 with 6 N aq NaOH. The mixture was extracted with CH2Cl2 (2×300 mL), and the combined organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. To a solution of the residue in CH2Cl2 (10 mL) and MeOH (30 mL) was added hydrazine monohydrate (7.0 mL, 144.2 mmol), and the solution was stirred for 16 h at which time a white precipitate was observed. This solid was collected by vacuum filtration, washed with water, and dried in vacuo to provide 2.20 g of the title compound (30%) as an off-white solid. MH+188.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH2:18]([P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH:19]=[CH2:20].C(N(CC)CC)C>>[C:2]1([C:1]2[CH2:20][CH:19]([CH2:18][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=Cc1ccccc1
Reactant: C=CCP(=O)(OCC)OCC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC1CC(c2ccccc2)=NO1)OCC

Procedure:
In analogy to Example 1, 76.7 g of an oily crude product are obtained starting from 30.3 g (0.25 mol) of benzaldoxime, 36.7 g (0.275 mol) of N-chlorosuccinimide, 49 g (0.275 mol) of diethyl allylphosphonate and 38.2 ml (0.275 mol) of triethylamine and can be purified as described in Example 1.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10](=[S:12])=[S:11]>C(O)(C)C>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:10](=[S:11])[SH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: S=C=S
Solvent: CC(C)O
Product: CCCCN(CCCC)C(=S)S
Reaction time: 1 h

Procedure:
5′-(Dibutyldithiocarbamyl)-2,5-dimercapto-1,3,4-thiadiazole (i.e., formula (I) where X is hydrogen and R1 and R2 are n-butyl radicals) was prepared in the following manner. In 100 grams of isopropyl alcohol 26 grams of dibutyl amine was combined with 16 grams of CS2 and held at a temperature of about 40° C. for about 1 hour to yield a dibutyl dithiocarbamic acid intermediate. Subsequently, 30 grams of 2,5-dimercapto-1,3,4-thiadiazole was added to the mixture along with 20 grams of 35 wt. % hydrogen peroxide. The mixture was reacted for about 1 hour at a temperature of about 28° C. to yield the liquid end product 5′-(dibutyldithiocarbamyl)-2,5-dimercapto-1,3,4-thiadiazole.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[NH2:17])C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42]Cl)=[CH:34][CH:33]=1.ClCCOCN1C2C(=NC=NC=2N)N=C1.CCO>C(Cl)Cl>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][N:15]2[C:14]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:17])[N:8]=[CH:16]2)=[CH:34][CH:33]=1
Reactant: COc1ccc(OCCOCCl)cc1
Reactant: Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Nc1ncnc2ncn(COCCCl)c12
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(OCCOCn2cnc3ncnc(N)c32)cc1
Reaction time: 10 h
Yield: 86 %

Procedure:
After 10 h, compound 13 (2.79 g, 8.86 mmol) was synthesized in 86% yield from 11 (3.90 g, 10.3 mmol) and (2-(p-methoxyphenyloxy)ethoxy)methyl chloride (2.25 g, 10.4 mmol) in CH2Cl2 (100 mL) by the method used for the synthesis of 12: mp 129-130° C.; Rf(hexanes/EtOAc=1:2) 0.21; UV (EtOH) λmax 270 (ε 15,100); 1H NMR (CD3OD) δ 3.68 (s, 3 H, OCH3), 4.04 (br s, 4 H, O(CH2)2O), 5.83 (s, 2 H, H2C1′), 6.58, 6.68 (AA′BB′, J=9.0 Hz, 4 H, C6H4), 8.29 (s, 1 H, HC2), 8.61 (s,1 H, HC8); 13C NMR (CD3OD) δ 56.03 (CH3), 68.70 (OCH2), 70.18 CH2OPh 82.27 (C1′), 119.59 (C5), 144.17 (C2), 147.57 (C8), 150.25 (C4), 151.97 (C6), 115.50, 116.35, 153.44, 155.53 (C6H4); MS m/z 315 (M+). Anal. (C15H17N5O3) C, H, N; calcd (%): 57.13, 5.43, 22.21; found (%): 57.24, 5.49, 22.34.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@H:19]([C@@H:28]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:29])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][O:11][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C@H:9]([C@@H:19]([C@@H:28]([CH2:30][O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[OH:29])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: OC[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 54.8 %

Procedure:
A solution of 240 (6.50 g, 12.1 mmol) in THF (60 mL) containing p-nitrobenzoic acid (4.06 g, 24.2 mmol) and triphenylphosphine (6.36 g, 24.2 mmol) was cooled to 0° C. A solution of diisopropylazodicarboxylate (4.8 mL, 24.2 mmol) in THF (30 mL) was added to the mixture over 2 h. After stirring for 20 h at ambient temperature, the reaction mixture was concentrated and then partitioned between Et2O (200 mL) and H2O (100 mL). The organic phase was washed with saturated aqueous NaHCO3 (3×50 mL), followed by brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was dissolved in MeOH (50 mL) and 1N NaOMe/MeOH (1.0 mL) was added. The mixture was stirred at room temperature for 1 h and concentrated. The residue was partitioned between Et2O (150 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was re-dissolved in THF (50 mL) and a solution of tetrabutylammonium fluoride (1M in THF, 13.0 mL, 13.0 mmol) was added. The mixture was stirred at room temperature for 1.5 h and partitioned between Et2O (150 mL) and H2O (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by flash chromatography (hexanes:EtOAc, 4:1→1:1) to give a colorless oil 242 (2.80 g, 57%). See Ref. 100 for experimental data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:5][CH:4]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:17][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCCBr)cc1
Reactant: CC(C)N
Product: COc1ccc(CCCCNC(C)C)cc1
Temperature: 100 °C

Procedure:
A solution of (50 ml) isopropylamine and 4-(4-methoxyphenyl)butyl bromide (13.7 g) in a glass lined vessel was heated under nitrogen (initial pressure, 500 psi) for 12 hours at 100° C. The solvent was removed in vacuo and water (200 ml) was added to the residue. The solution was acidified with concentrated hydrochloric acid and the solution was extracted with ether. The extract was dried over potassium carbonate and the solvent was removed in vacuo. The residue, 4-(4-methoxyphenyl)-N-(1-methylethyl)butylamine, weighed 9.3 g (75%). The identity and purity (94.8%) of the product was determined by mass spectrum and gas chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([OH:21])[CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][C:8](=[O:35])[NH:7]1.[CH3:40][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[CH:22]([N:12]1[C@@H:11]([C@H:10]2[O:9][C:8](=[O:35])[NH:7][C@H:6]2[CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:38]=[C:37]([F:39])[CH:36]=2)[CH2:20][C:19]2[C:14](=[C:15]([O:21][CH3:40])[CH:16]=[CH:17][CH:18]=2)[CH2:13]1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2Cc3cccc(O)c3CN2C(c2ccccc2)c2ccccc2)O1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 60 mg (0.11 mmol) portion of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-2-benzhydryl-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one from Step F (14) was dissolved in 2.5 mL of a 4:1 solution of diethyl ether and methanol. A 0.5 mL portion of 2M trimethylsilyldiazomethane was added and the solution was stirred at rt for 16 h. The excess diazomethane was quenched with the addition of several drops of acetic acid and the solvents were removed in vacuo to provide the desired product. 1H NMR (500 MHz, CDCl3) δ ppm 2.45-2.59 (m, 1H) 3.16-3.22 (m, 1H) 3.25 (dd, J=10.07, 5.49 Hz, 1H) 3.67 (s, 3H) 3.76 (s, 1H) 3.80 (d, J=2.14 Hz, 1H) 3.83 (d, J=2.44 Hz, 1H) 3.97-4.03 (m, 1H) 4.08 (d, J=18.62 Hz, 1H) 4.70 (dd, J=10.22, 6.56 Hz, 1H) 4.85 (s, 1H) 4.92 (s, 1H) 6.66 (d, J=7.93 Hz, 1H) 6.78 (d, J=7.63 Hz, 3H) 7.14-7.19 (m, 1H) 7.20-7.29 (m, 5H) 7.32 (t, J=7.63 Hz, 2H) 7.35 (d, J=7.02 Hz, 2H) 7.42 (d, J=7.32 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxybenzaldehyde (10.0 g, 81.8 mmol), 1-bromooctane (15.8 g, 81.8 mmol), and K2CO3 (34.0 g, 0.25 mol) in DMF (150 mL) was heated to reflux for 8 hours and then cooled to room temperature. The reaction mixture was subsequently diluted in toluene. The organic layer was washed with HCl (10%), brine, and water. The solvent was concentrated in vacuo and the oil was purified by short silica gel plug (dichloromethane (DCM) in n-hexanes, 10%). Solvent was dried in vacuo to afford the product 4-octyloxy benzaldehyde as a slightly colored oil.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].[CH3:13][N:14]1CCNC[CH2:15]1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:13][N:14]([CH3:15])[C:5]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CN1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN(C)C1=NS(=O)(=O)c2ccccc21
Reaction time: 8 h

Procedure:
10.0 g (54.6 mM) Saccharin and 10.9 g (109.2 mM) N-methylpiperazine are refluxed in 50 ml of hexamethylphosphoramide for 6.5 hours, and the reaction mixture is allowed to stand overnight at room temperature. The resulting precipitate is filtered off, washed with 100 ml toluene, to yield N,N-dimethyl-1,2-benzisothiazole-3-amine 1,1-dioxide. After standing for a day the combined filtrate and toluene washings yield the crystalline product which is filtered off, washed with toluene, and recrystallized from toluene. The resulting free base (3-(4-methyl-1-piperazinyl)-1,2-benzoisothiazole, 1,1-dioxide) is taken up in hot ethyl acetate and shaken with 10% aqueous HCl. The precipitated salt is filtered from the two phases, washed with ethyl acetate, and dried at 80°/vacuum to give 3.9 g of the title compound, m.p. 323°-324°.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:19]=[CH:20][C:21]([C:24]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1cc2c(s1)CCCCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCCCc2sccc21

Procedure:
As described for Example 1, a solution of 2 mmol of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine, 5 mmol of triethylamine and 2.1 mmol of [1,1'-biphenyl]-4-carbonyl chloride in 10 ml of CH2Cl2 is stirred at room temperature for 16 hours to give the product as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:16]([C:10]1[C:11](=[O:15])[NH:12][C:13]([CH3:14])=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:4][CH:5]=2)[CH:9]=1)[CH3:17]
Reactant: CCc1cc(-c2ccc(CN)o2)c(C)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Product: CCc1cc(-c2ccc(CNC(=O)c3ccccc3)o2)c(C)[nH]c1=O

Procedure:
Example 269 is substantially repeated except for utilizing 5-(5-aminomethylfuran-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one and benzoyl chloride to afford the title compound. MS: m/e=337 (M+H).