Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.Cl.[F:11][C:12]1([F:16])[CH2:15][NH:14][CH2:13]1.C(N(C(C)C)C(C)C)C.FC(F)(F)C(O)=O.CN([CH:36]=[C:37]([N:43]1[CH:47]=[C:46]([C:48]#[N:49])[N:45]=[CH:44]1)[C:38](OCC)=[O:39])C>O>[F:11][C:12]1([F:16])[CH:15]([C:2]2[N:3]=[CH:4][N:5]=[C:6]([N:8]3[C:38](=[O:39])[C:37]([N:43]4[CH:47]=[C:46]([C:48]#[N:49])[N:45]=[CH:44]4)=[CH:36][NH:9]3)[CH:7]=2)[NH:14][CH2:13]1
Reactant: FC1(F)CNC1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Reactant: NNc1cc(Cl)ncn1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1cn(-c2c[nH]n(-c3cc(C4NCC4(F)F)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 120 mg (0.8 mmol) of the compound from Example 11A, 129 mg (1.0 mmol) of 3,3-difluoroazetidine hydrochloride and 174 μl (129 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred at 100° C. for 16 h. Following the addition of 32 μl (47 mg, 0.4 mmol) of trifluoroacetic acid and 194 mg (0.8 mmol) of the compound from Example 6A, the reaction mixture is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 32 mg (11% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[N:3]=1.[CH2:15]([O:22][C:23]1[C:28]([CH2:29][CH3:30])=[CH:27][C:26](B(O)O)=[C:25]([O:34][CH3:35])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([O:22][C:23]1[C:28]([CH2:29][CH3:30])=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]3[CH3:14])[N:3]=2)=[C:25]([O:34][CH3:35])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(C)n1-c1cccc(Br)n1
Reactant: CCc1cc(B(O)O)c(OC)cc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cc(-c2cccc(-n3c(C)ccc3C)n2)c(OC)cc1OCc1ccccc1
Yield: 73.1 %

Procedure:
Under a nitrogen atmosphere, 5.00 g (19.91 mmol) of 2-bromo-6-(2,5-dimethylpyrrol-1-yl)pyridine, 5.98 g (20.91 mmol) of 4-benzyloxy-5-ethyl-2-methoxy-phenylboronic acid (5), 8.44 g (79.64 mmol) of sodium carbonate and 1.15 g (0.996 mmol) of tetrakis(triphenylphosphine)palladium(0) were combined in 90 mL of ethanol and 10 mL of water. The solution was allowed to reflux for 64 hours, and then the reaction mixture was concentrated in vacuo. The resultant yellow residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted again with ethyl acetate (200 mL). The combined organic extracts were washed with brine (1×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield crude product as a yellow oil which crystallized upon standing. Recrystallization of this solid from absolute ethanol afforded 6.00 g (73%) of 2-(4-benzyloxy-5-ethyl-2-methoxy-phenyl)-6-(2,5-dimethyl-pyrrol-1-yl)-pyridine (6) as a tan solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][Si:6]([O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[O:7][Si:8]([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30].O>C(OCC)C>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][Si:6]([O:7][Si:8]([CH3:9])([CH3:10])[CH3:11])([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[O:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[C:28](=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: C=C(C)C(=O)Cl
Reactant: CNCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)C(=O)N(C)CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
In 200 ml of ethyl ether was dissolved 32.6 g of the N-methyl-3-[tris(trimethylsiloxy)silyl]propylamine obtained above, and the solution was added with 11 g of pyridine. The mixture was cooled in ice bath to 0°-5° C. Separately, 14.5 g of methacryloyl chloride was dissolved in 45 ml of ethyl ether. The methacryloyl chloride solution was placed in a separating funnel and dropped therefrom to the above mixture over about one hour. The mixture was continuously stirred for 16 hours. After the stirring, 200 ml of water was added to the reaction mixture, and the resulting mixture was stirred and then supernatant was separated. The supernatant was combined with the extract from the bottom layer with ethyl ether, and then ethyl ether was removed by heating. The residue was distilled in vacuo to give 33.0 g of a distillate at 155° C./3 mmHg.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:34])[N:9]([C@@H:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:10]2=[O:15])=[O:4].[CH3:35][NH:36][CH3:37].O1CCCC1>C(#N)C.C(OCC)(=O)C>[CH3:35][N:36]([CH3:37])[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:34])[N:9]([C@@H:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:10]2=[O:15])=[O:4]
Reactant: CNC
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2C(=O)c3cccc(NC(=O)CN(C)C)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of (3R)-3-[4-(2-chloroacetylamino)-1,3-dioxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide (8.10 g, 16.6 mmol) and dimethylamine in tetrahydrofuran (27 mL, 2N, 54 mmol) in acetonitrile (150 mL) was stirred at room temperature overnight. The solvent was removed in vacuo to give an oil. The oil was dissolved in ethyl acetate (150 mL), washed with sodium hydrogen carbonate (2×50 mL, sat), brine (50 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was purified by column chromatography (Silica Gel, 1.5% methanol in methylene chloride) to give (3R)-3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide as a white solid (6.3 g, 76% yield). To the solid in ethyl acetate (40 mL) was added hydrogen chloride in ether (20 mL, 1N). The suspension was filtered and washed with ether to give (3R)-3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide hydrogen chloride as a yellow solid (6.4 g, 72% yield); mp, 122-124° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=7 Hz, 3H, CH3), 2.75 (s, 3H, CH3), 2.89 (s, 6H, 2CH3), 2.98 (s, 3H, CH3), 3.22 (dd, J=5.4, 16.5 Hz, 1H, CHH), 3.60 (dd, J=9.2, 16.5 Hz, 1H, CHH), 3.71 (s, 3H, CH3), 3.97 (q, J=7 Hz, 2H, CH2), 4.30 (s, 2H, CH2), 5.62 (dd, J=5.6, 8.7 Hz, 1H, NCH), 6.86-6.93 (m, 2H, Ar), 7.00 (s, 1H, Ar), 7.65 (t, J=7.1 Hz, 1H, Ar), 7.84 (t, J=7.5 Hz, 1H, Ar), 8.17 (d, J=7.9 Hz, 1H, Ar), 10.49 (s, 1H, ClH), 10.64 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.72, 34.41, 34.81, 36.59, 43.21, 50.43, 55.53, 57.77, 63.78, 111.79, 112.38, 119.32, 119.45, 119.58, 127.97, 131.90, 131.95, 134.12, 135.77, 147.76, 148.47, 164.28, 167.24, 167.33, 169.15; Anal Calcd for C26H32N4O6+HCl+1.1H2O: C, 56.49; H, 6.42; N, 10.13; Cl, 6.41; H2O, 3.58. Found: C, 56.33; H, 6.61; N, 9.95; H2O, 3.51.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16]C2C3C(=C(Br)C=CC=3)C=CC=2OC)[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)N[C@@H]1C(=O)NC2C=CC=CC=2NC1)(C)(C)C.BrC[C:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:59]([C:66]2[CH:73]=[CH:72][CH:71]=[CH:70][C:67]=2[C:68]#[N:69])[N:58]=1>>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:57]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]([C:66]3[CH:73]=[CH:72][CH:71]=[CH:70][C:67]=3[C:68]#[N:69])[N:58]=2)[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Agent: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O
Yield: 72.9 %

Procedure:
In a similar manner to that described for the preparation of [(S)-1-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester (Intermediate 5), ((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (Intermediate 2)(500 mg, 1.8 mmol) and 2-(3-bromomethyl-indazol-1-yl)-benzonitrile (Intermediate 1) (676.18 mg, 2.16 mmol) were converted to the title compound (670 mg, 72.9%) which was obtained as light yellow solid. LC-MS: 509 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16](=[O:17])[C:15](=[O:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[C:13]2([CH3:31])[CH3:30])=[CH:7][CH:6]=1)=[O:4]>C(O)CCC.[Ti].CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:29]([O:28][C:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:14]2[C:15](=[O:18])[C:16](=[O:17])[N:12]([CH2:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH2:1][CH2:7][CH2:8][CH3:9])=[O:4])=[CH:6][CH:7]=3)[C:13]2([CH3:31])[CH3:30])=[CH:21][CH:22]=1)=[O:27])[CH2:3][CH2:5][CH3:6]
Reactant: COC(=O)c1ccc(CN2C(=O)C(=O)N(Cc3ccc(C(=O)OC)cc3)C2(C)C)cc1
Agent: [Ti+4]
Agent: [Ti]
Agent: CC(C)[O-]
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc(CN2C(=O)C(=O)N(Cc3ccc(C(=O)OCCCC)cc3)C2(C)C)cc1
Yield: 140 %

Procedure:
5 g (0.0118 mole) of 1,3-bis-(4'-methoxycarbonylphenylmethyl)-2,2-dimethylimidazolidine-4,5-dione, with the addition of 0.01% of titanium as titanium tetraisopropylate, are refluxed for 2 hours in n-butanol. The methanol which forms is distilled off continuously. The colourless crystals which precipitate after the reaction mixture has cooled are collected by suction filtration and recrystallised from n-butanol to yield 4.2 g of colourless crystals with a melting point of 111°-112° C. The IR and NMR spectra confirm the presumed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-])=[O:2].[CH3:13]S(C)=O.[H][H].C(N(CC)C1C=CC(C=O)=CC=1)C>[Pt].CO.C(O)(=O)C>[C:8]([C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:2])=[CH2:13])=[CH:5][CH:6]=1)([OH:10])=[O:9]
Reactant: [H][H]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CS(C)=O
Agent: [Pt]
Agent: CCN(CC)c1ccc(C=O)cc1
Solvent: CO
Solvent: CC(=O)O
Product: C=[N+]([O-])c1ccc(C(=O)O)cc1
Reaction time: 5 h

Procedure:
122.2 g (731 mmols) of p-nitrobenzoic acid, 11.3 g of dimethylsulfoxide, 2.0 g of a 5% platinum-supported catalyst, and 260 g of methanol were charged into a one liter autoclave, followed by filling hydrogen at a pressure of about 4 kg/cm2 and continuing agitation at room temperature until an equivalent of hydrogen was reacted with p-nitrobenzoic acid. After removal of the catalyst, 120.0 g (677 mmols) of 4-diethylaminobenzaldehyde, 30.0 g of acetic acid and 100 g of methanol were added to the resultant residue, followed by agitation at room temperature for 5 hours. After removal of the resultant crystals by filtration, they were washed with methanol to obtain yellow crystals and dried to isolate 187.6 g (yield 88.7%) of α-p-(diethylamino)phenyl]-N-(4-carboxyphenyl)nitrone with a purity of 96%. The thus obtained α-[p-(diethylamino)-phenyl]-N-(4-carboxyphenyl)nitrone had the following results with respect to mass spectra (MS), NMR spectra (NMR), IR spectra (IR) and elementary analysis.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:14]([C:15]2(O)[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1>[Pd].CO>[C:21]1([CH:18]2[CH2:17][CH2:16][CH:15]([C:14]3[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=3)[CH2:20][CH2:19]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ncccc1C1CCC(c2ccccc2)CC1
Temperature: 40 °C
Reaction time: 6 h
Yield: 16.7 %

Procedure:
TFA (3 mL) was added to 1-(2-aminopyridin-3-yl)-4-phenylcyclohexanol (246 mg) and the mixture was stirred at 40° C. under nitrogen for 6 hr. TFA was removed in vacuo and this product was subjected to the next reaction without further purification. MeOH (1 mL) and Pd/C (10 mg) were added and the mixture was stirred at room temperature under hydrogen for 2 days. The insoluble solid was removed by filtration through Celite-pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (38.6 mg) as colorless oil.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[N:8][CH:9]=[C:4]2[N:3]=[CH:2]1.C(O[C@@H:19]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@:20]1([CH3:52])[O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.[Si]([O:68]S(C(F)(F)F)(=O)=O)(C)(C)C.[Na]>C(#N)C>[CH3:52][C@@:20]1([O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:41][C@H:19]1[N:1]1[C:5]2=[CH:6][N:7]=[N:8][C:9](=[O:68])[C:4]2=[N:3][CH2:2]1
Reactant: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: c1nc2cnncc2[nH]1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1N1CN=C2C(=O)N=NC=C21
Temperature: 80 °C
Yield: 16.5 %

Procedure:
To a suspension of imidazo[4,5-d]pyridazine (3.48 g, 25.5 mmol) [for preparation see Journal of Heterocyclic Chemistry, 1969, Vol 6, 93] in dry acetonitrile (35 mL) was added 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (14.48 g, 25.0 mmol) at 20° C. and stirred for 15 mn. DBU (11.5 mL, 76.3 mmol) was added at 0° C. and the solution was stirred for 15 nm at 0° C. TMSOTf (24.7 mL, 127.8 mmol) was added at 0° C. and the mixture was heated at 80° C. for 20 hours. The reaction mixture was poured into an aqueous solution of sodium hydrogenocarbonate and extracted by ethyl acetate. The organic layer was evaporated to dryness to give a yellow powder. The crude product was purified on silica gel using dichloromethane/methanol (99.3/0.7) as eluant to give a slight yellow powder which was crystallized from isopropanol to give the title compound (2.45 g) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[I:14]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[I:14]
Reactant: II
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc(N)c(I)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 165.9 %

Procedure:
To a stirred solution of 4-amino-N,N-dimethylbenzenesulfonamide (3.0 g, 14.98 mmol) in EtOH (165 mL) at 50° C. was added a slurry of iodine (1.3 g, 4.99 mmol) and silver sulfate (2.8 g, 9.00 mmol) in EtOH (40 mL). The same addition was repeated after 1 h of stirring at 50° C., then the reaction mixture was stirred at 50° C. for 16 h. Iodine (0.76 g, 3.00 mmol) was again added, and the mixture stirred at 50° C. for 2 h before being filtered through Celite®. The filtrate was concentrated in vacuo, and EtOH (70 mL) was added. The suspension was stirred at 50° C. for 1 h, cooled to r.t., then filtered to give the title compound (2.7 g, 55%) as a brown solid that was used without further purification. δH (DMSO-d6) 7.81 (1H, d, J 2.1 Hz), 7.42 (1H, dd, J 8.6 and 2.1 Hz), 6.83 (1H, d, J 8.6 Hz), 6.12 (2H, br. s), 2.58 (6H, s). LCMS (ES+) 326.9 (M+H)+, RT 2.50 minutes (Method 3).
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:13][O:14][CH3:15])[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1.CC(C)=O.O.CC1C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][O:2][C:3]1([CH2:13][O:14][CH3:15])[CH2:4][CH2:5][C:6](=[O:7])[CH2:11][CH2:12]1
Reactant: COCC1(OC)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COCC1(OC)CCC(=O)CC1

Procedure:
A mixture comprising 217 g (1.00 mol) 8-methoxy-8-(methoxymethyl)-1,4-dioxaspiro[4.5]decane (prepared according to intermediate example 16e), 1.7 L acetone, 0.86 L water and 30.5 g 4-methylbenzenesulfonic acid hydrate was stirred at 23° C. overnight. The acetone was removed, 0.5 L saturated aqueous sodium hydrogencarbonate added followed by 0.4 L brine. The mixture was extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. After filtration and removal of the solvent 180 g (max. 100%) of the title compound were obtained that was used without further purification.
Reaction SMILES: C(C1OC1)Cl.C(C(CCCCC)CO)CC.Cl[CH2:18][CH:19]([OH:32])[CH2:20][O:21][CH2:22][CH:23]([CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CC(C)([O-])C.[K+]>O1CCCC1>[CH2:20]([O:21][CH2:22][CH:23]([CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:19]1[O:32][CH2:18]1
Reactant: CCCCCC(CCC)COCC(O)CCl
Agent: CC(C)(C)[O-]
Agent: CCCCCC(CO)CCC
Agent: [K+]
Solvent: ClCC1CO1
Solvent: C1CCOC1
Product: CCCCCC(CCC)COCC1CO1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a flame dried, 500 mL round bottomed flask equipped with an addition funnel charged with epichlorohydrin (15.62 gm., 0.17 moles), is added 2-propylheptanol (Pfaltz & Bauer, Inc., 172 E. Aurora Street, Waterbury Conn., 06708, USA) (20 gm., 0.127 moles) and stannic chloride (0.20 gm., 0.001 moles). The reaction is kept under an argon atmosphere and warmed to 90° C. using an oil bath. Epichlorohydrin is dripped into the stirring solution over 60 minutes followed by stirring at 90° C. for 18 hours. The reaction is fitted with a vacuum distillation head and 1-chloro-3-(2-propyl-heptyloxy)-propan-2-ol is distilled at a temperature range of 90° C.→95° C. under 0.2 mm Hg. Wt.=22.1 gm. The 1-chloro-3-(2-propyl-heptyloxy)-propan-2-ol (5.0 gm., 0.020 moles) is dissolved in tetrahydrofuran (50 mL) and stirred at RT under an argon atmosphere. To the stirring solution is added potassium tert-butoxide (2.52 gm., 0.022 moles) and the suspension is stirred at RT for 18 hours. The reaction is then evaporated to dryness, residue dissolved in hexanes and washed with water (100 mL). The hexanes phase is separated, dried with Na2SO4, filtered and evaporated to dryness to yield the crude 2-propylheptyl glycidyl ether, which can be further purified by vacuum distillation.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.I[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38]S(C)(=O)=O>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[OH:38])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:29])[CH2:17]1
Reactant: CS(=O)(=O)Oc1ccccc1CI
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: O=C1CN(c2ccc(Cc3ccccc3O)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and methanesulfonic acid 2-iodomethylphenyl ester analogous to Example 306, steps C-F: (M−1)−=333. HPLC retention time=1.04 min (Method A).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19]O)[O:7][CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>N1C=CC=CC=1>[Cl:41][CH2:19][C@H:8]1[O:7][CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]1[O:15][C:16](=[O:18])[CH3:17]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO)OC[C@@H]1OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CCl)OC[C@@H]1OC(C)=O
Yield: 59 %

Procedure:
895 mg (3.08 mmol) of 1,5-anhydro-2,3,4-tri-O-acetyl-D-glucitol was dissolved in 30 ml of pyridine, and 1.95 g (7.4 mmol) of triphenylphosphine and 10 ml of carbon tetrachloride were added. The mixture was allowed to react at 45° to 50° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure and the residue extracted with chloroform (80 ml). The chloroform layer was washed with 1N aqueous hydrochloric acid solution (80 ml) and water (80 ml), dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (Waggle C-200, 40 g) and eluted with chloroform-methanol (300:1). The eluate was crystallized from ethyl acetate-hexane to obtain 562 mg (1.82 mmol, 59%) of 1,5-anhydro-6-chloro-6-deoxy-2,3,4-tri-O-acetyl-D-glucitol as a colorless needle crystal. Shown below are physicochemical properties of the crystalline compound thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[S:20][C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH:10]=1.C(OO)(=[O:31])C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[S:20](=[O:31])[C:19]([CH3:27])([CH3:26])[C:18]2=[O:28])[CH:10]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)SC(C)(C)C1=O
Reactant: CC(=O)OO
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)S(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.1 %

Procedure:
A mixture of 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylthiopyran-3,5-dione (79 mg, 0.1816 mmol), peracetic acid (1.8 g, 7.2 mmol, 36-40% solution in acetic acid) and dichloromethane (0.23 ml) is stirred for 4 hours at ambient temperature. The reaction mixture is partitioned between water and dichloromethane, and the organic phase is separated then concentrated under reduced pressure. The residue is purified by preparative reverse phase HPLC to give 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethyl-1-oxothiopyran-3,5-dione (32.9 mg) as a clear gum.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[C:3]1=[O:28].[C:29]1([CH3:38])[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>O1CCCC1>[O:28]=[C:3]1[CH:2]([NH:1][C:36]([NH:35][C:31]2[CH:30]=[C:29]([CH3:38])[CH:34]=[CH:33][CH:32]=2)=[O:37])[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccccc2)C1=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(CC(=O)c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a mixture of 0.74 g 3-amino-1,3-dihydro-1-phenacyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 5 ml tetrahydrofuran, was added a solution of 0.27 g 3-tolyl isocyanate in 3 ml tetrahydrofuran, and the resulting mixture was stirred at room temperature for four hours. The solvent was distilled off from the reaction mixture, and the residue was recrystallized from a mixture of toluene and n-hexane, thus giving 0.78 g of 1-[2,3-dihydro-2-oxo-1-phenacyl-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea.