Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]OC(=O)CC(C)=O.[CH2:9]([OH:13])[CH2:10][CH2:11][CH3:12].C(OCCCC)(=O)CC(C)=O.[C:25]1([CH3:31])[CH:30]=CC=[CH:27][CH:26]=1>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>[CH3:30][C:25]1([CH3:31])[CH:11]2[C:10]3([CH3:1])[O:13][CH:9]3[CH2:27][CH:26]1[CH2:12]2
Reactant: Cc1ccccc1
Reactant: CCCCO
Reactant: COC(=O)CC(C)=O
Agent: [Fe+2]
Agent: CCCCOC(=O)CC(C)=O
Agent: c1cc[cH-]c1
Product: CC1(C)C2CC3OC3(C)C1C2
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
2.1 mL of methylacetoacetate (20 mmol) and 1.8 mL of n-butanol (20 mmol) were added into 20 mL of toluene and stirred at 30° C. and 400 rpm for 15 minutes. 155 mg of the catalyst (FerlipaseCB(7) polymer beads) prepared in (2) was added into the mixture to initiate reaction. A clear liquid sample was periodically sampled and analyzed using gas chromatography to identify n-butyl acetoacetate, which was the reaction product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][C:4]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+]>C(O)C>[C:23]([CH2:22][CH2:21][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[C:6]([CH:5]=1)[C:11](=[N:27][OH:28])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([OH:25])=[O:24]
Reactant: NO
Reactant: COc1ccc(C(=O)c2cc(CCC(=O)O)c(OC)cc2OC)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=NO)c2cc(CCC(=O)O)c(OC)cc2OC)cc1

Procedure:
37 g of 3-[2,4-dimethoxy-5-(4-methoxybenzoyl)phenyl]propionic acid, 22.4 g of hydroxylamine hydrochloride and 21 g of sodium acetate (anhydrous) are added to 300 ml of absolute ethanol, and the mixture is refluxed with exclusion of moisture for 24 hours. Insolubles are removed by suction, the filtrate is concentrated, and water is added to the residue. The pH is then adjusted to 2 with 1N hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The residue is recrystallized from ethyl acetate/hexane.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37]>C1COCC1.CCOC(C)=O>[OH:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][OH:40])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: OCCNCCO
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N(CCO)CCO)c3)n2)n1
Yield: 50 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.210 g, 0.429 mmol) by treatment with excess diethanolamine in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.120 g, 50%) as a white solid. MS (ISP) 557.6 [(M+H)+]; mp 176° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C:7]([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH2:20])[CH2:14]2)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[C:7]([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][C:22](=[O:24])[CH3:23])[CH2:14]2)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc2c(c1)CC(N)C2
Solvent: ClCCl
Product: CC(=O)NC1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 70.6 %

Procedure:
To 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester (14.6 g; 47.4 mmol), dissolved in CH2Cl2 (100 mL), is added TEA (8.6 mL; 61.7 mmol) and the reaction mixture is cooled to 0° C. Acetyl chloride (4.1 mL; 57.6 mmol) is added dropwise at a rate to maintain the temperature between 0-5° C. The reaction was allowed to warm to RT, stirred for 16 h, diluted with CH2Cl2, washed with H2O, dried over Na2SO4 and evaporated under reduced pressure. The crude oil was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 11.7 g (71%) of 2-(2-acetylaminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester as a beige solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:18]1([CH:25]=[CH:24][C:22]([OH:23])=[CH:21][CH:20]=1)[OH:19]>CN(C=O)C>[OH:19][C:18]1[CH:25]=[CH:24][C:22]([O:23][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[CH:21][CH:20]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=C(CCl)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COc1ccc(O)cc1)Nc1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 31 %

Procedure:
A mixture of compound 1a (338 mg, 2 mmol), K2CO3 (553 mg, 4 mmol), and KI (66 mg, 0.4 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (440 mg, 4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography on silica gel to provide the compound (150 mg, 0.62 mmol, 31% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.32 (br s, 1H), 7.60 (d, J=7.6 Hz, 2H), 7.38 (t, J=7.8 Hz, 2H), 7.18 (t, J=7.4 Hz, 1H), 6.90 (d, J=9.2 Hz, 2H), 6.84 (d, J=9.2 Hz, 2H), 5.07 (br s, 1H), 4.58 (s, 2H).
Reaction SMILES: I[CH3:2].[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[C:5]=1[N+:15]([O-:17])=[O:16].[H-].[Na+]>O1CCCC1>[CH3:14][C:6]1[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([NH:3][CH3:2])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CI
Reactant: COC(=O)c1ccc(N)c([N+](=O)[O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)OC)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
Iodomethane (125 uL, 2.0 mmol) was added to a mixture of the methyl 4-amino-2-methyl-3-nitrobenzoate (400 mg, 1.9 mmol) and sodium hydride (60% oil dispersion, 84 mg, 2.1 mmol) in tetrahydrofuran (10 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extract was washed with water (2×30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated, then purified by flash chromatography (25% ethyl acetate in hexanes) to give methyl 2-methyl-4-(methylamino)-3-nitrobenzoate (308 mg, 72% yield). 1H NMR (400 MHz, CDCl3): 7.94 (d, 1H), 6.63 (d, 1H), 5.68 (br, 1H), 3.86 (d, 2H), 2.58 (s, 3H); MS (EI) for C10H12N2O4: 225 (MH+).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[F:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[F:12][CH:13]1[CH2:18][CH2:17][N:16]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:14]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: FC1CCNCC1
Agent: Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(F)CC1
Yield: 99 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 4-fluoropiperidine hydrochloride gave 4-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a white solid (280 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 4.86 (dtt, J=47.9, 7.1, 3.6 Hz, 1H), 3.77 (s, 3H), 3.37 (d, J=9.4 Hz, 2H), 3.20-3.12 (m, 2H), 2.16-2.06 (m, 1H), 2.07-1.92 (m, 3H)
Reaction SMILES: C([O:9][C@@H:10]([CH3:36])[C@@H:11]([C:32]([O:34][CH3:35])=[O:33])[NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C1C=CC=CC=1.C[O-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:13]([NH:12][C@H:11]([C:32]([O:34][CH3:35])=[O:33])[C@H:10]([CH3:36])[OH:9])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C)OC(=O)c1ccccc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C)O
Reaction time: 48 h
Yield: 61.7 %

Procedure:
A solution of the methyl O-benzoyl-N-trityl-L-allothreoninate (1.24 g, 2.59 mmol) dissolved in 15 mL of anhydrous methanol was treated with 0.1 mL of a 25% solution of sodium methoxide in methanol. The reaction mixture was stirred under N2 for 2 days. The reaction was then treated with 10 mL of saturated aqueous NaHCO3 solution and the methanol was removed under reduced pressure. The reaction mixture was then treated with 30 mL of ethyl acetate and washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give a colorless solid. Crystallization from ethyl acetate and hexanes gave methyl N-trityl-L-allothreoninate (0.60 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:24](=[O:25])[N:23]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22]COCC4)=[CH:13][N:12]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:31].C([Sn](CCCC)(CCCC)[C:37]([O:39][CH2:40][CH3:41])=[CH2:38])CCC.[C:50]1(C)[CH:55]=CC=[CH:52][CH:51]=1>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>[CH:26]1([N:23]2[C:5]3[N:6]=[C:7]([NH:10][C:11]4[N:12]=[CH:13][C:14]([N:17]5[CH2:22][CH2:52][CH2:51][CH2:50][CH2:55]5)=[CH:15][CH:16]=4)[N:8]=[CH:9][C:4]=3[C:3]([CH3:31])=[C:2]([C:37]([O:39][CH2:40][CH3:41])=[CH2:38])[C:24]2=[O:25])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1ccccc1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCOCC4)cn3)ncc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCCCC4)cn3)nc2n(C2CCCC2)c1=O
Yield: 59.2 %

Procedure:
6-Bromo-8-cyclopentyl-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.310 g, 0.641 mmol), tetrakis(triphenylphosphine)palladium (0.089 g, 0.077 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (0.361 g, 1.0 mmol) were dissolved in toluene (3 mL) and slowly brought to reflux for 2 hours. The reaction mixture was allowed to cool, then purified by silica gel chromatography to give 8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.180 mg, 59.2%). 1H NMR δvvv (400 MHz, CDCl3) 8.73 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J=2.9 Hz, 1H), 7.36 (dd, J=2.9, 9.3 Hz, 1H), 5.90 (m, 1H), 4.52 (d, J=2.4 Hz, 1H), 4.18 (d, J=2.2 Hz, 1H), 3.93 (q, J=7.1 Hz,2H), 3.14 (m, 4H), 2.41 (s, 3H), 2.36 (m, 2H), 2.06 (m, 2H), 1.84 (m, 2H), 1.56-1.77 (m, 8H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[N:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[N:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cnnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nncc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 82.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-1,2,3-triazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (270 mg, 0.450 mmol) prepared in Example 92b, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (168 mg, 83%) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([O:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])(=[O:26])[CH3:25]
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\COC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.5 g (0.0021 mol) of (6E,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one dissolved in 5 ml of methylene chloride and 1.3 ml of pyridine is treated with 1 ml of acetic anhydride. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is taken up three times in toluene and freed from the solvent on a rotary evaporator. The residue is chromatographed on silica gel with ether-hexane 1:5. There is obtained (2Z,6E)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienyl acetate which has the following bands in the IR spectrum: 1735 cm-1, 1677 cm-1, 1630 cm-1, 1448 cm-1, 1368 cm-1, 950 cm-1.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=2)O1>>[CH:20]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:33]5[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnc(N)nc4)cc2OCC3)n(C(C)C)n1

Procedure:
8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine to give 257. MS (ESI+) 403.2
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1(Cl)[CH2:9][CH2:8][CH2:7][C:6]([Cl:11])([Cl:10])[CH:5]1O.C([O:16]CC)C>O>[Cl:3][C:4]12[O:16][CH:9]1[CH2:8][CH2:7][C:6]([Cl:11])([Cl:10])[CH2:5]2
Reactant: OC1C(Cl)(Cl)CCCC1(Cl)Cl
Reactant: CCOCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClC1(Cl)CCC2OC2(Cl)C1
Reaction time: 0.25 h

Procedure:
7 g (175 mmol) of sodium hydroxide pellets were added in three portions at 10°-15° C. to 15.2 g (63.88 mmol) of 2,2,6,6-tetrachlorocyclohexanol 1a in suspension in 70 cm3 of distilled water. The reaction mixture was kept at room temperature for 1 h 15 min, 20 cm3 of ethyl ether were then added, stirring was continued for 5 min and then the phases were separated and the aqueous phase was extracted with ether (6×50 cm3). The ether phases were combined, dried over MgSO4, filtered, and the mixture was concentrated with a rotary evaporator. A liquid epoxide 2a (m=12.42 g) was obtained, representing 96.5% of the theoretical yield. The compound 2a will be frequently employed without further purification in the following stages (semicapillary GC purity>96%). The epoxide 2a can be purified by distillation at reduced pressure (boiling at 40° C. at 0.1 mm Hg); after distillation, the yield of compound 2a was 92%.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])/[C:6](/[NH:15][C:16](=[O:35])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([OH:33])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:19][C:18]=1[Cl:34])=[CH:7]/[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[CH3:14]>CO.O1CCCC1>[Cl:34][C:18]1[CH:19]=[C:20]([CH:23]([OH:33])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[CH:21]=[CH:22][C:17]=1[C:16]([NH:15]/[C:6](=[CH:7]\[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[CH3:14])/[C:5]([OH:36])=[O:4])=[O:35]
Reactant: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C)c(/C=C(\NC(=O)c2ccc(C(O)CCc3cccc(O)c3)cc2Cl)C(=O)O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
An aqueous 1N solution of sodium hydroxide (0.5 mL, 0.5 mmol) was added to a solution of rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (Example 229; 70 mg, 0.14 mmol) in methanol/tetrahydrofuran (1:1; 2 mL). After the solution was stirred at room temperature for 5 h and the solvents were removed under reduced pressure. Water (5 mL) was added and the mixture was filtered through Celite®. The filter pad was washed with water (2 mL) and the combined filtrates were acidified with 1N hydrochloric acid solution (0.5 mL). The mixture was stirred for 1 h, then the solids were filtered off, washed with water, dried and crystallized from tetrahydrofuran/methanol/water to give rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid (39.3 mg, 58% yield) as a colorless solid.
Reaction SMILES: [C:1]([Si:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][O:12]C1CCCCO1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[C:1]([Si:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[O:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][OH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OCC#CCCOC1CCCCO1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)(C)[Si](OCC#CCCO)(c1ccccc1)c1ccccc1
Yield: 77.9 %

Procedure:
A solution of compound 4 (6.12 g, 14.5 mmol) in MeOH (100 mL) was treated with PPTS (0.36 g, 1.43 mmol) at room temperature for overnight. After concentration, the residue was purified by silica gel column chromatography with 20% EtOAc in hexanes to give 3.84 g of product 5 (11.3 mmol, 78%); 1H NMR (CDCl3) δ 7.80˜7.66 (m, 4H), 7.49˜7.35 (m, 6H), 4.33 (t, J=1.9 Hz, 1H), 3.60 (t, J=6.0 Hz, 2H), 2.40 (tt, J=2.2, 6.1 Hz, 2H) 1.05 (s, 9H).
Reaction SMILES: [Na+].[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]([S:13]([O-:16])(=O)=[O:14])[CH:10]=[CH:9][CH:8]=2)=[CH:3]1.S(Cl)([Cl:19])=O>CN(C)C=O>[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]([S:13]([Cl:19])(=[O:16])=[O:14])[CH:10]=[CH:9][CH:8]=2)=[CH:3]1
Reactant: O=S(=O)([O-])c1cccc(-c2ccsc2)n1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1cccc(-c2ccsc2)n1
Temperature: 70 °C

Procedure:
A mixture of 6-(3-thienyl)-2-pyridinesulfonic acid sodium salt (D9) and N,N-dimethylformamide (1 drop) in thionyl chloride (2 ml) was heated at 70° C. for 2 hours. After cooling to room temperature the solution was concentrated in vacuo and the residue co-evaporated with toluene (×2). The residue was triturated with diethyl ether to afford the title product (D10).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][S:29](=[O:32])[CH2:28][CH2:27]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][S:29](=[O:32])[CH2:28][CH2:27]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCNCC1
Reactant: Clc1nc(N2CCSCC2)c2ncnc(SCc3ccccc3)c2n1
Product: O=S1CCN(c2nc(N3CCSCC3)c3ncnc(SCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-thiomorpholino-pyrimido[5,4-d]pyrimidine (melting point: 175°-177° C.) and thiomorpholine1-oxide.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[CH:7]=[C:6]1[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH3:3].[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:3][N:2]([CH2:4][CH:5]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[CH:7]=[C:6]1[C:13]1[CH:14]=[C:15]([O:19][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1)[CH3:1]
Reactant: CN(C)CC1C(c2cccc(O)c2)=CC2CCC1C2
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC1C(c2cccc(OC(=O)C(C)(C)C)c2)=CC2CCC1C2
Yield: 87.3 %

Procedure:
Stir a mixture of 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol (200 mg, 0.778 mmol), 2,2-dimethyl-propionyl chloride (111 mg, 0.927 mmol) and triethyl amine (234 mg, 2.316 mmol) in CH2Cl2 (40 mL) at ambient temperature for 12 hours. Concentrate the mixture under vacuum, and purify the residue by Preparative TLC to give 2,2-dimethyl-propionic acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester as white solid (232 mg, Yield: 87.5%). MS (m/z): 342 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.29-7.32 (t, J=15.6 Hz, 1H), 7.06-7.08 (d, J=7.6, 1H), 6.88-6.90 (d, J1=8.0, J2=1.6, 1H), 6.84-6.85 (t, J=3.6, 1H), 6.05-6.07 (d, J=6.8, 1H), 3.22-3.32 (m, 1H), 2.52-2.60 (m, 1H), 2.62-2.63 (m, 1H), 2.37-2.41 (m, 1H), 2.17 (s, 6H), 2.07-2.14 (m, 1H), 1.71-1.85 (m, 6H), 1.37 (s, 9H).
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].[C:20]1([S:26]([OH:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.C1C=CC=CC=1>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH2:9][CH:8]([S:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:28])=[O:27])[C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=S(O)c1ccccc1
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: O=C1CC(S(=O)(=O)c2ccccc2)C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Yield: 88 %

Procedure:
38 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared as in Example 1, were dissolved in 250 ml. of benzene, 15 g. of freshly generated benzene sulfinic acid were added and then a few drops of water were added. This reaction mixture was heated at 40°-45° C. for 12 hours and then the benzene was evaporated. The white solid residue obtained was recrystallized from benzene twice and yielded white crystals, m.p. 157°-158° C. The yield was about 88%.