Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:23][C:24](OC(C)=O)=[O:25]>>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH:16][C:24](=[O:25])[CH3:23])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylpyrimidine-4,5-diamine (350 mg, 1.19 mmol, 1.0 eq) and Ac2O (12 mL) was stirred at rt for 3 h and concentrated. The residue was dissolved in MeOH (3 mL). Sat. aqueous NaOH was added dropwise until pH=12 and stirred for 10 minutes. The final mixture was concentrated and purified by silica gel chromatography (hexane/EtOAc=10:1 as eluent)) to obtain target product N-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-phenylpyrimidin-5-yl)acetamide.
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[C:6](Cl)[C:5]=1[OH:13])([O-])=O.ClC1C(C)=CC(O)=CC=1.[S:23](=O)(=[O:26])([OH:25])[OH:24]>>[S:23]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[OH:13])([OH:26])(=[O:25])=[O:24]
Reactant: O=S(=O)(O)O
Reactant: Cc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl
Agent: Cc1cc(O)ccc1Cl
Product: Cc1cc(O)c(S(=O)(=O)O)cc1Cl

Procedure:
According to the present invention there is provided a process for preparing 2-nitro-4,6-dichloro-5-methylphenol comprising sulphonation of 4-chloro-5-methyl-phenol with concentrated sulphuric acid at elevated temperature to form 2-sulpho-4-chloro-5-methylphenol, thereafter diluting the reaction mixture with water to a sulphuric acid content of 20 to 30%, chlorinating the resulting 2-sulpho-4-chloro-5-methylphenol with chlorine at elevated temperature and normal or elevated pressure to form 2-sulpho-4,6-dichloro-5-methylphenol and reacting the 2-sulpho-4,6-dichloro-5-methylphenol with nitric acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=2[CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:7]=1)[CH3:2].[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:35]3[CH:36]=[CH:37][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=3)=[CH:15][C:14]=2[CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 84, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester and 4-(methanesulfonyl)phenylboronic acid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].O.[NH2:30][NH2:31]>CO.CC1C=CC(S(O)(=O)=O)=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][C:3]([NH:30][NH2:31])=[O:2])[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: NN
Reactant: COC(=O)CCC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2C(CCC(=O)NN)CCC2c2ccc(F)cc2)cc1
Yield: 83.3 %

Procedure:
To a stirred solution of (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester (1.5 g, 3.7 mmol) in MeOH (15 ml) was added hydrazine hydrate (0.54 ml, 11.1 mmol) and p-TsOH (10 mg) and the reaction mixture was heated under reflux conditions for 24 h. Evaporation and purification by column chromatography on silica gel (dichloromethane/MeOH 19:1) yielded (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid hydrazide (1.25 g, 83%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[N:7][C:6]([NH2:27])=[N:5]1.CN(C)[CH:30]=[O:31]>>[CH3:3][N:4]1[C:8]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[N:7][C:6]([NH:27][CH:30]=[O:31])=[N:5]1
Reactant: CN(C)C=O
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cn1nc(NC=O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C

Procedure:
A mixture of sodium hydride (0.72 g) and 1-methyl-N5 -[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (3.44 g) in dimethylformamide (50 ml) was heated under reflux for 8 h. The reaction mixture was cooled, poured onto water (300 ml) and extracted with ether. Evaporation of the organic extract gave a yellow oil, which was extracted with boiling cyclohexane (500 ml). As the cyclohexane extract was cooled a brown oil precipitated out. This oil was discarded and the supernatant solution was cooled to room temperature to give the title compound which was recrystallised from a mixture of ethyl acetate and light petroleum (b.p. 60°-80°) as a pale yellow solid (0.35 g) m.p. 68°-75° (decomposition). tlc, System C: Rf 0.6.
Reaction SMILES: O.O.C(O)(=O)C(O)=O.C[O:10][CH:11]=[C:12]1[CH2:15][CH:14]([C:16]([OH:19])([CH3:18])[CH3:17])[CH2:13]1.C([O-])(O)=O.[Na+]>C1COCC1.O>[OH:19][C:16]([CH:14]1[CH2:15][CH:12]([CH:11]=[O:10])[CH2:13]1)([CH3:18])[CH3:17]
Reactant: COC=C1CC(C(C)(C)O)C1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)C1CC(C=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalic acid dihydrate (68 g, 0.54 mol) was added to a solution of 2-[3-(methoxymethylidene)cyclobutyl]propan-2-ol (70 g, 0.45 mol) in THF:H2O (1:1, 700 mL) at 0° C. and stirred at ambient temperature for 1 hour. Then, 10% aqueous NaHCO3 solution was added to the reaction mixture and extracted with EtOAc (500 mL×4). The combined organic layer was then washed with water (200 mL×2), brine (200 mL) dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound as a pale yellow liquid (mixture of cis and trans isomers). 1H NMR (400 MHz, CDCl3, mixture of cis and trans): δ 1.09-1.11 (2 s, 6H), 2.07-2.26 (m, 4H), 2.31-2.39 (m, 1H), 2.95-2.99 (m, 1H), 9.75 & 9.84 (2 s, 1H). 13C NMR (100 MHz, CDCl3, mixture of cis and trans): δ 21.8, 26.1, 39.4, 40.7, 41.8, 70.3, 202.6. 1H NMR (400 MHz, DMSO-d6, mixture of cis and trans): δ 0.96 (s, 3H), 0.98 (s, 3H), 1.88-2.29 (m, 5H), 2.87-2.92 (m, 1H), 4.13 & 4.21 (2 s, 1H), 9.56 & 9.74 (2 s, 1H). 13C NMR (100 MHz, DMSO-d6, mixture of cis and trans): 22.1, 22.7, 26.8, 40.9, 41.9, 42.4, 68.8, 69.1, 203.8, 204.1. 1H NMR (400 MHz, DMSO-d6-D2O exchange, mixture of cis and trans): δ 0.94 (s, 3H), 0.96 (s, 3H), 1.85-2.22 (m, 5H), 2.86-2.90 (m, 1H), 9.53 & 9.71 (2 s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:32][CH2:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC

Procedure:
To a solution of methyl 2-methoxy-4-methylbenzoate (2.07 g, 11.5 mmol) in chloroform (30 mL) was added benzoyl peroxide (0.14 g, 0.57 mmol) and N-bromosuccinimide (2.04 g, 11.5 mmol). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was washed with saturated sodium hydrogen carbonate and the organic phase was poured through a hydrophobic frit and the solvent evaporated at reduced pressure. The crude material was used in the next step without further purification.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][S:12]C(=O)NCC)=[O:8])(=O)C.C[O-].[Na+]>CO.Cl>[SH:4][CH2:5][CH:6]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][SH:12])=[O:8]
Reactant: CCNC(=O)SC[C@H](NC(=O)C(CSC(C)=O)CC(=O)OC)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(CS)C(=O)N[C@@H](CS)C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of N-[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-S-(N-ethylcarbamoyl)-L-cysteine (1.9 g.) in methanol (10 ml.), sodium methoxide (0.84 g.) is added. After 30 minutes, the solution is diluted with 0.1 N hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo to yield N-[3-mercapto-2-(methoxycarbonylmethyl)propanoyl]-L-cysteine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C.C(Cl)Cl>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:24])[O:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)Nc2ccc(Cl)cc2)C1

Procedure:
Into a solution of (R)-(-)-N-tert-butoxycarbonyl-3-piperidinol (Reference Example 2) (23 g) in dry tetrahydrofuran (20 ml) were added 4-chlorophenyl isocyanate (1.43 ml) and triethylamine (1.87 mi) successively at room temperature with stirring, and then the mixture was stirred at room temperature for 10 hours. The reaction mixture was distilled under reduced pressure to give residues which was adsorbed on ca. 20 g of silica gel with employment of 50 ml of methylene chloride and purified through column chromatography (alumina, n-hexane:ethyl acetate =5:1) to give (R)-(+)-N-tert-butoxycarbonyl-3-piperidyl 4-chlorophenylcarbamate (3.07 g) of colorless prism crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:9])=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:15]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:9])=[CH:4][N+:3]=1[O-:15]
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(CCl)ccc1Cl
Temperature: 25 °C
Reaction time: 168 h
Yield: 90 %

Procedure:
To an icecold solution of 2-chloro-5-(chloromethyl)-pyridine (5 g, 29.6 mmol) in DCM (130 mL) was added dropwise a solution of 3-chlorobenzo-peroxoic acid (10.23 g, 59.3 mmol) in DCM (80 mL). The resulting solution was warmed to RT and stirred for 7 d till all starting material was consumed as judged by TLC. After this the reaction mixture was carefully treated with a saturated K2CO3 solution. The resulting precipitate was removed by filtration and the organic layer was washed with a saturated K2CO3 solution and brine. The organic layer was dried, filtered, and evaporated yielding the titled compound as an oil which slowly crystallizes (5.3 g, 90% yield).
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[CH:20](=[O:24])[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>O1CCCC1.CS(C)=O.ClCCl>[C:20]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)(=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC=O
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc(C(=O)OCC)cc1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
At −40° C., isopropylmagnesium chloride lithium chloride (15.3 mL, 1.3M in THF, 19.9 mmol) was added dropwise to a solution of ethyl 4-iodobenzoate (5.00 g, 18.11 mmol) in tetrahydrofuran (30 mL). The solution was stirred at −40° C. for 40 minutes. Butyraldehyde (1830 mg, 25.4 mmol) was added. The reaction was allowed to warm to room temperature over 3 hours. The reaction was quenched with 1N HCl and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude residue (1.0 g, 4.5 mmol) was combined with dichloromethane (16.7 mL), dimethylsulfoxide (4.79 mL), and triethylamine (2.28 g, 22.5 mmol) and cooled to 0° C. Sulfur trioxide pyridine complex (2.15 g, 13.5 mmol) was added in portions and the mixture was stirred at 0° C. for 1 hour. The reaction was allowed to gradually warm to room temperature and stir over 2 hours. The reaction was quenched with brine and diluted with dichloromethane. The layers were separated and the aqueous layer was extracted again with dichloromethane (20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave ethyl 4-butyrylbenzoate. 1H NMR (400 MHz, CDCl3, δ): 8.05-8.17 (m, 2H), 7.92-8.04 (m, 2H), 4.40 (q, J=7.15 Hz, 2H), 2.96 (t, J=7.22 Hz, 2H), 1.69-1.86 (m, 2H), 1.40 (t, J=7.12 Hz, 3H), 1.00 (t, J=7.22 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[S:18]([O-:21])([O-:20])=[O:19].[Na+].[Na+].C(O)C>O>[OH:21][S:18]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)(=[O:20])=[O:19]
Reactant: O=c1ccc2cc(OCCCCCl)ccc2[nH]1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1ccc2cc(OCCCCS(=O)(=O)O)ccc2[nH]1
Reaction time: 72 h
Yield: 75.4 %

Procedure:
A solution of 53.3 g of 6-(4-chlorobutoxy)carbostyril and 32 g of sodium sulfite dissolved in 500 ml of water and 200 ml of ethanol was refluxed for 1 day. The solution was allowed to cool and stand for 3 days and then filtered. The filtrate was made acidic with diluted hydrochloric acid. The solvent was removed by distillation. To the resulting residue was-added water, and the precipitate was collected by filtration to obtain 47.5 g of 6-(4-hydroxysulfonylbutoxy)carbostyril as a white powder.
Reaction SMILES: COC([C:5]1[C@H]2C[C@@H]3O[C@@]3(CO)[C@@H:7]2[C@H:8](OC(=O)NC)[O:9][CH:10]=1)=O.N1C=CC=CC=1.[C:28]([O:31][C:32](=[O:34])[CH3:33])(=O)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:28][O:31][C:32]([C:33]1[CH:7]=[CH:8][O:9][CH2:10][CH:5]=1)=[O:34]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@@]3(CO)[C@H]12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1=CCOC=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
500 mg of the (1S,4aS,6S,7R,7aR)-6,7-epoxy-7-(hydroxymethyl)-1-(methylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydrocyclopenta [c] pyrane-4-carboxylic acid methylester were dissolved in dichloromethane followed by addition of 0.4 ml of pyridine and 50 mg of DMAP. Next, 0.32 ml of acetic anhydride were dropped in followed by stirring for 4 hours at room temperature. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with 2N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless foamy substance from the hexane-ether eluate in the form of (1S,4aS,6S.7R,7aR)-7-(acetoxymethyl)-6,7-epoxy-1-(methylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydro [c] pyrane-4-carboxylic acid methylester (465 mg, yield: 82%). The physicochemical properties of this compound are described in Table 10, Compound No. 46.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:34])[C@@H:13]([NH:19][C:20]([C:22]2[CH:31]=[C:30]([OH:32])[C:29]3[C:24](=[CH:25][C:26]([CH3:33])=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50])=[O:44]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:34])[C@@H:13]([NH:19][C:20]([C:22]2[CH:31]=[C:30]([O:32][CH2:42][C:43](=[O:44])[N:45]3[CH2:49][CH2:48][CH2:47][C:46]3=[O:50])[C:29]3[C:24](=[CH:25][C:26]([CH3:33])=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][C:26]([CH3:33])([CH3:27])[CH3:25])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(CCl)N1CCCC1=O
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCCC3=O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 200 mg of 4-{(S)-4-Carboxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2.5 ml of DMF, 184 mg of cesium carbonate and 91 mg of 1-(2-Chloro-acetyl)-pyrrolidin-2-one was added and the reaction mixture was stirred for 3 days at RT. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the isolated crude product was pure enough for the next reaction step.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:19]1CCC(N=C=NC2CCCCC2)CC1>CO>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCCCCCCC(=O)O
Solvent: CO
Product: COC(=O)CCCCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
BocNH(CH2)7CO2H (prepared, Example 8, Step 1) (300 mg, 1.2 mmol) was dissolved in methanol (5 mL) and DCC (239 mg, 1.2 mmol) was then added. The solution was stirred at room temperature overnight. The DCU was removed by filtration and the solvent was removed in vacuo. The residue was then taken up in EtoAc and washed with dilute HCl (200 mL×3), water (200 mL×3), and then dried over MgSO4, filtered, and the solvent was removed in vacuo to yield an oil, 0.259 g (79% yield);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9]/[CH:10]=O)[CH:5]=[CH:6][CH:7]=1.[C:17]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH3:20])=[O:18]>ClCCl>[CH3:20][O:19][C:17](=[O:18])/[CH:21]=[CH:10]/[CH:9]=[C:8](/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC/C(=C\C=O)c1cccc(F)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)OC)c1cccc(F)c1

Procedure:
As described in Example 99, (E)-3-(3-fluorophenyl)-2-octenal (5.43 g) was treated with (carbomethoxymethylene)triphenylphosphorane (9 g) in dichloromethane (50 mL) for 4 days at room temperature. The ester was isolated in the usual manner and purified by HPLC (ether-hexane; 1:9) to provide 6.04 g of (E,E)-5-(3-fluorophenyl)-2,4-decadienoic acid methyl ester as an oil.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].CC1OC1.[Na].[CH:10]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1)=[CH2:11]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:10]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:4][CH2:1][CH:2]=[CH2:3])=[CH:14][CH:13]=1)=[CH2:11]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: C=CCO
Agent: CC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Product: C=CCOCc1ccc(C=C)cc1
Yield: 91.3 %

Procedure:
After 691.0 g (5.0 mole) of a 50% 2-propenyl alcohol solution of sodium 2-propenoxide, 16.0 g of tetrabutylammonium bromide and 1.0 g of BHT were placed and mixed in a 3-liter glass flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 763.0 g (5.0 mole) of 4-vinylbenzyl chloride was added dropwise to the mixture from the dropping funnel as the temperature was kept at 35°-40° C. to make them undergo the reaction. At the conclusion of the reaction, water was added to dissolve the produced salt. The resulting organic phase was separated, and then distilled to collect a 83°-84° C./2 mmHg fraction. Thus, 795.4 g of 3-(4-vinylbenzyloxy)-1-propene was obtained in a 91.3% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([C:6]2([C:4]([OH:5])=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCCC2)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid was prepared starting from 1-(4-methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid ethyl ester (2.2 g, 7.0 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.66 g, 83%. Colorless solid; mp 112-115° C.; MS: 285 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.S(OC)(O[CH3:25])(=O)=O.[OH-]>CO.O1CCCC1.O>[CH3:25][O:20][CH3:9].[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2
Reactant: COS(=O)(=O)OC
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC
Reaction time: 1 h

Procedure:
Into a mixture of 1 g of estrone, 0.5 ml of dimethyl sulfate and 5 ml of tetrahydrofuran, 6 ml of 10% methanolpotassium hydroxide solution was added over a period of 1 hour. The reaction temperature was maintained at 10° - 15°C. The resulting mixture was stirred for one hour to complete the etherification. Then, 15 ml of water was added to the reaction mixture, tetrahydrofuran and methanol were distilled off under atmospheric pressure. The residue was extracted with chloroform, washed with water, and dried. Evaporation of chloroform yielded 1.032 g of the 100% purity methyl ether of estrone in a 98.4% yield.
Reaction SMILES: [F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].CO.C1(C)C=CC=CC=1>N1C=CC=CC=1>[Si:23]([O:9][CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@@:2]([F:1])([CH3:18])[C@@H:6]1[OH:7])([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2′-deoxy-2′-fluoro-2′-C-methyluridine (3, 81.1 g, 312 mmol) in dry pyridine (750 mL) was added drop-wise a solution of TBDMSCl (103.19 g, 685.6 mmol) in dry pyridine (500 mL) over a period of 45 min at ambient temperature. The reaction was allowed to stir at ambient temperature for 24 h. Methanol (85 mL) was added to the reaction mixture and it was allowed to stir for 10 min and then the solvents were distilled off under reduced pressure. Hot water (45° C.) (1 L) was added to the reaction mass and the mixture extracted with ethyl acetate (2×500 mL), washed with water (1×500 mL). The organic layer was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off and the residue obtained was co-evaporated with toluene (2×500 mL) to give crude 9 as a white foam. Yield=116.9 g (quantitative). 1H NMR (CDCl3, 300 MHz): δ 0.1 (s, 6H), 0.91 (s, 9H), 1.22 (d, 3H, J=21 Hz), 2.50 (s, 2H), 3.75-4.05 (m, 4H), 5.54 (d, 1H, J=9 Hz), 5.73 (s, 1H), 6.0 (d, 1H, J=18 Hz), 7.81 (d, 1H, J=9 Hz), 8.57 (br, s, 1H), 11.1 (s, 1H).