Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:9]1[N:13]([CH2:14][CH3:15])[N:12]=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7])=[O:4].[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][O:27][CH3:28])[C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([N:13]1[C:9]([N:5]([CH:6]([CH3:8])[CH3:7])[C:3](=[O:4])[CH2:2][O:16][C:17]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][O:27][CH3:28])[C:18]=2[CH:19]=[O:20])=[CH:10][CH:11]=[N:12]1)[CH3:15]
Reactant: CCn1nccc1N(C(=O)CCl)C(C)C
Reactant: COCOc1cccc(O)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nccc1N(C(=O)COc1cccc(OCOC)c1C=O)C(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
2-Chloro-N-(1-ethyl-1H-pyrazol-5-yl)-N-isopropylacetamide (0.39 g, 1.7 mmol) and 2-hydroxy-6-(methoxymethoxy)benzaldehyde (0.309 g, 1.7 mmol) were dissolved in DMF (8.5 ml) and purged with N2 gas. Potassium carbonate (0.47 g, 3.4 mmol) was added and the mixture was stirred in a heat block at 60° C. After 2 h, the reaction was cooled and partitioned into ethyl acetate (100 ml) and water (100 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with water (50 ml) and a saturated aqueous sodium chloride solution (50 ml), and dried over sodium sulfate. After evaporation the residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to give 0.38 g (59%) of N-(1-ethyl-1H-pyrazol-5-yl)-2-(2-formyl-3-(methoxymethoxy)phenoxy)-N-isopropylacetamide as a faintly-colored viscous oil. MS (ESI) m/z 376 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC=CC=1.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1Cl
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.8 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), toluene (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The cis to trans ratio is 75 to 80/25 to 20. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.80 to 0.82%].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:12][CH:13]1[CH2:20][CH2:19][CH2:18][NH:17][C:15](=O)[CH2:14]1)(OCC)=[O:8].O>O1CCCC1>[OH:8][CH2:7][CH2:12][CH:13]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:15][CH2:14]1
Reactant: CCOC(=O)CC1CCCNC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCC1CCCNCC1

Procedure:
To a stirred slurry of lithium aluminium hydride (5.70 g) in dry tetrahydrofuran (100 ml) was added β-carbethoxymethyl-caprolactam (10.3 g) in dry tetrahydrofuran (150 ml) over a period of 30 minutes. The mixture was refluxed for 2.5 hours, cooled and treated very slowly with water. The precipitate was filtered off and the filtrate was evaporated to yield the title compound as a viscous oil, which was used in the next step without purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][S:22]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)(=[O:24])=[O:23]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
To a solution of 4-hydroxy-1-(p-nitrobenzyloxycarbonyl)piperidine (2.96 g, 14.8 mmol) (obtained as described in Reference Example 51(1)) in methylene chloride (90 ml) were added methanesulfonyl chloride (1.15 ml, 14.8 mmol) and triethylamine (2.07 ml, 14.8 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes, and then stirred for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was recrystallized from a solution of n-hexane:ethyl acetate (1:1) to afford 4-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)piperidine (3.31 g, yield 87%) as pale yellow crystals.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:26][N:27]1[C:31]([NH2:32])=[CH:30][C:29]([CH3:33])=[N:28]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:32][C:31]4[N:27]([CH3:26])[N:28]=[C:29]([CH3:33])[CH:30]=4)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(N)n(C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
To a solution of 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (121 mg, 0.358 mmol) in N,N-dimethylformamide (5.0 mL) were added 1,3-dimethyl-1H-pyrazol-5-amine (47.8 mg, 0.43 mmol), 1-hydroxybenzotriazole (58 mg, 0.43 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (82.4 mg, 0.43 mmol) and triethylamine (45 mg, 0.43 mmol), and the mixture was stirred at room temperature for 24 hr. The solvent was evaporated under reduced pressure, ethyl acetate, tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→90/10, then methanol/ethyl acetate=0/100→15/85), and precipitated from ethyl acetate/hexane to give the title compound (116 mg, 75%) as a white powder.
Reaction SMILES: [C:1]1([CH2:11]O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2c1CCCC2
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCc1cccc2c1CCCC2
Yield: 56 %

Procedure:
61 g (0.376 mol) of (5,6,7,8-tetrahydro-1-naphthyl)methanol with a purity of 78 % are dissolved in 450 ml of chloroform, in the presence of 35 g (0.38 mol) of pyridine. 90 ml of thionyl chloride in solution in 30 ml of chloroform are introduced dropwise and between 30 and 40°C into the solution which is obtained and this is heated under reflux for 6 hours. After partial evaporation of the chloroform and the thionyl chloride excess, washing is carried out with water and with a sodium bicarbonate solution, followed by drying over anhydrous sodium sulphate. Distillation of the oily residue permits the isolation of a liquid of boiling point b.p.0.5 = 81°-83°C, with a purity of 86 % (vapour phase chromatography), and this is taken up in 150 ml of hot hexane. The crystallisation is seeded by scratching with a glass rod. There are isolated 29.5 g of a product melting at 51°-52°C, with a yield of 56 % (theoretical yield = 53 g, depending on the degree of purity of the starting product). Vapour phase chromatography confirms a purity of 100 %.
Reaction SMILES: CC([O-])(C)C.[K+].[F:7][C:8]([F:45])([F:44])[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[CH2:23][C@H:22]([O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][C@H:20]2[CH2:42]O)=[O:18])=[CH:12][CH:11]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.O>C1COCC1>[C:38]([Si:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:24][C@H:22]1[CH2:23][N:19]2[C:17](=[O:18])[N:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][C:8]([F:44])([F:45])[F:7])=[CH:11][CH:12]=3)[CH2:42][C@@H:20]2[CH2:21]1)([CH3:39])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](O[C@@H]1C[C@@H](CO)N(C(=O)Nc2ccc(OC(F)(F)F)cc2)C1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
t-BuOK (1.0 g, 8.9 mmol) was added to a solution of (2S,4R)-4-(tert-Butyl-diphenyl-silanyloxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (2.0 g, 3.6 mmol) in anhydrous THF (50 mL) at 0° C. The mixture was stirred for 15 minutes at 0° C. Then tosyl-chloride (0.88 g, 4.6 mmol) was added to the mixture, and the mixture was stirred for 30 minutes at 0° C. The mixture was poured into water (50 mL), extracted with ethyl acetate (3×50 mL). The organic layers was combined, washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica-gel column chromatography (petroleum ether/ethyl acetate=10:1) to give 1.6 g (83%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.68-7.63 (m, 4H), 7.58 (d, 2H, J=9.3 Hz), 7.50-7.39 (m, 6H), 7.19 (d, 2H, J=9.0 Hz), 4.56 (t, 1H, J=5.1 Hz), 4.30-4.22 (m, 1H), 4.04 (t, 1H, J=8.4 Hz), 3.86 (dd, 1H, J1=12.6 Hz, J2=5.7), 3.67 (dd, 1H, J1=9.3 Hz, J2=2.4 Hz), 3.18 (d, 1H, J=12.6 Hz), 2.07 (dd, 1H, J1=12.6, J2=5.4), 1.46-1.37 (m, 1H), 1.11 (s, 9H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10](S(O)(=O)=O)=[CH:9][CH:8]=1>>[CH:10]1([CH:9]([O:5][C:1](=[O:6])[CH:2]=[CH:3][CH3:4])[CH3:8])[CH2:11][CH2:12][CH2:7][CH2:17]1
Reactant: C/C=C/C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC=CC(=O)OC(C)C1CCCC1

Procedure:
Cyclopentene reacted with carbon monoxide (CO) and hydrogen (H2) in the presence of a Wilkinson's catalyst to provide cyclopentanecarboxaldehyde, which then reacted with methylmagnesium chloride (MeMgCl) to provide 1-cyclopentylethanol, which further reacted with crotonic acid in the presence of p-toluenesulfonic acid (pTSA) to afford product but-2-enoic acid 1-cyclopentyl-ethyl ester.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1([NH:4][C:2]#[N:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cccc2ccccc12
Reactant: N#CBr
Solvent: Cc1ccccc1
Product: N#CNc1cccc2ccccc12
Reaction time: 0.5 h

Procedure:
Cyanogen bromide (4.4 gm, 41.9 mmol) was added in portions to the stirred and ice-bath cooled solution of 1-aminonaphthalene (10.0 gm, 69.8 mmol) in toluene (100 mL). After 0.5 hour, the cooling bath was removed the reaction mixture was stirred at room temperature for 12 hours. The precipitate was filtered and the solid was triturated with water (150 mL) for 0.5 hour. The resulted solid was filtered and washed with water (4×20 mL) and the solid was dried in vacuum oven at 40° C. This material (4.6 gm) was used as such without any further purification.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[C@H:18]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23]O)[CH2:17][O:16][C:15]1([CH3:26])[CH3:25])=[O:13])([CH3:10])([CH3:9])[CH3:8].[Br:27]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:7]([O:11][C:12]([N:14]1[C@H:18]([CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][Br:27])[CH2:17][O:16][C:15]1([CH3:26])[CH3:25])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1[C@H](C=CCCCO)COC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1[C@H](C=CCCCBr)COC1(C)C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
7 ml of pyridine are added dropwise at 0° to a solution of 18.5 g of alcohol 3 according to c), 28.2 g of tetrabromomethane and 22.3 g of triphenylphosphine in 600 ml of dichloromethane. The mixture is stirred at 0°-2° for 12 hours, concentrated by evaporation, taken up in 150 ml of ethyl acetate, filtered, concentrated to 50 ml and chromatographed on 200 g of silica gel. Elution with hexane/ethyl acetate 10:1 yields 19.9 g of bromide 4, [α]D =-18.9° (c=1, CHCl3); C15H26NO3Br; calculated: C 51.73%, H 7.53%, N 4.02%, Br 22.94%; found: C 51.7%, H 7.7%, N 4.2%, Br 23.0%.
Reaction SMILES: N#N.[SH:3][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].C(N(CC)CC)C.[C:24](Cl)(=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CCCCCC>[C:24]([S:3][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])(=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCO[Si](CCCS)(OCC)OCC
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCCCCCCC(=O)SCCC[Si](OCC)(OCC)OCC
Yield: 86.8 %

Procedure:
Into a 12-liter, three-necked round bottom flask equipped with mechanical stirrer, addition funnel, thermocouple, heating mantle, N2 inlet, and temperature controller were charged 1,021 grams of 3-mercaptopropyltriethoxysilane (SILQUEST® A-1891 silane from Crompton Corp.), 433 grams of triethylamine, and 3,000 mL of hexane. The solution was cooled in an ice bath, and 693 grams of octanoyl chloride were added over a two hour period via the addition funnel. After addition of the acid chloride was complete, the mixture was filtered two times, first through a 0.1 :m filter and then through a 0.01 :m filter, using a pressure filter to remove the salt. The solvent was removed under vacuum. The remaining yellow liquid was vacuum distilled to yield 1,349 grams of octanoylthiopropyltriethoxysilane as a clear, very light yellow liquid. The yield was 87 percent.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:16][S:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:16][S:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:23][CH:24]=1)[N:22]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CSc1ccc(N)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(SC)cc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 4-methylthio-aniline were reacted and treated with phenyl oxide to obtain ethyl 6-methylthio-4-hydroxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1.Cl.C([OH:16])C.C(=O)([O-])O.[Na+]>O>[OH:16][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1
Reactant: CCO
Reactant: CSc1nc2cccccc-2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1nc2cccccc-2n1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
In accordance with the method described in Journal of the Americal Chemical Society, Vol. 76, pages 3352 to 3353 (1954), 60 g of 2-methylthiocycloheptimidazole, as obtained in Example 1-(c), was added to 300 ml of concentrated hydrochloric acid (hydrogen chloride content: 35%) and heated under reflux for 2 hours and 30 minutes. Next, 500 ml of ethanol was added and everything was stirred at room temperature, and then the crystals precipitated were separated by filtration. The crystals thus obtained were dissolved in 0.5 liter of water, and sodium hydrogencarbonate was added to adjust the pH thereof to about pH 7 or so. The crystals precipitated were separated by filtration, washed with water and then dried. 40 g of pale yellow crystals were obtained.
Reaction SMILES: OC1C=CC=CC=1C1SC=C(CC(O)=O)N=1.C([O:19][C:20](=[O:35])[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][C:28]=2[OH:34])[S:25][CH:26]=1)C.[Li+].[OH-]>>[OH:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:24]1[S:25][CH:26]=[C:22]([CH2:21][C:20]([OH:35])=[O:19])[N:23]=1
Reactant: CCOC(=O)Cc1csc(-c2c(O)cccc2O)n1
Agent: O=C(O)Cc1csc(-c2ccccc2O)n1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1csc(-c2c(O)cccc2O)n1
Yield: 93.6 %

Procedure:
The procedure used for the preparation of 5a was repeated with 4b (805 mg, 2.89 mmol) and 2N LiOH (5.1 mL) to provide 5b (680 mg, 94%) as a yellowish solid, which was recrystallized from THF/hexane. mp 210° C. (dec); IR (KBr) 3540-2500 (br), 3256 (br), 1688, 1461, 1230 cm-1 ; 1H NMR (DMSO-d6) δ3.78 (2H, s, CH2), 6.42 (2H, d, J=8.1 Hz, Ar), 7.08 (1H, t, J=8.1 Hz, Ar), 7.46 (1H, s), 12.21 (2H, s, OH), 12.47 (1H, br s, CO2H); FDMS m/z 251 (M+), 252 (M+ +1); Anal. Calcd for C11H9NO4S: C, 52.58; H, 3.61; N, 5.57. Found: C, 52.36; H, 3.57;N, 5.38.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)[CH:7]=[CH:6]2.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>O1CCCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)[CH:7]=[CH:6]3)=[O:36])=[CH:33][CH:32]=1
Reactant: NCc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a cooled (ice bath) and stirred solution of (6-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (130 mg, 0.45 mmol) and triethyl amine (50 mg, 0.49 mmol) in tetrahydrofurane (2.6 ml) was added 4-fluorobenzoyl chloride (78 mg, 0.49 mmol) and the mixture was allowed to stir at room temperature for 1 h. Evaporation and purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as white foam (150 mg, 81%). MS: m/e=412.2 (M+H+).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C1(C(Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C1C=CC=CN=1)C.N1C=CN=C1.[Si:51](Cl)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]>N1C=CC=CC=1>[Si:51]([O:4][C@@H:3]1[C@@H:5]([CH2:6][OH:7])[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a solution of 2'-deoxyuridine (5.00 g, 22 mmol) in pyridine (20 ml) was added triphenylmethyl chloride (6.72 g, 24 mmol) and dimethylaminopyridine (0.20 g, 1.6 mmol). The mixture was allowed to stir at 80° C. for 30 min. The pyridine was removed under reduced pressure and the residue dissolved in DMF (30 ml). Imidazole (3.59 g, 53 mmol) and t-butyldimethylsilyl chloride (3.92 g, 26 mmol) were added, and the mixture was allowed to stir overnight at room temperature. The DMF was removed under reduced pressure, and the residue was dissolved in 80% aqueous acetic acid (20 ml). The mixture was allowed to reflux for 30 min, cooled, and neutralized with NaOH. The mixture was lyophilized, and the residue was purified by chromatography (1:1 EtOAc: hexanes) to give 22 as a white solid (3.13 g, 9.14 mmol, 41.51% yield): mp 140° C. (softens), 160°-170° C. (melts); Rf 0.65 (1:9 MeOH:CH2Cl2); 1H NMR (CDCl3) 7.62(d, 1H, J=6.87 Hz), 6.16(t, 1H, J=6.61), 5.73(d, 1H, J=5.70 Hz), 4.49(m, 1H), 3.93(m, 2H), 3.76(m, 1H), 2.30(m, 1H), 2.19(m, 1H), 0.89(s, 9H), 0.09(s, 6H)ppm.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([O:25][CH3:26])[CH:22]([NH2:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([O:25][CH3:26])[CH:22]([NH:24][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:23]
Reactant: COC(c1ccc(Cl)cc1Cl)C(C)N
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(c1ccc(Cl)cc1Cl)C(C)NC(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (195 mg, 1.0 mmol) in dichloromethane (2 ml) was added dropwise to a stirred solution of (234 mg, 1.0 mmol) 2-(2,4-dichloro-phenyl)-2-methoxy-1-methyl-ethylamine, which was prepared as described in example P2, and triethylamine (202 mg, 2.0 mmol) in dichloromethane (6 ml) at 0° C. The reaction mixture was stirred for 1 hr at ambient temperature then allowed to stand for 4 h. After removal of the solvent the residue was purified by flash chromatography over silica gel (eluant:hexane/ethyl acetate 1:1). 170 mg (43% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-2-methoxy-1-methyl-ethyl]-amide was obtained in the form of a resin as a mixture of diastereomeres.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([O:36][C:37](=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44])[CH3:35]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:43]([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:46])=[O:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCOC(=O)CCCCCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 50.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.26 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 6-(chloroformyl)hexanoic acid ethyl ester (0.46 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 1:1) to give ethyl 6-(N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}carbamoyl)hexanoate (0.43 g, 50%) as a white solid: mp 82-84° C.; 1H NMR (DMSO-d6) δ d 11.11 (s, 1H), 8.41 (t, J=5.6 Hz, 1H), 7.86-7.65 (m, 3H), 5.18-5.11 (dd, J=5.4 and 12.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 4.05 (q, J=7.1 Ha, 2H), 2.97-2.83 (m, 1H), 2.64-2.48 (m, 2H), 2.30-2.15 (m, 4H), 2.08-2.04 (m, 1H), 1.56-1.47 (m, 4H), 1.32-1.23 (m, 2H), 1.17 (t, J=7.1 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.80, 172.71, 172.52, 169.77, 167.45, 166.92, 139.49, 134.67, 133.13, 131.49, 127.04, 121.78, 59.60, 48.84, 37.57, 35.02, 33.38, 30.91, 28.08, 24.83, 24.16, 21.96, 14.09; Anal. Calcd. For C23H27N3O7: C, 60.39; H, 5.95; N, 9.18. Found: C, 60.10; H, 5.82; N, 8.82.