Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:5]=1[C:6]#[N:7].[CH2:15]([OH:17])[CH3:16]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:5]=1[C:6](=[NH:7])[O:17][CH2:15][CH3:16]
Reactant: COCc1ccc(OC)c(C#N)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cc(COC)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2-methoxy-5-methoxymethyl-benzonitrile (235 mg, 1.326 mmol) in anhydrous ethanol (15 mL) at room temperature. After 2 h, hydrogen chloride gas was stopped and the reaction vessel was sealed. After stirring at room temperature for 12 h, the reaction vessel was cooled to 0° C. and opened. The solvent was evaporated in vacuo and the residue was triturated in diethyl ether to afford ethyl 2-methoxy-5-methoxymethyl-benzimidate hydrochloride (340 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].C1C(=O)N([Cl:18])C(=O)C1>CN(C=O)C.CCOCC>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([Cl:18])[C:3]=1[F:10]
Reactant: Nc1cc(F)c(Br)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1cc(F)c(Br)c(F)c1Cl
Reaction time: 48 h

Procedure:
4-Bromo-3,5-difluoroaniline (10.5 g, 50.5 mmol) is dissolved in DMF (100 mL). NCS (28.6 g, 50.5 mmol) is added portionwise at room temperature. After 48 hours, the reaction is diluted with Et2O and washed with brine. The separated organic phase is dried (Na2SO4) and concentrated to give an oil. The residue is purified by column chromatography (EtOAc/hexanes) to give 4-bromo-2-chloro-3,5-difluoroaniline.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][O:9]C(=O)C)(=[O:6])[O:4][CH3:5].C(OC)(=O)C.CO>CO.S(=O)(=O)(O)O>[CH3:1][O:2][P:3]([CH2:7][CH2:8][OH:9])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CCOC(C)=O)OC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: COC(C)=O
Product: COP(=O)(CCO)OC
Yield: 85 %

Procedure:
A solution of 50 g of 2-acetoxyethane phosphonic acid dimethyl ester in 100 ml of anhydrous methanol is heated to 65°-70°C for 5 hours, while adding one drop of concentrated sulfuric acid. A mixture of methyl acetate/methanol is removed continuously by distillation in the course of the reaction. After a distillation under reduced pressure 33.5 g of 2-hydroxyethane-phosphonic acid dimethyl ester are obtained, corresponding to a yield of 85% of the theoretical.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:44]=[CH:45][CH:46]=4)[C:28]([NH:30][C@@H:31]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]([O:34]CC)=[O:33])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].O.Cl>O1CCCC1.CO.O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:44]=[CH:45][CH:46]=4)[C:28]([NH:30][C@@H:31]([CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]([OH:34])=[O:33])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of ethyl (2S)-2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoylamino}-3-phenylpropionate (119 mg, 0.195 mmol) in tetrahydrofuran (4 ml) was added a solution of lithium hydroxide-water (16.4 mg, 0.390 mmol) in MeOH-water (1:1) (2.8 ml) at 5° C. The reaction mixture was stirred at the same temperature for 1 hour, and then stirred at room temperature for 30 minutes. To the reaction mixture was added 1N hydrochloric acid (0.5 ml) at 5° C. and extracted with EtOAc. The organic layer was washed with water and brine. The resultant mixture was dried over magnesium sulfate, and evaporated in vacuo to give (2S)-2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-benzoylamino}-3-phenylpropionic acid (113.0 mg, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:14])[O:15][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21

Procedure:
A mixture of 21.1 g of 4-nitrophthalic acid and 50.0 g of acetic anhydride were heated at reflux for 6 hours, following which the acetic acid was removed by distillation at atmospheric pressure. The excess acetic anhydride was removed by distillation at 15 mm Hg pressure with the flask temperature not exceeding 120° C, leaving a quantitative yield of crude 4-nitrophthalic anhydride, m.p. 114°-116° C. The product was recrystallized from chloroform to afford a 93% yield of product, m.p. 123°-124° C, identical to that of Example 1.
Reaction SMILES: I[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:11][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([O:12][CH3:13])=[CH:3][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[F:14]
Reactant: COc1cc(I)c(Cl)cc1C(=O)O
Reactant: OB(O)c1ccccc1F
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2F)c(Cl)cc1C(=O)O
Yield: 70.9 %

Procedure:
To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid of Example 20, Step A (3.72 g, 19.1 mmol) in N,N-dimethylformamide (20 mL) was added 2-fluorophenyl boronic acid (5.0 g, 35.7 mmol) and potassium carbonate (14.8 g, 107 mmol). This mixture was purged with nitrogen and then treated with a catalytic amount of tetrakis(triphenylphosphine) palladium(0) (0.688 g, 0.59 mmol). The reaction was heated to reflux overnight, cooled, acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was flash chromatographed on acid washed silica using a 10 to 50% gradient of diethyl ether in hexane to provide the desired title compound (3.8 g) as a white solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][NH:16][CH2:15]C3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C#CC2CC3(CCN(C(OC(C)(C)C)=O)C3)ON=2)C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][NH:16][CH2:15]3)[O:11][N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Agent: CC(C)(C)OC(=O)N1CCC2(CC(C#Cc3ccccc3)=NO2)C1
Solvent: ClC(Cl)Cl
Product: C(#Cc1ccccc1)C1=NOC2(CCNC2)C1
Yield: 91.3 %

Procedure:
The title compound was synthesized following the method reported for the Compound 1c, substituting Compound 1b with Compound 36a and running the reaction in chloroform. The crude brownish oily residue was used without further purification in the next reaction step. Yield: 91.3%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:26]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[N:15]1[CH2:16][CH2:17][N:12]([C:10]([C:5]2[CH:4]=[CH:3][C:2]([N:27]3[CH2:28][CH2:29][CH2:30][S:26]3(=[O:32])=[O:31])=[CH:9][C:6]=2[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C#N)CC2)c(C)c1
Yield: 91.8 %

Procedure:
Using 5-bromo-2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]benzonitrile (797 mg) described in Preparation Example 188 and isothiazolidine 1,1-dioxide (315 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (806 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@H]3C)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
Into a 20-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (500 mg, 1.67 mmol, 1.00 equiv), 2-methylpyrrolidine (285 mg, 2.92 mmol, 2.00 equiv), potassium carbonate (693.8 mg, 4.01 mmol, 3.00 equiv), N,N-dimethylformamide (6 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting aqueous solution was extracted with 12×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 590.7 mg (92%) of methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil. Then the isomer was sent for chiral-prep-HPLC to get the product of (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (178 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH3:5].[O:6]1[CH2:10][CH2:9][O:8][CH2:7]1>>[CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:10][O:6][CH2:7][O:8][CH3:9]
Reactant: C1COCO1
Reactant: COCOC
Product: COCOCCOCOC
Yield: 50 %

Procedure:
The reaction of 500 g dimethoxymethane (6.6 moles) with 100 g 1,3-dioxolane (1.4 moles), in the presence of an acidic catalyst, gave a mixture of unreacted dimethoxymethane, low molecular weight oligomers of 1,3-dioxolane and a product having the formula: CH3OCH2OCH2CH2OCH2OCH3 which was isolated in 50% yield. Fluorination of 80 g of the product in a 4 liter reactor containing 1.5 liters (CF2Cl)2CFOCF2OCF(CF2Cl)2 and 400 g sodium fluoride in an 18 hour reaction at 10° C., gave a 60% yield of perfluoro-2,4,7,9-tetraoxadecane (b.p. 79.0° C.).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:28]=[C:29]([N+:34]([O-:36])=[O:35])[CH:30]=[CH:31][C:32]=1F>CN(C)C=O.C(OCC)(=O)C>[F:26][C:27]1[CH:28]=[C:29]([N+:34]([O-:36])=[O:35])[CH:30]=[CH:31][C:32]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 112.3 %

Procedure:
To a stirred solution of 3-(1-Methyl-1H-pyrazol-5-yl)biphenyl-4-ol (Preparation 28, 600 mg, 2.39 mmol) in N,N-dimethylformamide (6 mL) at 0° C. was added potassium carbonate (332 mg, 2.39 mmol). The mixture was stirred for 30 minutes at 0° C. 3,4-Difluoronitrobenzene (318 mg, 1.99 mmol) was added drop wise to the reaction mixture and allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was washed sequentially with water (3×10 mL) and brine (1×10 ml), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound (870 mg, quantitative). This material was used without purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:27])[NH:20][C:21]([CH3:26])=[CH:22][C:23]=2[CH2:24][CH3:25])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[Na].[CH:29]1([S:32]([OH:34])=[O:33])[CH2:31][CH2:30]1>>[CH:29]1([S:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:27])[NH:20][C:21]([CH3:26])=[CH:22][C:23]=3[CH2:24][CH3:25])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)(=[O:34])=[O:33])[CH2:31][CH2:30]1
Reactant: O=S(O)C1CC1
Reactant: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Agent: [Na]
Product: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(S(=O)(=O)C2CC2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared from 6-bromo-N-[(4-ethyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (70 mg, 0.162 mmol) and the sodium salt of cyclopropanesulfinic acid (41.9 mg, 0.325 mmol) in the same manner as described for example 91. The product was collected an off-white solid (52 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.16 (m, 5H), 1.19-1.27 (m, 2H), 1.50 (d, J=6.57 Hz, 6H), 2.15 (s, 3H), 2.58 (m, 2H), 2.97 (m, 1H), 4.41 (d, J=4.80 Hz, 2H), 5.26 (m, 1H), 5.94 (s, 1H), 8.01 (d, J=1.26 Hz, 1H), 8.43 (s, 1H), 8.53 (s, 1H), 8.83 (m, 1H), 11.58 (s, 1H); LCMS: (M+H)+=457.0
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[F:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[F:20]>C(Cl)Cl>[F:13][C:14]1[CH:15]=[C:16]([S:21]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: Nc1nccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(F)c(F)c1
Reaction time: 48 h

Procedure:
To a slurry of 2-aminothiazole (23.88 g, 0.2384 mol) in methylene chloride (150 mL) and pyridine (38.0 mL, 0.470 mol) was added dropwise a solution of 3,4-difluorobenzenesulphonyl chloride (25.0 g, 0.118 mol) in 10 mL of methylene chloride. After stirring for 48 hours the reaction was diluted with more dichloromethane and extracted with 1N HCl. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give 3,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide as a white solid. LCMS Rt=1.24 minutes MS m/z 277 [MH]+
Reaction SMILES: [CH3:1][O:2][SiH:3]([O:6][CH3:7])[O:4][CH3:5].[CH3:8][OH:9]>>[Si:3]([O:9][CH3:8])([O:6][CH3:7])([O:4][CH3:5])[O:2][CH3:1]
Reactant: CO
Reactant: CO[SiH](OC)OC
Product: CO[Si](OC)(OC)OC

Procedure:
1642 gm of crude product prepared in Example 3 was added to the distilling flask and heated slowly. Distillation fractions were collected at the head temperatures shown in Table 4 . From the composition of the fractions, the 1642 gm of crude product afforded 660 gm trimethoxysilane, which is more than that calculable from the composition of the starting material (first row of Table 4). The additional tri-methoxysilane was formed via the disproportionation of the mixed dimethylaminomethoxysilanes, e.g., HSi(OCH3)2 [N(CH3)2 ]. The vapor phase methanolysis consumed 2521 gm tris(dimethylamino)silane and 1005 gm methanol and produced a total of 1166 gm trimethoxysilane. The stoichiometric amount of trimethoxysilane obtainable from 1005 gm (31.4 moles) methanol is 1277 gm. So the yield of trimethoxysilane was 91.3 wt. % based on methanol converted. Note, however, that the methanol not converted to trimethoxysilane in this pass through the reactor was converted mainly to the mixed dimethylaminomethoxysilanes, e.g., HSi[N(CH3)2 ]2 (OCH3), and mixed methoxydimethylcarbamatosilanes, e.g., HSi[OOCN(CH3)2 ]x (OCH3)3-x (x=1,2,3), which are recyclable. Only negligible quantities of Si(OCH3)4 were formed.
Reaction SMILES: [CH2:1]=[C:2]1[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]([NH2:15])=[N:13][C:11]1=[O:12].[C:18](Cl)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>N1C=CC=CC=1>[C:18]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:3]2[O:4][C@H:5]([CH2:8][O:9][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@@H:6]([OH:7])[C:2]2=[CH2:1])[C:11](=[O:12])[N:13]=1)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: C=C1[C@H](n2ccc(N)nc2=O)O[C@H](CO)[C@H]1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: C=C1[C@H](n2ccc(NC(=O)CCCCCCCCCCCCCCCCC)nc2=O)O[C@H](COC(=O)CCCCCCCCCCCCCCCCC)[C@H]1O
Reaction time: 0.25 h

Procedure:
2'-Deoxy-2'-methylidenecytidine, 239 mg, was dissolved in 5 ml of pyridine, 1.7 ml of stearoyl chloride was added portionwise under ice cooling, and the solution was stirred for 15 minutes. After the reaction, the reaction solution was partitioned with chloroform and the chloroform layer was distilled off under reduced pressure. The resulting residue was treated with silica gel chromatography (elution solvent: a mixture solvent of chloroform and methanol) to give the objective compound. m.p. 135°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([NH:12][C:13]([CH3:18])([C:15]#[C:16][CH3:17])[CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH3:23]I>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([N:12]([CH3:23])[C:13]([CH3:14])([C:15]#[C:16][CH3:17])[CH3:18])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC#CC(C)(C)N(C)C(=O)C(CC)Oc1cncc(Cl)c1
Reaction time: 0.75 h

Procedure:
To a solution of 2-(5-chloro-3-pyridyloxy)-N-(2-methylpent-3-yn-2-yl)butyramide (0.10 g; prepared as described in Example 1) in dry tetrahydrofuran (9 ml) was added sodium hydride (0.011 g) at ambient temperature under an atmosphere of nitrogen. The mixture was stirred for 0.75 hours, a solution of methyl iodide (0.023 ml) in dry tetrahydrofuran was added then the reaction mixture stirred for a further 0.5 hours at ambient temperature. The reaction was diluted with water, extracted with ethyl acetate (three times) and the extracts were combined, washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residual oil was fractionated by chromatography (silica:hexane/ethyl acetate, 3:1 by volume) to give the required product as a beige solid, 0.075 g. m.p. 67–68° C. 1H NMR (CDCl3) δ: 1.14 (3H, t); 1.68 (3H, s); 1.69 (3H, s); 1.85 (3H, s); 2.02 (2H, m); 3.20 (3H, s); 4.70 (1H, t); 7.18 (1H, m); 8.18 (1H, m); 8.20 (1H, m).
Reaction SMILES: CO[C@H](C([O:12][CH2:13][CH2:14][C:15]1[C:23]2[CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:21]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:20]([CH3:38])[NH:19][C:18]=2[S:17][N:16]=1)=O)C1C=CC=CC=1.[OH-].[K+]>C(O)C>[OH:12][CH2:13][CH2:14][C:15]1[C:23]2[CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:21]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:20]([CH3:38])[NH:19][C:18]=2[S:17][N:16]=1
Reactant: CCOC(=O)C1=C(C)Nc2snc(CCOC(=O)[C@@H](OC)c3ccccc3)c2C1c1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2snc(CCO)c2C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.08 h

Procedure:
In an argon stream, 5 ml of ethanol was added to 175 mg (0.329 mM) of (-)-ethyl 3-[2-((S)-alpha-methoxybenzylcarbonyloxy)ethyl]-6-methyl-4-(3-nitrophenyl)-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxylate obtained in Example 55 to form a solution. While the solution was cooled with ice-sodium chloride, 7 ml of a 7% aqueous solution of potassium hydroxide was added, and the mixture was stirred at the above temperature for 5 minutes. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (-)-ethyl 3-(2-hydroxyethyl)-6-methyl-4-(3-nitrophenyl)-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxylate quantitatively.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH:28]([CH3:30])[CH3:29])[NH:5][C:6](=[O:27])[C:7]([CH3:26])([CH3:25])[NH:8][C:9](=[O:24])[C@H:10]([CH2:19][O:20][CH2:21][CH:22]=[CH2:23])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH:8][C:7]([CH3:25])([CH3:26])[C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH:28]([CH3:29])[CH3:30])=[O:27])=[O:24])[CH2:19][O:20][CH2:21][CH:22]=[CH2:23])=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)N[C@H](C(=O)OC)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)N[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
N-tert-butoxycarbonyl O-allyl L-seryl α,α-dimethylglycyl L-valine methyl ester 12 (8.56 g, 19.3 mmol) was dissolved in THF (150 mL). The solution was cooled to 0° C. (icebath). LiOH monohydrate (0.891 g, 21.2 mmol) was dissolved in de-ionized water (75 mL) and the solution cooled to 0° C. The solution was added dropwise to the solution of 12 over 20 min. The reaction mixture was stirred for an additional 2 h 40 min before solid NaHCO3 (3.24 g, 38.6 mmol) was added. The mixture was stirred for 5 min and the bulk of THF evaporated. The solution was diluted with water (150 mL), washed with Et2O (2×150 mL), acidified to pH 2 by addition of 2 M aqueous H2SO4 and extracted with EtOAc (3×300 mL). The combined organic fractions were dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a white solid (7.30 g, 88%); δH (300 MHz; d6-DMSO) 12.62 (1H, br s, COOH), 8.01 (1H, s, NH(Aib)), 7.12 (1H, d, J 9, NH(Val)), 6.85 (1H, d, J 8, NH(Ser(All))), 5.92-5.79 (1H, m, CH═CH2), 5.29-5.21 (1H, m, CH═CHH), 5.15-5.10 (1H, m, CH═CHH), 4.19-4.10 (2H, m, CαH(Ser(All))/CαH(Val)), 3.94 (2H, dt, J 1 and 5, CH2CH═CH2), 3.57-3.45 (2H, m, CH2), 2.08-1.97 (1H, m, CH(CH3)2), 1.38 (12H, s, CH3(Aib)/(CH3)3), 1.35 (3H, s, CH3(Aib)), 0.84 (3H, d, J 7, CH3(Val)), 0.81 (3H, d, J 7, CH3(Val)); δC (75 MHz; d6-DMSO): 173.6, 172.7, 169.5, 155.1, 134.9, 116.3, 78.2, 70.9, 69.5, 57.0, 56.1, 54.4, 30.1, 28.1, 25.7, 23.8, 19.0, 17.8; m/z (ESI) 452.2357 ([M+Na]+; C20H35N3O7Na requires 452.2372)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([C:35](O)=[O:36])[C:29]=2[CH:28]=[CH:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35]([C:30]4[CH:31]=[CH:32][CH:33]=[C:34]5[C:29]=4[CH:28]=[CH:27][NH:26]5)=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5[nH]ccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1H-indole-4-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.