Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[F:15][C:16]1[C:23]([F:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[C:21]([F:29])=[C:20]([F:30])[C:17]=1[CH2:18]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([NH:14][CH2:18][C:17]2[C:20]([F:30])=[C:21]([F:29])[C:22]([C:25]([F:26])([F:28])[F:27])=[C:23]([F:24])[C:16]=2[F:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: CC(=O)Oc1ccc(N)cc1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)cc1C(=O)O
Yield: 53 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 2-ethanoyloxy-5-aminobenzoic acid (0.81 g, 4.10 mmole) which was prepared from Synthesis Example (14-3), DMF (15 ml), TEA (0.1 ml), tetrabutyl ammonium iodide (5 mg), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.02 ml, 6.15 mmole), 0.92 g (53.0% yield) of was obtained 2-ethanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[ClH:36].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:36].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:22]5[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:34])[F:35])=[CH:20][CH:21]=5)=[CH:30][CH:29]=4)=[O:32])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl.[Al+3].[Cl-].[Cl-].[Cl-]>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:10][CH:9]=1
Reactant: COc1ccccc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A procedure similar to step 2 of Example 47 was used. Propionyl chloride prepared in the step 1 and methylphenyl ether were used as starting materials, allowed to react in dichloromethane with AlCl3 as catalyst, stirred at −5° C. to −10° C. for 30 minutes and then at room temperature for 1 hour, a crude product was obtained, purified under a reduced pressure by silica gel column chromatography eluted with petroleum ether and ethyl acetate at a ratio of 25:1 (V:V) to obtain a product of colorless liquid in a yield of 71.8%, 1H-NMR (CDCl3, 400 MHz) δ: 1.22 (3H, t, J=7.00 Hz, CH2CH3), 2.96 (2H, q, J=7.00 Hz, CH2CH3), 3.87 (3H, s, OCH3), 6.93 (2H, d, J=8.72 Hz, ArH), 7.95 (2H, d, J=8.72 Hz, ArH); ESI-MS: 187.2 (M+Na, 20), 165.2 (M+1, 100).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9](F)=[CH:10][CH:11]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]2=[O:26])=[CH:4]1)[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][OH:34].[H-].[Na+]>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([O:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[CH:10][CH:11]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]2=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c2ccc(F)nc21
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c2ccc(OCc3ccccn3)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a stirred solution of tert-butyl 4-(1-ethyl-6-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-oxopiperazine-1-carboxylate (5.00 g, 13.80 mmol) and 2-pyridine methanol (1.60 mL, 16.56 mmol) in dimethyl sulphoxide (50 mL), under a nitrogen atmosphere, is added 60% sodium hydride (0.662 g, 16.56 mmol) portionwise. The reaction is stirred at room temperature for 1 h and then heated at 135° C. overnight. The reaction is cooled to room temperature and further 60% sodium hydride (0.662 g, 16.56 mmol) added, and the reaction stirred overnight at room temperature. The reaction is poured onto brine (ca. 500 mL) and the product extracted with CHCl3 (ca. 2×300 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 80% EtOAc in DCM, to give the title compound as an orange foam (4.952 g, 10.97 mmol). MS (m/z): 452 (M+1).
Reaction SMILES: [Cl-].[Gd+3:2].[Cl-].[Cl-].[CH2:5]([N:16]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][C:18]([OH:20])=[O:19])[CH2:6][N:7]([CH2:12][C:13]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=[O:10].C1C(C(N)=O)=CN(C2OC(COP(OP(OCC3OC(N4C5N=CN=C(N)C=5N=C4)C(OP([O-])([O-])=O)C3O)([O-])=O)([O-])=O)C(O)C2O)C=C1.[Na+:73].[Na+].[Na+].[Na+]>O>[Na+:73].[CH2:6]([N:7]([CH2:12][C:13]([O-:15])=[O:14])[CH2:8][C:9]([O-:11])=[O:10])[CH2:5][N:16]([CH2:21][C:22]([O-:24])=[O:23])[CH2:17][C:18]([O-:20])=[O:19].[Gd+3:2]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: NC(=O)C1=CN(C2OC(COP(=O)([O-])OP(=O)([O-])OCC3OC(n4cnc5c(N)ncnc54)C(OP(=O)([O-])[O-])C3O)C(O)C2O)C=CC1
Agent: [Cl-]
Agent: [Gd+3]
Solvent: O
Product: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Reaction time: 0.25 h

Procedure:
Gadolinium chloride (10 mmol) was dissolved in water (5 ml). Ethylenediaminetetraacetic acid, tetrasodium salt hydrate (10 mmol) was dissolved in water (10 ml) and added portionwise to the gadolinium chloride solution. The solution became warm, and after ca. 15 minutes, a white precipitate was formed. The mixture was left for a further 2 hours. The precipitate was filtered off to give a white solid which was washed with water (2×5 ml) and dried in air to yield Gadolinium ethylenediaminetetraacetate sodium salt, Na[Gd(EDTA)]
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:7]([OH:8])[CH:6]=[CH:5][CH2:4]1.[C:9]([Si:13](Cl)([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)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:13]([O:1][CH2:2][C@H:3]1[C@@H:7]([OH:8])[CH:6]=[CH:5][CH2:4]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC[C@@H]1CC=C[C@@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1CC=C[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of (1S,5S)-5-(hydroxymethyl)cyclopent-2-en-1-ol (1.14 g, 9.99 mmol) in DCM (50.0 mL) was added TEA (4.18 mL, 30.0 mmol) and DMAP (60.0 mg, 0.491 mmol). The solution was cooled to 0° C., tert-butylchlorodiphenylsilane (3.90 mL, 15.0 mol) was added and the mixture was stirred at rt for 2 h. TLC indicated complete conversion, and the reaction was quenched by addition of MeOH (1.00 mL). Concentration in vacuo and silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes afforded the title compound (2.88 g, 86%). LC/MS: Rt=2.51 min, ES+ 353 (AA standard).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[NH:7]1[C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: O=C(O)CCNc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: O=C1CCNc2ccccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
The mixture of 3-phenylamino-propionic acid (1.22 g, 7.39 mmol) in Eaton's reagent (40 mL) is stirred at 70° C. for overnight. The resulting mixture is poured into ice and basified by the slow addition of NaOH (50%) solution. The basified mixture is extracted with ethyl acetate and washed by brine, and dried over anhydrous sodium sulfate. After concentration, the residue is purified by flash chromatography, and gives the title compound (0.5 g, 46.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[N:29]=[C:30]([CH3:33])[NH:31][CH:32]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[N:29]=[C:30]([CH3:33])[NH:31][CH:32]=1)=[O:27]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: Cc1nc(C(=O)CBr)c[nH]1
Product: COC(=O)Cc1c(C(=O)c2c[nH]c(C)n2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 4-bromoacetyl-2-methylimidazole (Deady, Leslie W. et al., Aust. J. Chem., 1981, 34, 1295).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([OH:13])[CH:5]=1)[CH3:2].[C:14](OCC)(=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].[O-]CC.[Na+].Cl>C(O)C.O.C(OCC)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7]([C:10](=[O:12])[CH:11]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:13]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOc1ccc(C(C)=O)c(O)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc(=O)c2ccc(OCC)cc2o1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-ethoxy-2-hydroxyphenyl)ethanone (Aldrich, 5.0 g, 27.7 mmol) and diethyl oxalate (8.3 mL, 61 mmol) in ethanol (50 mL) was added sodium ethoxide (21% in EtOH, 31 mL, 83 mmol) and the mixture was refluxed for 1.5 hours. The mixture was cooled to ambient temperature, diethyl ether (150 mL), water (150 mL) and 12N hydrochloric acid (7 mL) were added. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and was concentrated under reduced pressure to afford ethyl 7-ethoxy-4-oxo-4H-chromene-2-carboxylate. The intermediate was dissolved in acetic acid (70 mL) and 12N hydrochloric acid (8.5 mL), heated to reflux for 2 hours, and cooled to ambient temperature. Water (300 mL) was added and the solids were collected by filtration, rinsed with water, and freeze-dried to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (t, 3H), 4.20 (q, 2H), 6.84 (s, 1H), 7.08 (dd, 1H), 7.19 (d, 1H), 7.92 (d, 1H). MS (APCI) m/z 235.04 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:14])[N:3]=1.[CH3:34]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:20]2[CH:19]=[N:18][C:17]3[C:21]2=[N:22][CH:23]=[N:24][C:16]=3[NH:15][C@H:13]([C:4]2[N:3]=[C:2]([CH3:34])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:12])[CH3:14])=[CH:27][CH:28]=1
Reactant: CB(O)O
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C)n4)ncnc32)cc1
Temperature: 25 °C

Procedure:
(S)-9-(4-Methoxybenzyl)-N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9H-purin-6-amine (1) (2.0 g, 4.2 mmol, 1.0 eq), methylboronic acid (277 mg, 4.62 mmol, 1.1 eq), Pd(PPh3)4 (485 mg, 0.42 mmol, 0.1 eq) and Na2CO3(1.34 g, 12.6 mmol, 3.0 eq) were suspended in a mixture of 1,4-dioxane (30 mL) and water (10 mL). The resulting mixture was degassed and back-filled with argon three times and then stirred at reflux under argon for 16 h. The mixture was allowed to cool to RT, concentrated in vacuo and the residue was purified by column chromatography on silica gel (1-3% MeOH-DCM) to afford the product, (S)-9-(4-methoxybenzyl)-N-(1-(8-chloro-1-methylisoquinolin-3-yl)ethyl)-9H-purin-6-amine (168). Compound 168 was then converted to compound 169 using the analogous procedures for the synthesis of 151 in Example 91 except that pyridin-3-ylboronic acid was used in place of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The PMB group of compound 169 was then subsequently deprotected using Method L to afford compound 170. ESI-MS m/z: 382.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[C:59]([CH3:64])=NOC=1C)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH2:58]([NH:55][C:56]([N:50]1[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48][CH2:49]1)=[O:57])[C:59]1[CH:64]=[CH:3][CH:2]=[CH:17][CH:16]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)NCc2ccccc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-isocyanato-3,5-dimethylisoxazole as starting materials in 30% yield. LCMS for C30H33ClN9O3 (M+H)+: m/z=602.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:21][C:22]1[N:26]([CH:27]2[CH2:29][CH2:28]2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[Cl:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([C:23]1[CH:24]=[N:25][N:26]([CH:27]2[CH2:29][CH2:28]2)[C:22]=1[OH:21])=[O:5]
Reactant: Oc1ccnn1C1CC1
Reactant: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C4CC4)c3O)c2Cl)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
At 0–5° C., a solution of 1.0 g (3 mmol) of 2-chloro-3-(3-methyl-4,5-dihydroisoxazol-5-yl)-4-methylsulfonylbenzoyl chloride in 50 ml of dimethoxyethane was added dropwise to a solution of 0.47 g (3 mmol) of 5-hydroxy-1-cyclopropylpyrazole and 0.5 g (3.6 mmol) of potassium carbonate in 36 ml of anhydrous dimethoxyethane. After 12 hours of stirring at room temperature, a further 1.0 g (7.2 mmol) of potassium carbonate were added and the batch was refluxed for 6 hours. After cooling, the reaction mixture was stirred into 600 ml of water and extracted with methylene chloride. The aqueous phase was then adjusted to pH 4 using 10% strength hydrochloric acid and extracted with methylene chloride. Drying of the organic phase and removal of the solvent gave 0.8 g (1.8 mmol, 63%) of the desired compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][CH2:6][C:7]1[C:8]([O:17][CH3:18])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([NH2:14])=[O:13])=[O:4].C(Cl)(=O)[C:22](Cl)=[O:23]>C(Cl)CCl>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][CH2:6][C:7]1[C:8]([O:17][CH3:18])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([N:14]=[C:22]=[O:23])=[O:13])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Cl)c(C(N)=O)cc1CNC(=O)C(F)(F)F
Solvent: ClCCCl
Product: COc1cc(Cl)c(C(=O)N=C=O)cc1CNC(=O)C(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-methoxybenzamide (1.0 g, 3.6 mmol), oxalyl chloride (1.0 mL) and EDC (10 mL) to afford 0.750 g of the desired product.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].C[O-].[Na+]>CO>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][C:1]([O:8][CH2:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:7])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: COC(=O)CC(=O)OC
Reactant: C=CCCCCCCCCO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCCCCCCCCOC(=O)CC(=O)OCCCCCCCCC=C
Reaction time: 6 h
Yield: 59.7 %

Procedure:
To a mixture of 150 g dimethyl malonate and 464 g dec-9-en-1-ol, 30 g sodium methoxide (5.4 M in methanol) was dropped in. The mixture was heated to 120° C. to and the methanol formed was distilled off. After 6 hours, the mixture was cooled down, diluted with ether and washed with HCl 2N, saturated sodium bicarbonate and water. The organic phase was dried, filtered and evaporated to dryness. The resulting yellow oil was purified by distillation to yield 258 g of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:13]2([C:26]([O:28]C)=[O:27])[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>[OH-].[Na+].CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:13]2([C:26]([OH:28])=[O:27])[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C1(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
A heterogeneous mixture of 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-4-[carbomethoxy]-piperidine (1.2 g, 2.26 mmol) in 50% aqueous sodium hydroxide (10 mL) and methanol (50 mL) is heated to reflux for 16 hours. The methanol is evaporated and the residue is neutralized with 4N hydrochloric acid. The aqueous solution is extracted with ethyl acetate. The combined organic extracts are dried (NaSO4) and the solvent is evaporated to give 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-4-[carboxy]-piperidine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:17]([O:19]CC)=[O:18].[OH-].[Na+].Cl>C(O)C>[C:13]([O:12][C:10]([C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[C:2]([C:17]([OH:19])=[O:18])[O:1][C:5]=2[CH:6]=1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1cc2ccc(C(=O)OC(C)(C)C)cc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc2cc(C(=O)O)oc2c1

Procedure:
A solution of 6-tert-butyl 2-ethyl 1-benzofuran-2,6-dicarboxylate (490 mg, 1.68 mmol) in ethanol (15 ml) was admixed with sodium hydroxide solution (3.36 ml, 1 M) and heated under reflux for 2 h. The cooled solution was added to ice-cooled hydrochloric acid (1 M), and the precipitate was filtered off with suction, washed with a little water and dried under reduced pressure.
Reaction SMILES: [NH4+].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9])#[N:3].Cl>>[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[N:3]
Reactant: N#CCCCCC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Product: N#CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A 200-mL portion of the filtrate of the product mixture described above, containing the 5-cyanopentanoic acid ammonium salt (1.13M ), was adjusted to pH 2.5 with 6N HCl, then saturated with sodium chloride and extracted with 4×200 mL of ethyl ether. The combined ether extracts were dried over magnesium sulfate, filtered, and the solvent removed by rotary evaporation at reduced pressure. Remaining ether was removed by stirring the colorless liquid at room temperature under high vacuum (60 millitorr) for 5 h to yield 27.32 g (95% isolated yield) of 5-cyanopentanoic acid. The 5-cyanopentanoic acid was then distilled under vacuum (75 millitorr) at 110°-112° C. without decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)=[O:21].C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)=[O:21])=[O:5]
Reactant: O=C(CCCCCCCBr)OCc1ccco1
Reactant: O=C(O)c1cc(O)ccc1O
Solvent: CC#N
Solvent: O
Product: O=C(CCCCCCCOC(=O)c1cc(O)ccc1O)OCc1ccco1

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (4.8 g), 1,8-diazobicyclo[5.5.0]undec-7-ene (4.7 g), 2-furylmethyl 8-bromooctanoate (7.8 g) and acetonitrile (150 ml) was heated, under reflux for 18 h. The cooled reaction mixture was added to water (500 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and water (2×20 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuum. The residue (8.4 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (5:1) as eluent, to give 8-(2-furylmethoxy)-8-oxooctyl 2,5-dihydroxybenzoate as colourless oil.
Reaction SMILES: C(O[C@H:5]1[C@H:10]2[C@H:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@:7]([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:8][O:9]2)[O:6]1)(=O)C.[C:29]([NH:37][C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[NH:40][CH:41]=[N:42]2)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:29]([NH:37][C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[C@@H:5]1[C@H:10]2[C@H:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@:7]([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:8][O:9]2)[O:6]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)O[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: O=C(Nc1ncnc2c1ncn2[C@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A solution of furanose 207 (167 mg, 0.434 mmol) and 6-N-benzoyladenine (194 mg, 0.813 mmol) in anhydrous acetonitrile (5.3 mL) was added BSA (0.43 mL, 1.76 mmol) and stirred at room temperature for 1 h. The solution was cooled to 0° C. and trimethylsilyl triflate (0.16 mL, 0.86 mmol) was added dropwise. After stirring at 65° C. for 2 h, the reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate (40 mL) and the mixture was extracted with dichloromethane (2×50 mL). The combined extract was dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by chromatography over silica gel with dichloromethane:methanol (98:2) as eluent to give the product 208 as a solid (111 mg, 45%); 1H NMR (CDCl3): δ 8.82 (1 H, s, H-8), 8.14 (1 H, s, H-2), 7.59-7.26 (15 H, m, Bz, Bn), 6.74 (1 H, s, H-1′), 4.92 (1 H, s, H-2′), 4.74-4.39 (4 H, m, Bn), 4.42 (1 H, s, H-3′), 4.19-4.10 (2 H, m, H-5″), 3.92 (1 H, d, J 11.8 Hz, H-5′), 3.88 (1 H, d, J 11.5 Hz, H-5′); MS FAB: 564 (M+H, 100%).