Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].C(O)(=O)C.[CH3:17][C:18]([CH:21]=O)([CH3:20])[CH3:19]>CO>[CH2:6]([O:5][C:1]([NH:2]/[N:3]=[CH:17]/[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)/C=N/NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
Benzyl carbazate (300 g, 1.81 moles) was dissolved in 1.2 L of methyl alcohol in a 3 L 4-neck flask equipped with reflux condenser, thermometer, magnetic stirring, and a 500 mL addition funnel. Glacial acetic acid (5 mL) was added to the mixture that was then brought to 45° C. Pivaldehyde (248.8 g of solution, 2.17 moles, ca. 75% in t-butanol) was added portionwise over 30 minutes. The reaction was heated at reflux for 30 minutes, while monitoring by TLC. The mixture was allowed to cool to nearly room temperature and was concentrated on a rotary evaporator to a total volume of ca. 700 mL. Ca. 7 g activated charcoal was added at ca. 30° C. The mixture was stirred overnight and filtered through a pad of Celite in a pore size “C” glass fritted Büchner funnel. The solvent was removed in vacuo to leave a light yellow oil that was poured into a crystallizing dish and induced to crystallize by manipulation with a spatula. The material was granulated and residual solvent was allowed to evaporate in air at room temperature for several days, leaving 420.4 g crude product. Recrystallization at room temperature from an initially boiling mixture of 300 mL ethyl acetate and 1 L hexanes produced 363.2 g of (E)-N′-(2,2-dimethyl-propylidene)-hydrazinecarboxylic acid benzyl ester as an off-white solid. A second crop of 43.1 g and identical melting point was obtained from a mixture of ca. 150 mL hexanes and 45 mL ethyl acetate. Total yield: 96.1%. Rf=0.32 (2:1 hexanes:ethyl acetate); mp=74-74.5° C.; 1H NMR (400 MHz, CDCl3) δ 8.0 (1H, br s), 7.4-7.3 (5H, m), 7.1 (1H, s), 5.20 (2H, s), 1.1 (9H, s).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid chloride (2.5 ml, 32.7 mmol, 1.5 eq) was added to an ice-cooled (0° C.) solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (5.0 g, 21.8 mmol, 1 eq) and triethylamine (6 ml, 43.6 mmol, 2 eq) in dichloromethane (30 ml), and stirring was carried out for 1 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was diluted with dichloromethane (100 ml), washed with water and sat. NaCl solution (in each case 50 ml), dried over sodium sulfate and concentrated under reduced pressure. A yellow oil was obtained, which was used in the next step without being purified further.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[N+:21]([O-])([OH:23])=[O:22]>>[Cl:1][C:2]1[CH:3]([CH2:12][C:13]2[CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])[NH:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: Cn1nc(Cc2cccc(Cl)c2Cl)c(Cl)c1OC(F)F
Reactant: O=[N+]([O-])O
Product: CN1NC(Cc2cc([N+](=O)[O-])cc(Cl)c2Cl)C(Cl)=C1OC(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At −10° C., 6.6 g (19 mmol) of 4-chloro-3-(2,3-dichlorobenzyl)-5-difluoromethoxy-methyl-1H-pyrazole were dissolved in 100 ml of nitric acid. After 30 minutes, the mixture was warmed to 0—5° C. and 200 g of ice were added. The product of value was then extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and finally concentrated. The product of value was purified by MPLC over silica gel (eluent: cyclohexane/ethyl acetate=4:1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][C@:4]1([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[C:6]#N.[OH-:18].[Na+].Cl>ClCCl>[C:8]1([C@:4]23[CH2:5][C@H:3]2[CH2:2][O:1][C:6]3=[O:18])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: [OH-]
Reactant: N#C[C@@]1(c2cccc3ccccc23)CC1CO
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OC[C@@H]2C[C@]12c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
(1S)-2-hydroxymethyl-1-(1-naphthyl)-cyclopropanecarbonitrile (300 mg, 1.3 mmol) ethanol (0.6 mL) and 25N sodium hydroxide solution (0.3 mL) were heated under reflux for 18 hours. The reaction is monitored by TLC (dichloromethane (100%)). The reaction mixture was cooled to room temperature and ice cold water (12 mL) was added to the reaction mixture followed by concentrated hydrochloric acid drop to adjust the pH of the reaction mass to 1-2 and stirred for overnight. The aqueous layer was extracted with dichloromethane (25 mL). The organic layer was washed with 3% sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 128 mg (44%) of product. 1H NMR δ(300 MHz,CDCl3): 1.51-1.54 (1H,t, J=4.58,), 1.74-1.78 (1H,dd, J=7.7,4.8 Hz), 2.53-2.57 (1H,m), 4.43-4.46 (1H,d,J=9.5 Hz), 4.71-4.76 (1H,dd,J=9.3,4.5 Hz), 7.40-7.58 (4H,m), 7.83-7.89 (2H,m), 7.95-7.98 (1H d,J=8.2 Hz).
Reaction SMILES: C(O[C:4](=[O:29])[C:5]([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:24]([C:5]1[C:4](=[O:29])[C:13]2[C:8](=[CH:9][C:10]([CH2:14][O:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(=O)C(=CNc1cccc(COC(=O)c2ccccc2)c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2cc(COC(=O)c3ccccc3)ccc2c1=O
Yield: 34.6 %

Procedure:
Ethyl-2-butyryl-3-(3-benzoyloxymethylphenylamino)-acrylate (34.37 g, 86.9 mmol) was added portionwise to refluxing diphenyl ether (300 ml) then heated at reflux for 1 hour. After cooling, petroleum ether (b.p. 40°-60°) was added, and the precipitated solid filtered off. Purification by column chromatography (silica, methanol-chloroform) gave the title compound as a solid (10.52 g) m.p. 228°-31°, from dichloromethane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(I)cc1
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Product: Cc1cc(SCC#Cc2ccc(Cl)cc2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and 1-chloro-4-iodo-benzene gave the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+].I[CH2:30][CH:31]([OH:34])[CH2:32][OH:33].O>CN(C)P(N(C)C)(N(C)C)=O.CCOCC>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCC(O)CI
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 7.34 g of 4-(n-hexadecylamino)benzoic acid, 4.80 g of 25% aqueous sodium hydroxide, and 12.6 g of 3-iodo-1,2-propanediol in 50 ml of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate, m.p. 112° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[C:4]([NH:16][S:17](=[O:27])(=[O:26])[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:3]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36].[N-:37]=[N+:38]=[N-:39].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[NH:39][N:38]=[N:37][N:15]=3)[CH:9]=2)[N:5]=[C:4]([NH:16][S:17](=[O:26])(=[O:27])[NH:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:3]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1NS(=O)(=O)NCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(-c3nnn[nH]3)c2)nc1NS(=O)(=O)NCc1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 37 %

Procedure:
Benzylsulfamic acid [6-chloro-2-(2-cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide (4.17 g) was dissolved in DMF (55 ml). Sodium azide (5.2 g) and ammonium chloride (4.28 g) were added and the mixture was stirred for 20 h at 80° C. Then the mixture was pored onto water and extracted with EtOAc. The layers were separated and the water layer was acidified with acetic acid to pH ˜5 and extracted with EtOAc. The combined organic layers from the 2nd extraction were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude material was purified by chromatography over silicagel with EtOAc/MeOH/ammonia=5/1/0.5 to give benzylsulfamic acid [6-chloro-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl]-amide (1.67 g). LC-MS: tR=5.02; [M+H]+=566.36.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[Cl:18][C:10]1[NH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:12]([C:13]#[N:14])[CH:11]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: N#Cc1cc[nH]c1-c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: N#Cc1cc(Cl)[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
To a 35° C. magnetically stirred solution of 2.40 g (11.8 mmol, 1.00 equivalent) of 2-(p-chlorophenyl)pyrrole-3-carbonitrile, and 65 mL of glacial acetic acid is added dropwise by syringe 0.75 mL (1.26 g, 9.34 mmol., 0.79 equivalent) of sulfuryl chloride over a period of 5 minutes. Approximately 5 minutes after the completion of the addition, a solid precipitated out of the reaction solution. After stirring at room temperature for 45 minutes, the reaction mixture is filtered and the collected solid is washed well with cold acetic acid to give 2.08 g (74% crude yield) of an off-white solid. This solid is recrystallized from 75 mL of hot acetic acid to give 1.63 g (58% yield) of 97 wt % pure. Product mp 258.5°-261° C.
Reaction SMILES: [CH2:1]([OH:24])[C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[O:25]1CCO[CH2:27][CH2:26]1>>[C:26]([O:24][CH2:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)(=[O:25])[CH3:27]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Reactant: C1COCCO1
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 89 %

Procedure:
1.16 g (3.5 mmoles) of 4-pregnene-3,20-dione-21-ol [prepared as described in Step (c) above] are acetylated as described in Example 2 to give 1.16 g (89% yield) of the aimed product, m.p.: 156°-158° C., [α]D =+174° (c=1.0 in dioxane).
Reaction SMILES: [F:1][C:2]1[C:3]([Si](C)(C)C)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[C:7]2([CH3:14])[CH3:13].[I:19]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:1][C:2]1[C:3]([I:19])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[C:7]2([CH3:14])[CH3:13]
Reactant: CN1C(=O)C(C)(C)c2ccc([Si](C)(C)C)c(F)c21
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)C(C)(C)c2ccc(I)c(F)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-fluoro-1,3,3-trimethyl-6-(trimethylsilyl)indolin-2-one (9.9 g, 37.3 mmol) in dichloromethane (500 ml) at 0° C. was added iodine monochloride (37.3 ml, 37.3 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as off-white crystals (9.82 g).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][N:4]1[C:9]([SH:10])=[CH:8][C:7](=[O:11])[N:6]([CH3:12])[C:5]1=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>CN(C)C=O.ClCCl.[Ti](Cl)(Cl)(Cl)Cl.O>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][N:4]1[C:9]2[S:10][CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:8]=2[C:7](=[O:11])[N:6]([CH3:12])[C:5]1=[O:13]
Reactant: Cn1c(=O)cc(S)n(CC(C)(C)C)c1=O
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2CC(C)(C)C
Reaction time: 0.17 h

Procedure:
To the product of step b) (6.3 g) in dry dimethylformamide (100 ml) was added potassium carbonate (1.9 g) and stirred for 10 min. Ethyl bromopyruvate (4 ml) was added and was stirred under nitrogen at room temperature for 2 h. The reaction was poured into water (1 L) and acidified (2M HCl) and extracted with ethyl acetate. The combined organics were washed with brine (100 ml). Drying and evaporation afforded an oil. The oil was dissolved in dichloromethane (100 ml) and cooled in ice whilst stirring. Titanium tetrachloride (6 ml) was added and stirring continued under nitrogen for 2 hours. The reaction was poured into water (1 L) and extracted with dichloromethane (×2). The combined organics were dried and concentrated in vacuo. The residue was purified by chromatography (SiO2/ethyl acetate-dichloromethane 0-8%) to afford the subtitle compound as an orange oil, 6.2 g
Reaction SMILES: C1(SCl)C=CC=CC=1.[CH2:9]([S:19][Cl:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCC.ClC(SCl)=CCl.C1C2C(=CC=CC=2)C=CC=1SCl.C1(SCl)CCCCC1>>[C:10]1([CH2:9][S:19][Cl:20])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCCCCCCCCSCl
Agent: ClC=C(Cl)SCl
Agent: ClSC1CCCCC1
Agent: ClSc1ccc2ccccc2c1
Product: ClSCc1ccccc1

Procedure:
Similarly, repeating the above procedure but replacing the benzenesulfenyl chloride as used therein with an equal molar proportion of each of decanesulfenyl chloride (prepared by chlorination of decanedisulfide according to the method of Douglass, supra.), 1,2-dichlorovinylsulfenyl chloride, 2-naphthalenesulfenyl chloride, cyclohexanesulfenyl chloride (prepared by chlorination of cyclohexanedisulfide, according to the method of Douglass, supra.) and α-toluenesulfenyl chloride, respectively, there is obtained:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:28][CH:22]([C:23]5([F:31])[F:30])[CH2:21]3)[CH2:27]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:28][CH:22]([C:23]5([F:31])[F:30])[CH2:21]3)[CH2:27]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)-methoxy)-2-fluorobenzoate (1.0 g, 2.29 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was triturated in mixture of dichloromethane and hexanes afforded the title compound as colorless solid (0.82 g, 94%): 1H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.34 (d, J=8.5 Hz, 1H), 6.88 (d, J=13.1 Hz, 1H), 3.57 (s, 2H), 2.24 (br s, 2H), 2.04-1.95 (m, 2H), 1.87-1.68 (m, 10H), 0.93-0.87 (m, 2H), 0.65-0.56 (m, 2H); MS (ES+) m/z 381.1 (M+1); MS (ES−) m/z 379.2 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:29])=O>>[N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]([Cl:29])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl

Procedure:
An amount of 550 g of 2-(p-nitrophenoxy)-myristic acid is heated together with 550 ml of thionyl chloride for 1 h to 60° C. so that a solution is obtained. The excess thionyl chloride is filtered off. Yield: 585 g (100%) of 2-(p-nitrophenoxyl]-myristoyl chloride (oil).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=O>>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:29]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: O=C(CBr)c1ccccn1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccn3)cs2)C1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 76 mg (0.269 mmol) of 2-bromo-1-pyridin-2-ylethanone were reacted according to the General Method 3. Yield: 8 mg (7% of theory)
Reaction SMILES: [CH:1]1([C:7]([C:9]2[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][CH:14]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:18]1[CH:23]=CC=C2C([O:26][C:27](=[O:28])[C:19]=12)=O.C1([Mg]Cl)CCCCC1>>[CH:1]1([C:7]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:15](=[O:17])[N:18]([CH3:23])[C:19]=2[C:27]([OH:28])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ncccc1C(=O)C1CCCCC1
Reactant: O=C1OC(=O)c2ncccc21
Agent: Cl[Mg]C1CCCCC1
Product: Cn1c(C(=O)O)c(C2CCCCC2)c2cccnc2c1=O

Procedure:
Starting from 3-cyclohexylcarbonyl-2-pyridinecarboxylic acid, which was prepared from 2,3-pyridinedicarboxylic anhydride and cyclohexylmagnesium chloride, substantially the same reaction and work-up as in Reference Exampe 1-Process 2-Step 1 to Step 4 were conducted to give the title compound as a pale yellow oil, which was used for the reaction of Example 76.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH:15]=[CH2:16])[CH3:14])(=[O:11])[CH3:10].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>C1COCC1>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]([CH2:10][C:9]([O:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH:15]=[CH2:16])[CH3:14])=[O:11])=[O:34]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide in the amount of 101.0 mL (2.0 M, 0.202 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is placed in a dry ice-acetone bath. Linalyl acetate in the amount of 18.66 g (0.095 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of 2-naphthoyl chloride in the amount of 17.43 g (0.090 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (53 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 5% ethyl acetate dissolved in petroleum ether) to give an oil. Purity of the product is determined by thin layer chromatography and GC analysis and the structure confirmed by mass spectrometry, 1 and 13C NMR.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:20][C:21]1[CH:22]=[C:23]([SH:28])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[CH3:20][C:21]1[CH:22]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: CC1(C)OC(=O)Nc2c(OCCCCCl)cccc21
Reactant: Cc1ccc(S)cc1C
Product: Cc1ccc(SCCCCOc2cccc3c2NC(=O)OC3(C)C)cc1C

Procedure:
Prepared analogously to Example 1 from 8-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethyl-thiophenol.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[O:12]3)[C:5]=12>CCOC(C)=O.[Pd]>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[O:12]3)[C:5]=12
Reactant: O=C1OC(=Cc2cccn3ccnc23)c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1OC(Cc2cccn3ccnc23)c2ccccc21
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 3-(imidazo[1,2-a]pyridin-8-ylmethylene)isobenzofuran-1(3H)-one (180 mg, 0.69 mmol) in EtOAc (12 mL) was added 10% Pd/C (110 mg). The mixture was stirred under a hydrogen balloon overnight. The catalyst was filtered off and the filtrate was concentrated and purified on silica gel with 10% MeOH/DCM as eluent to give 3-(imidazo[1,2-a]pyridin-8-ylmethyl)isobenzofuran-1(3H)-one (140 mg, 78%). 1H NMR (400 MHz, CD3OD) δ=8.37 (d, 1H), S 7.88 (s, 1H), 7.83 (d, 1H), 7.74-7.63 (m, 2H), 7.60-7.53 (m, 2H), δ 7.22 (d, 1H), 6.86 (t, 1H), 6.04 (dd, 1H), 3.76 (dd, 1H), 3.24 (dd, 1H). LRMS (M+H+) m/z 265.1