Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1COC2C=CC=C(OCC3C=CC=CC=3)C=2OC1C#N.[O:23]=[C:24]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:27]=2[O:26][CH2:25]1.[C-]#N.[K+]>>[OH:23][C:24]1([C:2]#[N:1])[CH2:30][O:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:27]=2[O:26][CH2:25]1
Reactant: N#CC1Oc2c(OCc3ccccc3)cccc2OCC1N
Reactant: O=C1COc2cccc(OCc3ccccc3)c2OC1
Agent: [C-]#N
Agent: [K+]
Product: N#CC1(O)COc2cccc(OCc3ccccc3)c2OC1

Procedure:
The 3-amino-4-cyano-6-benzyloxy-3,4-dihydro-2H-1,5-benzodioxepin and/or its 9-benzyloxy isomer is converted to 3-oxo-6-benzyloxy-3,4-dihydro-2H-1,5-benzodioxepin by the procedure described in Example 1, Step C, and the 3-keto compound then reacted with potassium cyanide by either the process of Step D of Example 1 or the alternative procedure there described to provide 3-hydroxy-3-cyano-6-benzyloxy-3,4-dihydro-2H-1,5-benzodioxepin. This product then is reduced with lithium aluminum hydride by the method outlined in the alternate of Step E, Example 1, to give 3-hydroxy-3-aminomethyl-6-benzyloxy-3,4-dihydro-2H-1,5-benzodioxepin which when reacted with acetone and then reduced by the process of Step F, Example 1, there is obtained 3,6-dihydroxy-3-isopropylaminomethyl-3,4-dihydro-2H-1,5-benzodioxepin hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)c1ccc(OCCCCl)cc1
Yield: 96.8 %

Procedure:
A mixture of 50 g (0.365 mole) of 4-hydroxybenzamide, 114.8 g (0.729 mole) of 1-bromo-3-chloropropane and 151.3 g (1.1 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure and the rsidue was stirred with 1.2 liter of water to remove inorganic solids. The mixture was filtered and the filter cake was washed with water and petroleum ether and dried to yield 75.5 g (97%) of the title compound as a white solid. An analytical sample was recrystallized from ethyl acetate, m.p. 142°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[CH:11]=[O:12].[I:13]I.[I-].[Na+].[OH-].[Na+]>CCO.OS([O-])=O.[Na+]>[F:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH:9]=[C:10]([I:13])[C:4]=2[C:3]=1[CH:11]=[O:12]
Reactant: II
Reactant: O=Cc1c(F)cnc2[nH]ccc12
Agent: O=S([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: O=Cc1c(F)cnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 151 %

Procedure:
To a solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (2.45 g, 14.93 mmol) in EtOH (20 mL) was added iodine (4.55 g, 17.91 mmol), sodium iodide (2.68 g, 17.91 mmol) and aqueous NaOH (1N, 15 mL). The reaction mixture was stirred for 4 h at 25° C. and diluted with aqueous NaHSO3 (0.1N). An orange precipitate was collected by filtration and dried under vacuum to afford the title compound as a yellow solid (6.54 g, 82%). [M+H] calc'd for C8H4F1N2O, 291; found, 291.5.
Reaction SMILES: [CH3:1][N:2]([O:12][CH3:13])[C:3](=[O:11])[C:4](=[O:10])[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.B1([C@H]2[C@H](C)[C@@H]3C(C)(C)[C@H](C3)C2)C2CCCC1CCC2.C(=O)C(C)C.C(CN)O>C1COCC1.CCOCC>[CH3:1][N:2]([O:12][CH3:13])[C:3](=[O:11])[C@@H:4]([OH:10])[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9]1
Reactant: CON(C)C(=O)C(=O)CC1CCC1
Agent: CC(C)C=O
Agent: C[C@@H]1[C@H]2C[C@H](C[C@H]1B1C3CCCC1CCC3)C2(C)C
Solvent: NCCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@@H](O)CC1CCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 11.40 g (61.5 mmol) of N-methyl-N-methoxy 2-oxo-3-cyclobutyl propanamide (from Step B) and 250 mL 0.5 N (R)-Alpine Borane® solution in THF was concentrated and stirred at rt for 5 days. The mixture was cooled to 0° C. and quenched with 6.8 mL (75.0 mmol) of isobutyraldehyde. The resulting mixture was diluted with 200 mL of ether and treated with 7.5 mL (125 mmol) of ethanolamine. The precipitate that formed was filtered and the filtrate was concentrated. Flash chromatography on 500 g of silica gel using 9:1 v/v CH2Cl2 as the eluant afforded 11.48 g (99%, 91% ee) of the title compound: 1H NMR (500 MHz) δ 1.59-1.70 (m, 2H), 1.67 (s, 1H), 1.77-1.83 (m, 2H), 1.82-1.92 (m, 1H), 2.03-2.13 (m, 2H), 2.53-2.60 (m, 1H), 3.23 (s, 3H), 3.72 (s, 3H), 4.31 (app d, J=5.5, 1H); HPLC: Chiralpak AS 4.6×250 mm column, 75/25 hexanes/iPrOH, 0.5 mL/min, 210 nm. Retention Times: (S)-Enantiomer, 13.3 min; (R)-enantiomer, 17.2 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9]2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[OH-].[NH4+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][N:10]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11][CH2:12][CH:13]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:23])[F:24]
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCCN(Cc2ccccc2)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1cc(C2=CCCN(Cc3ccccc3)C2)ccc1Cl
Yield: 92.5 %

Procedure:
A suspension of 25 g of the product of Step A in about 10 volumes of water cooled in an ice bath was made basic by addition of ammonium hydroxide and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 22 g of 3-(4-chloro-3-trifluoromethyl-phenyl)-1-benzyl-1,2,5,6-tetrahydropyridine which were dissolved in 250 ml of anhydrous xylene. The solution was refluxed for 5 hours with vigorous stirring while adding 10 g of phosphoric acid anhydride each hour for a total of 50 g and the mixture was allowed to stand overnight at room temperature. Then, ice was continuously added to the reaction mixture and the mass formed was dissolved in a mixture of water, ethyl acetate and triethylamine. After total dissolution, it was ascertained that the mixture was basic and the organic phase was washed with aqueous sodium chloride solution. The wash water was extracted with ethyl acetate and the combined organic phases were dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture. The fractions corresponding to the desired product were distilled to dryness and the residue was taken up in methylene chloride. The solution was filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 17 g of the said base. 7 g of the base were dissolved in 50 ml of ethyl acetate and a solution of gaseous hydrogen chloride in ethyl acetate was added thereto dropwise until the pH was acidic. The mixture was iced for 2 hours and was vacuum filtered and the recovered product was washed with ethyl acetate and was dried under reduced pressure to obtain 6.37 g of the desired hydrochloride which was crystallized from isopropanol to obtain 5.25 g of the product melting at 200° C.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:9]1[C:8]2[C:17]3=[C:16]4[C:5](=[CH:6][CH:7]=2)[CH:4]=[CH:3][CH:2]=[C:15]4[CH:14]=[CH:13][C:12]3=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2cc(-c3ccc4ccc5cccc6ccc3c4c56)ccc2c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
A mixed solution of 7.0 g of 1-bromopyrene, 4.7 g of 2-naphthaleneboronic acid, 11.6 g of tripotassium phosphate, 1.8 g of tetrabutylammonium bromide, 0.11 g of palladium acetate and 248 ml of dimethylformamide was heated with stirring under a nitrogen gas flow at 130° C. for 5 hours. After cooling the solution to room temperature, 300 ml of water was injected, followed by stirring at room temperature for 0.5 hours. The precipitated solid was collected by filtration and then washed twice with 100 ml of water. The resultant solid was dissolved in 200 ml of dichloromethane, dried over magnesium sulfate, evaporated and then filtered using Celite. The filtrate was evaporated and the residue was washed twice with 100 ml of methanol, and then the precipitated solid was collected by filtration. The solid was vacuum-dried to obtain 7.5 g of 1-(2-naphthyl)pyrene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.C(O)CCC.C(N(CC)CC)C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:1][C:2]1[C:7]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:6][CH:5]=[N:4][C:3]=1[Cl:9]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: NCc1ccccc1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1c(Cl)ncnc1NCc1ccccc1
Temperature: 100 °C
Yield: 96.1 %

Procedure:
To a solution of 5-amino-4,6-dichloropyrimidine (8.4 g, 0.051 mol) in 1-butanol (50.0 mL, 0.547 mol) was added triethylamine (12 mL, 0.084 mol) and benzylamine (17 mL, 0.15 mol), and the mixture was heated at 100° C. for 3 hours. The reaction was cooled at 0 C, filtered and washed with ethanol. The residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3, and concentrated. The residue was triturated in diethyl ether to obtain 11.5 g (96%) of a light brown solid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[C:8]1([CH2:18][CH2:19][CH2:20]I)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.Cl>O1CCCC1.O>[C:3]([CH:2]([CH2:20][CH2:19][CH2:18][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:1]#[N:5])#[N:4]
Reactant: N#CCC#N
Reactant: ICCCc1cccc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(C#N)CCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
A solution of 0.7 gram (0.011 mole) of malononitrile in 50 mL of tetrahydrofuran was stirred, and 0.5 gram (0.011 mole) of sodium hydride (60% in mineral oil) was added portionwise during a ten minute period. Upon completion of addition, the reaction mixture was stirred for 30 minutes at ambient temperature. After this time a solution of 3.0 grams (0.010 mole) of 3-(naphth-1-yl)propyl iodide (prepared as in Example 9, Steps A-D) in about 5 mL of tetrahydrofuran was added in one portion. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 20 hours. The reaction mixture was acidified with aqueous 6N hydrochloric acid and then was further diluted with 100 mL of water. The mixture was extracted with two 100 mL portions of diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated to a residue which was subjected to column chromatography on silica gel. Elution was accomplished using 40% to 65% methylene chloride and petroleum ether. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.1 grams of 2-cyano-5-(naphth-1-yl)pentanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:3]1.[CH3:17][N:18]([CH3:21])[S:19]Cl.O>N1C=CC=CC=1>[CH3:17][N:18]([CH3:21])[S:19][N:14]([CH3:15])[C:12](=[O:13])[O:11][C:8]1[C:9]2[O:10][C:2]([CH3:16])([CH3:1])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CN(C)SCl
Solvent: c1ccncc1
Solvent: O
Product: CN(C)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 18 h

Procedure:
A mixture of 16 g of carbofuran and 8.5 g of (dimethylamino)sulfenyl chloride in 50 ml of pyridine was allowed to stand at room temperature for about 18 hours. The mixture was poured into water, the aqueous mixture extracted with chloroform, the extracts washed with dilute hydrochloric acid, followed by water and saturated sodium chloride solution. Concentration under reduced pressure gave an oil which was found by nuclear magnetic resonance spectroscopy to contain about 20% unreacted carbofuran. This oil was subjected to column chromatography on silica gel using diethyl etherhexane (3:1) as eluting solvent to obtain 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (dimethylaminosulfenyl)(methyl)carbamate
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([Cl:35])[C:32]=1[O:33][CH3:34].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:26].[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)[CH:30]=[C:31]([Cl:35])[C:32]=1[O:33][CH3:34]
Reactant: COc1c(Cl)cc(B(O)O)cc1Cl
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1c(Cl)cc(-c2ccc3ncc(C(C)=O)c(N[C@H]4CC[C@H](CN(C)C)CC4)c3n2)cc1Cl

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)ethanone (77 g, 0.21 mmol) was reacted with (3,5-dichloro-4-methoxyphenyl)boronic acid (70 g, 0.32 mmol) followed by formation of the dihydrochloride salt to afford the desired product (80 g, 66%) as a brown solid: 1H NMR (300 MHz, CD3OD) δ 9.18 (s, 1H), 8.52 (d, J=9.0 Hz, 1H), 8.39 (d, J=9.0 Hz, 1H), 8.20 (s, 2H), 5.74-5.59 (m, 1H), 3.99 (s, 3H), 3.09 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.76 (s, 3H), 2.48-2.40 (m, 2H), 2.10-2.00 (m, 3H), 1.79-1.61 (m, 2H), 1.50-1.31 (m, 2H);
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:34])C=1.S([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:25])=[O:34])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
To a solution of 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (300 mg, 0.79 mmol) in methylene chloride (10 mL) was added dropwise at −20° C. a solution of 3-chloroperbenzoic acid (204 mg, 1.12 mmol) in methylene chloride (2 mL), and at the same temperature, the mixture was stirred for 30 minutes. A 10% aqueous sodium hydrogensulfite was added to the reaction mixture, and then, the mixture was extracted with chloroform. The extract was successively washed with a saturated aqueous sodium hydrogencarbonate and brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform-hexane to yield the title compound as a colorless crystalline powder (139 mg, 44.5%).
Reaction SMILES: [CH2:1]([N:4]([CH2:7][CH3:8])[CH2:5][CH3:6])[CH:2]=[CH2:3].[C:9]1([PH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)CP(C1C=CC=CC=1)C1C=CC=CC=1)C>>[CH2:5]([N:4]([CH2:1][CH2:2][CH2:3][P:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH3:6]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CCN(CC)CC
Agent: CCN(CC)C(C)CP(c1ccccc1)c1ccccc1
Product: CCN(CC)CCCP(c1ccccc1)c1ccccc1

Procedure:
A mixture of 17 g (0.15 mole) allyl diethyl amine and 30.7 g (0.165 mole, 10% excess) of diphenyl phosphine is reacted in the usual manner with u.v. irradiation for 17 hours. A subsequent analysis of the reaction mixture indicated that about one third of the reactants was converted. The only product formed was the desired adduct, 2-diethylaminopropyl diphenylphosphine. It was isolated as a clear colorless liquid (Table 4).
Reaction SMILES: C([Mg]Br)C.C1(C=NC2CCCCC2)CCCCC1.[O:19]1[CH2:22][CH2:21][CH2:20]1.C1(N=C[C:31]2([CH:37]([OH:40])CC)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)CCCCC1>O.CCCCCC.C(O)(=O)C.O1CCCC1>[CH:37]1([OH:40])[C:31]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:20][CH2:21][CH2:22][O:19]1
Reactant: CCC(O)C1(C=NC2CCCCC2)CCCCC1
Reactant: C1COC1
Agent: C(=NC1CCCCC1)C1CCCCC1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: OC1OCCCC12CCCCC2
Reaction time: 2 h

Procedure:
To a mixture of 44 g of ethylmagnesium bromide and 120 g of tetrahydrofuran was added a mixture of 50 g of cyclohexylmethylenecyclohexylamine and 50 g of tetrahydrofuran. The resulting mixture was stirred for 2 hours under tetrahydrofuran reflux conditions. Thereafter, 21 g of oxetane was added under ice cooling to the reaction mixture, which was stirred for a further 20 hours at room temperature. Then 30 g of acetic acid was added to quench the reaction, followed by ordinary aqueous workup, obtaining 67 g of a crude product, 1-[(1-cyclohexyliminomethyl)cyclo-hexyl]propan-1-ol. To 67 g of the crude product were added 16 g of acetic acid, 400 g of hexane, and 280 g of water. The mixture was stirred at 50° C. for 12 hours. The reaction mixture was then subjected to ordinary aqueous workup and distillation for purification, obtaining 22 g (yield 500) of the target compound, 2-oxaspiro[5.5]undecan-1-ol.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]([F:43])([C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[CH2:44](O)[CH2:45]/[CH:46]=[CH:47]\[CH2:48][CH2:49][CH2:50][CH3:51].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:43][C:14]([F:13])([C:33]([F:41])([F:42])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[N:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48][CH2:49][CH2:50][CH3:51])=[CH:30][CH:31]=2)=[N:22][CH:21]=1
Reactant: CCCC/C=C\CCO
Reactant: Oc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC/C=C\CCOc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of DEAD (0.261 g, 1.50 mmol) in THF (20 ml) was added dropwise to a stirred solution of 4-[5-(5,5,6,6,7,7,8,8,8-nonafluorooctyloxy)-pyrimidin-2-yl]-phenol (0.858 g, 1.50 mmol), cis-3-octene-1-ol (0.192 g, 1.50 mmol) and triphenylphosphine (0.939 g, 1.50 mmol) in THF (30 ml) and the reaction mixture stirred at room temperature for 24 h. The solvent was removed in vacuo and the residues purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1)] to yield a colorless solid, which was recrystallized from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:5]=[C:6]([F:27])[C:7]=1[O:8][CH2:9][C:10]1[C:11]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[N:12][S:13][C:14]=1[C:15]([F:18])([F:17])[F:16].COC1C=CC(C(N)=O)=CN=1.O1CCCC1.[Li+].[OH-]>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[C:6]([F:27])[C:7]=1[O:8][CH2:9][C:10]1[C:11]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[N:12][S:13][C:14]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(OC)nc3)nsc2C(F)(F)F)c(F)c1
Agent: COc1ccc(C(N)=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cn1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-(3,5-difluoro-4-[[3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]phenyl)propanoate (prepared according to the procedure following Example 1 step 1-5 using 6-methoxynicotinamide as starting material) (50 mg, 0.10 mmol, 1.00 equiv), tetrahydrofuran (1 mL), LiOH (50 mg, 2.09 mmol, 20.98 equiv), water (1 mL). The resulting solution was stirred overnight at 20° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 6 with hydrogen chloride (2 mol/L). The solids were collected by filtration. The crude product (20 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Reversed Column, C18 silica gel; mobile phase, 0.05% TFA/ACN=1/4 increasing to 0.05% TFA/ACN=0/1 within 20 min; Detector, UV 254 nm. This resulted in 8.8 mg (18%) of 3-(3,5-difluoro-4-((3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)phenyl)propanoic acid as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.51 (s, 1H), 8.06 (d, J=6.3 Hz, 1H), 6.80-6.89 (m, 3H), 5.19 (s, 2H), 3.96 (s, 3H), 2.83 (t, J=7.5 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H15F5N2O4S, 475.1 (M+H). found 475.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([CH3:10])=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:7]([C:5]5[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1nn(C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nn(C)cc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 77.9 %

Procedure:
In the same manner as in Example 18-4 and using 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (269 mg, 1.92 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (217 mg, 78%) was obtained as a white solid.