Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccnc2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccnc3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 75.9 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.55 g), tetraethyl methylenediphosphonate (0.35 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.53 g, yield 77%) from a fraction eluted with ethyl acetate-hexane (19:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 128-129° C.
Reaction SMILES: ClC1C=C[CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].ClCC[N:14]1C[CH2:18][CH2:17][CH2:16][CH2:15]1>CS(C)=O>[N:10]1([CH2:18][CH2:17][CH2:16][C:15]#[N:14])[CH2:5][CH2:4][CH2:3][CH2:8][CH2:9]1
Reactant: ClCCN1CCCCC1
Reactant: N#CCc1ccccc1Cl
Solvent: CS(C)=O
Product: N#CCCCN1CCCCC1

Procedure:
A process for the preparation of a compound of the formula ##STR25## which comprises (a) reacting 2-chlorobenzeneacetonitrile with 1-(2-chloroethyl)piperidine in the presence of a base and DMSO to produce a piperidinebutanenitrile of the formula ##STR26## (b) alkylating the resulting piperidinebenzene-butanenitrile with an alkylating agent in the presence of a base and DMSO to produce a piperidinebutanenitrile of the formula ##STR27## (c) hydrolyzing the resulting piperidine-butanenitrile in toluene with hydrochloric acid to produce a compound of the formula ##STR28## (d) reacting the resulting compound with isopropylamine in a solvent to form an imine of the formula ##STR29## (e) reducing the imine with sodium borohydride in ethanol to form an amine of the formula ##STR30## (f) acetylating the resulting amine with acetic anhydride in a solvent to produce an acetylated amine of the formula ##STR31## (g) hydrolyzing the acetylated amine with sulfuric acid to produce ##STR32## (h) recovering the compound so produced.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[Cl:18])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Product: O=C(Cc1ccc(Cl)cc1Cl)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1

Procedure:
Example 18 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (2,4-dichlorophenyl)acetic acid (0.0.41 g) to give the title compound (0.019 g).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:15]1[N:16]([CH2:28][CH2:29][CH2:30][O:31][N:32]2[C:40](=[O:41])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]2=[O:42])[C:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:27]=1)[CH2:13][CH3:14]>C(Cl)(Cl)Cl>[O-:6][N+:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:17]2[N:16]([CH2:28][CH2:29][CH2:30][O:31][N:32]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])[C:15]([CH2:12][CH2:13][CH3:14])=[N:27][C:18]=2[CH:19]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCON1C(=O)c2ccccc2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 99 %

Procedure:
3-Chloroperoxybenzoic acid (14.9 g, 66.4 mmol)(mCPBA, available as an approximately 77% pure mixture) was added to a solution of 2-[3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione (25.0 g, 60.3 mmol) in chloroform (200 mL), and the reaction was stirred for seven hours at room temperature. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated that the reaction was incomplete, and additional mCPBA (4.96 g, 22.1 mmol) was added. The reaction was allowed to stir at room temperature overnight. The solution was then washed with brine (2×100 mL) and saturated aqueous sodium bicarbonate (2×100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a fluffy, light-brown solid. The solid was dried under high vacuum for one hour to provide 25.7 g of 2-[3-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione as a white solid.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:8][C:7]1=[O:21])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:23]([O:26][NH3+:27])[CH:24]=[CH2:25]>C(O)C.C([O-])(=O)C.[Na+]>[CH2:23]([O:26][NH:27][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:8][C:7]1=[O:21])[CH2:2][CH2:3][CH3:4])[CH:24]=[CH2:25]
Reactant: C=CCO[NH3+]
Reactant: CCCC(=O)C1C(=O)CC(CCC2OCCCO2)CC1=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(CCC2OCCCO2)CC1=O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
10.0 parts by weight of 2-butyryl-5-[2-(1,3-dioxan-2-yl)-ethyl]-cyclohexane-1,3-dione were dissolved in 150 parts by volume of ethanol, 3.72 parts by weight of allyloxyammonium chloride and 3.03 parts by weight of anhydrous sodium acetate were added, and the mixture was stirred at 20° C. for 20 hours. The suspension was then stirred into ice-water and extracted with methylene chloride. The organic phase was concentrated to give 11.5 parts by weight of 2-(1-allyloxyaminobutylidene)-5-[2-(1,3-dioxan-2-yl)-ethyl]-cyclohexane-1,3-dione (compound No. 2) as a solid having the following structure (melting point: 50°-52° C.): ##STR8##
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][Br:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH:3]([CH2:4][Br:5])[O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: OC(CBr)CBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: BrCC(CBr)OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 10 g of 1,3-dibromopropan-2-ol, 5.0 ml of 3,4-dihydro-2H-pyran and 50 ml of chloroform was added a catalytic amount of p-toluenesulfonic acid monohydrate followed by stirring at room temperature for 3 hours. The reaction solution was concentrated, diluted with diethyl ether and washed with saturated sodium bicarbonate and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)CCC>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:22]3[CH:23]=[CH:18][CH:19]=[C:20]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccnc2)c1
Reactant: COc1ccn2c(Br)cnc2c1
Product: COc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 11 from 3-bromo-7-methoxyimidazo[1,2-α]pyridine and 3-[3-(tri-n-butylstannanyl)phenyl]pyridine to furnish a white crystalline solid, m.p. 153-154° C. 1H NMR (360 MHz, CDCl3) δH 3.89 (3H, s), 6.57 (1H, dd, J 2 and 8), 6.94 (1H, d, J 2), 7.37-7.43 (1H, m), 7.55-763 (4H, m), 7.72 (1H, s), 7.89-7.94 (1H, m), 8.19 (1H, d, J 7), 8.62-8.65 (1H, m), 8.90 (1H, s); m/z (ES+) 302 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][CH2:10][C:11](O)=[O:12])=[C:4]([N+:14]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:9][CH2:10][C:11](=[O:12])[NH:14]2)=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CNc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: O=C1CNc2cc(F)c(Cl)cc2N1
Temperature: 25 °C

Procedure:
A suspension of N-(4'-chloro-5'-fluoro-2'-nitrophenyl)glycine sodiumsaltand N-(2'-chloro-5'-fluoro-4'-nitrophenyl)glycine sodium salt (0.175 g, 0.704 mmol) and tin (II) chloride dihydrate (0.475 g, 2.11 mmol) in ethanol (3.5 mL) was refluxed for 30 min. It was then cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with water (10 mL) and the pH was adjusted with saturated NaHCO3 (3.0 mL) to pH~8. The resulting white suspension was extracted with ethyl acetate (30 mL). The ethyl acetate was dried over anhydrous Na2SO4 and removed under vacuum to yield 0.041 g (29%) pure (1H NMR) title compound as a light yellow powder; mp 217-219° C. (dec); 1H NMR (DMSO-d6) δ 3.75 (s, 2H), 6.37 (s, 1H), 6.59 (d, 1H, J=10.5 Hz), 6.74 (d, 1H, J=7.2 Hz), 10.33 (s, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:17]([CH3:20])([O-:19])=[O:18].[OH-].[Na+]>CO.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:10]=[CH:20]/[N+:17]([O-:19])=[O:18])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1OC1CCCC1
Reaction time: 4 h

Procedure:
To a stirred solution of 1.02 g (4.63 mmol) of 3-cyclopentoxy-4-methoxybenzaldehyde in 20 mL of methanol was added 0.3 mL (5.5 mmol) of nitromethane followed by 0.2 g (5.0 mmol) of sodium hydroxide in 5 mL of water in single portions. The mixture was stirred for 4 hours after which time the decomposing mixture was concentrated, diluted with 20 mL of water and acidified to pH 1 with concentrated hydrochloric acid. The aqueous solution was extracted with three, 10 mL portions of chloroform and the combined organic fractions were dried over magnesium sulfate and concentrated. Liquid chromatography of the crude mixture over 100 g of silica gel eluting with 5% ethyl acetate in hexane provided an analytically pure solid.
Reaction SMILES: C1(P(=O)(O[C:16]([CH3:47])=[C:17]([N:31]2[C:37](=[O:38])[CH:36]3[CH:32]2[S:33][C:34]([CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:35]3)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])OC2C=CC=CC=2)C=CC=CC=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>O1CCCC1>[O:40]([CH2:39][C:34]1[S:33][CH:32]2[CH:36]([C:37](=[O:38])[N:31]2[C:17](=[C:16]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[CH3:47])[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:19])[N:35]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: C1COCCN1
Reactant: CC(OP(=O)(Oc1ccccc1)c1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: C1CCOC1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 3 h

Procedure:
To a stirred solution of phenyl 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-1-(p-nitrobenzyloxycarbonyl)-prop-1-en2-yl phenylphosphonate (1.37 g.) in tetrahydrofuran (20 ml.) at 0°-5° C. was added morpholine (0.383 ml.). After stirring for 3 hours at 0°-5° C., the solvent was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in essentially quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in example 8.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]=[O:11].Cl>>[OH:11][CH2:10][C:7]1[CH:8]=[C:2]([CH:1]=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1O
Reactant: C=O
Agent: Cl
Product: O=Cc1cc(CO)ccc1O
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 9 ml of salicylaldehyde (84.46 mmol), 17 ml of aqueous 37% formaldehyde solution (˜200 mmol) and 42 ml of concentrated HCl is heated on a water bath at 80° C. with stirring for 20 min. After cooling, the supernatant is removed by settling of the phases and the residual pink crystalline mass is taken up in 200 ml of boiling water. The suspension obtained is refluxed for 30 min. The supernatant is separated out after settling and placed at +4° C. to bring about crystallization of the final product. A further 200 ml of boiling water are added to the residual oil and the suspension is refluxed for 30 min. The supernatant is added to the first decantate. After cooling, the product is collected by filtration, washed with water and dried. It is then recrystallized from chloroform.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:24]#[C:25][C:26]3([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:4][CH:3]=1>C(OC(=O)C)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH2:24][CH2:25][C:26]3([OH:31])[CH2:27][CH2:28][CH2:29][CH2:30]3)=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(C#CC2(O)CCCC2)c(-c2ccc(Cl)cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(CCC2(O)CCCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
5-(4-Chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(1-hydroxy-cyclopentylethynyl)-nicotinamide (120 mg, 0.27 mmol) was dissolved in ethylacetate (15 mL) and hydrogenated in the presence of palladium on charcoal (10%) at room temperature and atmospheric pressure. After filtration and evaporation of the solvent the residue was purified by chromatography on silica gel with a ethyl acetate:methanol gradient to yield the product as colorless foam, MS (ISP) 443.1, 445.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1.[H][H]>CO.[Pd]>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1
Reactant: COC(=O)C=Cc1c[nH]cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1c[nH]cn1
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(4-imidazolyl)-2-propenoate (5.3 g) in methanol a t room temperature was added 10% palladium on carbon (20 mg) under a blanket of argon. A balloon of hydrogen was applied, and the reaction was stirred for one hour. The solution was filtered, and then concentrated in vacuo to dryness to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].[CH2:12](Br)[CH2:13]Br.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:10]#[N:11])[CH2:13][CH2:12]1
Reactant: BrCCBr
Reactant: COc1ccccc1CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1C1(C#N)CC1
Reaction time: 20 h

Procedure:
A mixture of (2-methoxyphenyl)acetonitrile (147 g and 1,2-dibromomethane (168 ml) in dimethylsulphoxide (250 ml) was added over 1 hour to a stirred suspension of powdered potassium hydroxide (250 g) and 18-Crown-6 (5 g) in dimethylsulphoxide (1200 ml) at 25° C. Stirring was continued for 20 hours. Water (1200 ml) was added and the mixture extracted with ether to give a crude oil which was purified by distillation (b.p. 102°/0.25) to give 1-(2-methoxyphenyl)cyclopropane carbonitrile.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:15]=[C:14]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])[CH:13]=[C:5]3[CH2:6][CH2:7][CH2:8][N:9]([C:10](=[O:12])[CH:11]=1)[C:4]=23.O.O.O.C([O-])(=O)C.[Na+]>[Pd].C(O)(=O)C>[F:24][C:21]([F:22])([F:23])[C:16]([C:14]1[CH:13]=[C:5]2[C:4]3[N:9]([CH2:8][CH2:7][CH2:6]2)[C:10](=[O:12])[CH:11]=[CH:2][C:3]=3[CH:15]=1)([OH:25])[C:17]([F:20])([F:19])[F:18]
Reactant: O=c1cc(Cl)c2cc(C(O)(C(F)(F)F)C(F)(F)F)cc3c2n1CCC3
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc2cc(C(O)(C(F)(F)F)C(F)(F)F)cc3c2n1CCC3

Procedure:
A mixture of 0.7 g. of 7-chloro-2,3-dihydro-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H,5H-benzo[ij]quinolizin-5-one, 150 ml. of glacial acetic acid, 5 g. of sodium acetate trihydrate, and 0.5 g. of 10% palladium on charcoal is hydrogenated in a Parr shaker apparatus for 4 hours at an initial pressure of 3 atm. The catalyst is removed by filtration, solvent is removed by evaporation, and the residue is triturated with water. The insoluble material is filtered off, dried and recrystallized to give 2,3-dihydro-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H,5H-benzo[ij]quinolizin-5-one, m.p. 295°-296°.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[N:23]=[N:24][C:25]=3[C:26]([F:29])([F:28])[F:27])=[CH:15][C:14]=2[CH3:38])[CH3:12])=[CH:6][C:5]=1[CH3:39].[OH-].[K+]>CO.C1COCC1>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[N:22]1[C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:40])=[O:2])=[C:5]([CH3:39])[CH:6]=3)[CH3:12])=[C:14]([CH3:38])[CH:15]=2)=[C:25]([C:26]([F:28])([F:29])[F:27])[N:24]=[N:23]1
Reactant: COC(=O)c1ccc(CN(C)c2ccc(OCc3c(C(F)(F)F)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CN(C)c2ccc(OCc3c(C(F)(F)F)nnn3-c3c(Cl)cccc3Cl)cc2C)ccc1C(=O)O
Temperature: 60 °C

Procedure:
To a solution of 4-[({4-[3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methylphenyl}-methylamino)-methyl]-2-methyl-benzoic acid methyl ester (24.2 g, 40.7 mmol) in MeOH (150 mL) and THF (150 mL) is added 2N potassium hydroxide (102 mL, 203 mmol). The mixture is heated at 60° C. for 2 hours. The solvent is removed under reduced pressure. The residue is diluted with water, acidified to pH 3 with 2N HCl, and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered, and evaporated under reduced pressure to afford the title compound as a white solid that is crystallized from MeOH (20 g, 80%). ES/MS m/e 579 (M+1).
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C:14]=3[CH:27]=2)=[CH:6][CH:5]=1)=[O:3].CCN(C(C)C)C(C)C.[F:37][CH:38]([F:41])[CH2:39][NH2:40]>O1CCCC1>[F:37][CH:38]([F:41])[CH2:39][NH:40][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C:14]=3[CH:27]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)Cl)cc3)cc2C1
Reactant: NCC(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)NCC(F)F)cc3)cc2C1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of 1,1-dimethylethyl 7-[4-(chlorocarbonyl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.0 g, 2.6 mmol) and DIPEA (2.2 mL, 13 mmol) in tetrahydrofuran (10 mL) was added 2,2-difluoroethylamine (0.21 g, 2.6 mmol). The reaction mixture was stirred for 2 h and then partitioned between ethyl acetate (20 mL) and 1M hydrochloric acid (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography on silica (30% ethyl acetate in hexanes) provided 1,1-dimethylethyl 7-(4-{[(2,2-difluoroethyl)amino]carbonyl}phenyl)-2,3-dihydro-1,4-benzoxazepine-4 (5H)-carboxylate (0.95 g, 85% yield). MS (EI) for C23H26F2N2O4: 433 (MH1).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:23])[CH:17]([NH:18][C:19](=[S:22])[CH2:20][CH3:21])[C@H:4]2[S:3]1.C(O)(=O)C>[Zn].CN(C)C=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:23])[CH:17]([NH:18][C:19](=[S:22])[CH2:20][CH3:21])[C@H:4]2[S:3]1
Reactant: CCC(=S)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12
Reaction time: 1 h
Yield: 88.1 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylate (0.48 g), glacial acetic acid (0.48 ml) and zinc powder (0.48 g) were added to anhydrous dimethylformamide (5 ml), and the mixture was stirred for 1 hour under ice-cooling. After the reaction, zinc powder was filtered off. The filtrate was poured into a mixture of 3% hydrochloric acid (10 ml) and ethyl acetate (10 ml), and the ethyl acetate layer was separated. The aqueous layer was further extracted three times with ethyl acetate (10 ml). The ethyl acetate layer was combined. The combined extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate, after which the solvent was distilled off under reduced pressure. The obtained residue was crystallized by adding ether and the crystals were collected by filtration and washed with ether to give 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid (0.29 g), mp 181° to 183° C. (dec.).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:17])[CH:11]=[CH:12][O:13][C:14](=[O:16])[CH3:15])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH3:24][CH:25]([CH2:36][CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[CH2:26][CH2:27][O:28][C:29](=[O:35])[CH2:30]CC(Cl)=O>C1COCC1.CCOCC>[CH:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:17])[CH:11]=[CH:12][O:13][C:14](=[O:16])[CH2:15][CH2:30][C:29]([O:28][CH2:27][CH2:26][CH:25]([CH3:24])[CH2:36][CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])=[O:35])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC=CC(C)c1cccc(C(C)C)c1
Reactant: CC(C)=CCCC(C)CCOC(=O)CCC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)CCOC(=O)CCC(=O)OC=CC(C)c1cccc(C(C)C)c1
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A solution of 7.60 g acetic acid 3-(3-isopropyl-phenyl)-but-1-enyl ester in 50 ml of THF was cooled to −70° C. A solution of 5.00 g potassium-tert-butoxide in 50 ml of THF was added at 70° C. and the resulting reaction mixture was stirred for 2 hours at the same temperature. 11.20 g 3-chlorocarbonyl-propionic acid 3,7-dimethyl-oct-6-enyl ester was then dropped in and the reaction mixture was stirred for another 2 hours at −70° C. Then the reaction mixture was diluted with ether, washed with saturated NaHCO3 and brine. The organic phase was dried, filtered and evaporated to dryness. The residue was purified by chromatography to yield 7.10 g of a yellow oil.