Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[I:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>>[I:63][C:64]1[CH:70]=[CH:69][C:67]([NH:68][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:66][CH:65]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Nc1ccc(I)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(I)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.25 g, 1.1 mmol), then reacted with 4-iodoaniline (Aldrich) (0.093 g, 0.43 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-iodo-phenyl)-amide as a off white solid (Yield 0.09 g, 38%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[O:19])[NH:16][C:15]1=[S:20]>CO>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:20][C:15]1[C:14]([CH3:21])([CH3:13])[NH:18][C:17](=[O:19])[N:16]=1
Reactant: CC1(C)NC(=O)NC1=S
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Solvent: CO
Product: CN(C)c1ccccc1CSC1=NC(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Initially, 2.5 g of 2-dimethylaminobenzylchloride hydrochloride was added to a solution of 1.5 g of 5,5-dimethyl-4-thiohydantoin in 50 mL of methanol (MeQH). The reaction mixture was stirred for two hours at the room temperature and concentrated in vacuo. To the residue, there was added 100 mL of CHCl3. The residue was washed two times with 100 mL of aqueous solution of NaHCO3, dried over MgSO4 and concentrated in vacuo. The residue purified by column chromatography [CHCl3 :MeOH=100:1 (v/v)]. Recrystallized from diethyl ether gave the desired compound in the form of needle-like crystal. The yield of this compound was 2 g with a yield ratio of 69.1%, and the melting point was 160°-162° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)=[N+]=[N-].[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1.O>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)[O:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: OC1C=CCCC1
Agent: [Rh]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(OC1C=CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A solution of (3-chloro-4-methanesulfonyl-phenyl)-diazo-acetic acid methyl ester (Example 6; 489 mg, 1.69 mmol) in dichloromethane (10 ML) at 25° C. was treated with 2-cyclohexen-1-ol (0.42 mL, 4.23 mmol) followed by rhodium (II) acetate dimer (15 mg, 0.034 mmol) and the resulting solution was stirred at 25° C. for 1 h. The reaction mixture was diluted with dichloromethane (10 mL), then was poured into water (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 40S column, 75/25 hexanes/ethyl acetate) provided rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid methyl ester (350 mg, 58% yield) as a colorless oil: EI-HRMS m/e calcd for C16H19ClSO5 (M+) 358.0642, found 358.0640.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:32][O:33][CH3:34])[C:4]([CH3:31])=[C:5]([C:20]([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:21])[C@@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[N+](=[CH2:37])=[N-].C(O)(=O)C>ClCCl.C(OCC)C>[CH3:1][C:2]1[N:3]([CH2:32][O:33][CH3:34])[C:4]([CH3:31])=[C:5]([C:20]([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:27])([CH3:28])[CH3:29])=[O:21])[C@@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH3:37])=[O:9]
Reactant: COCN1C(C)=C(C(=O)O)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOCC
Product: COCN1C(C)=C(C(=O)OC)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Reaction time: 1 h
Yield: 94 %

Procedure:
In 2 ml of dichloromethane was dissolved 476 mg of (S)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl)-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid obtained in Example 3 or 4, and 6 ml of a 0.5M solution of diazomethane in diethyl ether was added to the solution under cooling with ice, followed by stirring for 1 hour. Acetic acid was added to the reaction mixture until the yellow color disappeared, and the reaction mixture was concentrated. The residue was purified by short silica gel column chromatography (ethyl acetate/hexane=1/3) to give 460 mg (yield: 94%) of (S)-methyl pivaloyloxymethyl 1,4-dihydro-2,6- dimethyl-1-methoxymethyl-4-(3-nitrophenyl)-3,5-pyridinedi-carboxylate as a pale yellow crystal.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[CH:13][N:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[K+].[C:25]([O:31][CH2:32]I)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C.ClCCl>[OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH2:32][O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20])=[C:8]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[CH:13][N:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ncc4sccn34)[C@H](C)[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ncc4sccn34)[C@H](C)[C@H]12
Temperature: 25 °C
Yield: 112.1 %

Procedure:
To a solution of 40 mg of potassium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.8 ml of DMF was added at −30° C. 30 mg of pivaloyloxymethyl iodide, and the mixture was stirred for 1 hour during which the temperature was raised up to room temperature. The reaction mixture was diluted with 30 ml of dichloromethane, washed with semi-saturated aqueous saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue thus obtained was purified by column chromatography on silica gel (ethyl acetate:methanol=4:1) to give 54 mg of the title compound.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C:9]1([CH3:31])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]#[C:22][C:23]3[CH:30]=[CH:29]C(CO)=[CH:25][CH:24]=3)[CH:12]=[CH:11][C:10]1=2>N1C=CC=CC=1>[C:5]([O:4][CH2:1][C:2]1[CH:29]=[CH:30][C:23]([C:22]#[C:21][C:13]2[CH:12]=[CH:11][C:10]3[C:9]([CH3:31])([CH3:8])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]=3[CH:14]=2)=[CH:24][CH:25]=1)(=[O:7])[CH3:6]
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(CO)cc3)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
1.7 ml of acetic anhydride were added to a mixture of 1.5 g (4.7 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzyl alcohol (Example 20) and 8.7 ml of pyridine. The mixture was stirred for 16 hours at room temperature, after which it was poured onto ice/water and acidified. The precipitated solid was filtered off under suction, washed with water and dried. 1.3 g (77%) of the title compound of melting point 136°-139° C. were obtained in this manner.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.CCCC[N+](CCCC)(CCCC)CCCC.[N-:51]=[N+:52]=[N-:53].[F:54][C:55]1[N:60]=[CH:59][C:58]([CH:61](O)[CH3:62])=[CH:57][CH:56]=1>C(Cl)Cl>[N:51]([CH:61]([C:58]1[CH:57]=[CH:56][C:55]([F:54])=[N:60][CH:59]=1)[CH3:62])=[N+:52]=[N-:53]
Reactant: CC(O)c1ccc(F)nc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a 1-L flask kept cold in an ice bath, add triphenylphosphine (27.9 g, 106.3 mmol), 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (24.12 g, 106.3 mmol). Add DCM slowly with stirring (150 mL). To the dark solution add tetra-N-butylammonium azide (30.23 g, 106.3 mmol) slowly, followed by 1-(6-fluoro-pyridin-3-yl)-ethanol (10 g, 70.85 mmol) dissolved in DCM (10 mL). Remove the flask from the ice bath and stir at RT for 1 h. Remove the solvent on a rotovap and purify by normal phase chromatography 5% to 20% ethyl acetate in hexanes to obtain the title compound as a colorless oil (7.75 g). GCMS m/z 166 [M]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[C:14]([F:17])([F:16])[F:15]>CO.[Pd]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[C:3]1[C:14]([F:16])([F:15])[F:17]
Reactant: Cn1c(C(F)(F)F)nc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(C(F)(F)F)nc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In an argon purged RBF was suspended 1-methyl-5-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (2.0 g, 8.2 mmol, 1.0 eq.) in 50 ml of MeOH. Pd/C (cat.) was added and the atmosphere was replaced by H2 (3×). The reaction was stirred for 16 h at RT at balloon pressure. The Pd was filtered off and the MeOH removed in vacuo to yield 1-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-amine.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH3:18])(=O)C.[OH-].[K+]>C(O)C>[CH3:18][C:10]1[N:9]([CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(=O)OCCCCn1c(C)nc2cnccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cnccc2n1CCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
1-(4-Acetoxybutyl)-2-methylimidazo[4,5-c]pyridine (0.55 g) was dissolved in ethanol (10 ml) and 2M potassium hydroxide (2 ml) was added dropwise. The mixture was stirred at room temperature for 3 hours and then evaporated under vacuum. The residue was dissolved in 2M hydrochloric acid, washed with methylene chloride (2×20 ml), basified with solid NaHCO3 to pH 7.5 and then extracted with methylene chloride (10×20 ml). The combined organic extracts were evaporated under vacuum to leave the desired product as a brown oil (0.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[O:4][CH2:5][CH2:6]Br.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CC(CC)=O>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[O:4][CH2:5][CH2:6][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: Cc1cccc(C)c1OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1cccc(C)c1OCCN1CCNCC1

Procedure:
To methylethylketone (1 liter) are added 2-(2,6-dimethylphenoxy)-1-bromo-ethane (132 g), sodium iodide (85 g), potassium carbonate (80 g) and piperazine (200 g). The mixture is refluxed for 24 hours, with stirring. After cooling, the mixture is filtered and then washed with 3×300 ml benzene. After evaporation of the benzene, the piperazine derivative is distilled; b.p. 25 mm Hg=190° C.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.[Mg].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1)=[O:19])[CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Fc1cc(Br)c2occc2c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(F)cc2ccoc12
Temperature: 20 °C
Yield: 79 %

Procedure:
Dissolve 7-bromo-5-fluorobenzofuran (2 g, 9.3 mmol) in 5 ml tetrahydrofuran under nitrogen. Add magnesium turnings (0.25 g, 1.1 equivalents) and heat to reflux to facilitate Grignard formation. In a separate flask place diethyl oxalate (1.3 mL, 2 equivalents) in 3 mL tetrahydrofuran, and cool to 0° C. under nitrogen. When Grignard formulation is complete, add via canula to the diethyl oxalate solution. Stir the reaction for 2-4 hours while slowly warming to 20° C. Extract with diethyl ether. Wash organic layer with brine. Dry over magnesium sulfate, filter and concentrate to a light yellow oil. Purifacation by column chromatography (4:1 hexanes:ethyl acetate) affords 1.74 g (79%) of an oil which solidifies upon standing. MS (ES, m/z): 237.0 (M+1).
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C@:22]1([CH3:28])[CH2:26][O:25]C(=O)[NH:23]1)[CH:16]=[CH:15]2.C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH:2]3[CH2:3][CH2:4][CH:5]4[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]4)[CH2:1]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: C[C@@]1(c2ccc3cc(OC4CCC5CCCCC5C4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2cc(OC3CCC4CCCCC4C3)ccc2c1
Temperature: 80 °C
Yield: 2.3 %

Procedure:
(R)-4-[6-(Decahydro-naphthalen-2-yloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol) was dissolved in ethanol (2.2 g, 0.049 mol) and treated with 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol). The mixture was then heated to 80° C. overnight. The reaction was then cooled to room temperature and quenched with 1 N HCl. The reaction was then diluted with water and white solid formed. Solid was removed via filtration and dried overnight on filter to give 4 mg the desired product as a white solid (2%). ESI-MS: 337 (M-16)+. 1H NMR (400 MHz, DMSO-d6) δ=7.11-6.92 (m, 3 H), 6.75-6.64 (m, 1 H), 6.48-6.29 (m, 2 H), 3.74-3.58 (m, 1 H), 3.20-2.95 (m, 2 H), 1.21-0.96 (s, 22 H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.[N:8]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>CN1CCCC1>[F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH2:4][N:11]1[CH2:10][CH2:9][N:8]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12]1
Reactant: FC(F)(F)C1CO1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CN1CCCC1
Product: O=C(OCc1ccccc1)N1CCN(CC(O)C(F)(F)F)CC1
Temperature: 80 °C

Procedure:
0.47 ml of 1,1,1-trifluoro-2,3-epoxypropane is added to a solution of 1 g of benzyl piperazine-1-carboxylate in 100 ml of N-methylpyrrolidine and it is heated at 80° C. for 12 hours. 0.05 ml of 1,1,1-trifluoro-2,3-epoxypropane is added and it is heated at 80° C. for 48 hours, The reaction mixture is extracted with DCM, the organic phase is washed with a 4% solution of LiCl in water, it is dried over MgSO4 and the solvent is evaporated under vacuum. The residue is purified by preparative HPLC and 1.7 g of the expected compound is obtained.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:11])[CH:9]=[CH2:10].C(N(CC)C(C)C)(C)C.Cl>ClCCl.CN(C1C=CN=CC=1)C>[C:4]([O:11][CH2:8][CH:9]=[CH2:10])(=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: C=CCO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)CCC(=O)O
Reaction time: 1 h

Procedure:
To a solution of commercially available succinic anhydride (2.00 g, 20.0 mmol) in dichloromethane (10 ml) were added allyl alcohol (1.75 g, 30.1 mmol), N,N-diisopropylethylamine (3.88 g, 30.1 mmol) and 4-(N,N-dimethylamino)pyridine (10 mg) at room temperature. The mixture was stirred for 1 hour, then 1N hydrochloric acid was added thereto, and the resulting solution was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to afford crude allyl hydrogen succinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]([F:21])([F:19])[F:20])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2nnnc2C(F)(F)F)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1C(=O)O
Reaction time: 2 h

Procedure:
Combine methyl 2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoate (1.46 g, 5.27 mmol) and an aqueous solution of sodium hydroxide (20 mL, 2 M, 40 mmol) in methanol/tetrahydrofuran (20 mL/10 mL). After 2 hours, adjust the pH of the reaction mixture to about 2 using a 1M aqueous hydrochloric acid solution. Extract the reaction mixture with ethyl acetate and then dichloromethane. Dry the combined organic layers over MgSO4, filter, and evaporate in vacuo to give a the title compound: Rf=0.55 (silica gel, 85% chloroform/10% methanol/5% acetic acid).
Reaction SMILES: [N:1]1([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:21].O1CCOCC1>ClCCl>[ClH:21].[NH:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C([C@@H]1CCCNC1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (58.82 g, 208.3 mmol) in anhydrous dichloromethane (100 mL) was added hydrogen chloride in 1,4-dioxane (260 mL, 1040 mmol, 4M). The reaction mixture was stirred vigorously at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was left standing overnight at room temperature. The residue was triturated with ether (250 mL). The ether was decanted and dichloromethane was added followed by sonication in a warm bath. The solvent was removed under reduced pressure and the resulting solid was placed under high vacuum at 40° C. for 1 h to afford (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (48.41 g). The material was used for the next step without further purification. 1H NMR (400 MHz, CD3OD) δ 1.75-2.05 (m, 8H) 3.04-3.17 (m, 2H) 3.19-3.28 (m, 3H) 3.35-3.66 (m, 4H); MS (ES+) (M+H) 183.3.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[CH3:15][C:16]12[CH2:25][CH:20]([C:21]([CH3:24])([CH3:23])[O:22]1)[CH2:19][CH2:18][C:17]2=[O:26].[OH-].[Na+].OO>O1CCCC1.C(O)C.O>[CH3:15][C:16]12[CH2:25][CH:20]([C:21]([CH3:23])([CH3:24])[O:22]1)[CH2:19][CH2:18][CH:17]2[OH:26]
Reactant: CC12CC(CCC1=O)C(C)(C)O2
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC2(C)CC1CCC2O
Temperature: -70 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of 24 ml of a 1M solution of lithium tri(secbutyl)borohydride in tetrahydrofurane at -70° C. was added dropwise 3.49 g of 5,7,7-trimethyl-6-oxabicyclo[3.2.1]octan-4-one in 3 ml of tetahydrofuran. The resulting solution was stirred under nitrogen for one hour at -70° C. and one hour at room temperature. Then while controlling the temperature at 0° C., the following were successively added: 2.6 ml of water, 5.2 ml of ethanol, 19.2 ml of 10% sodium hydroxide solution and dropwise 8.5 ml of 30% hydrogen peroxide solution. The resulting reaction mixture was stirred for one hour at 25° C., then saturated with solid potassium carbonate and extracted four times with 50 ml portions of a 1:1 solvent mixture of diethyl ether and tetrahydrofuran. The combined organic extracts were washed with 50 ml of saturated aqueous sodium chloride, dried (Na2SO4) and concentrated in vacuo to leave 6.44 g of an opaque, colorless oil. Kugelrohr distillation of the oil gave 3.13 g of the desired product as a colorless oil, b.p. 71° C. (0.35-0.15 mm), predominate (4:1) in the endo versus exo alcohol form.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[Br:19][CH2:11][C:6]1[CH:7]=[C:8]([Cl:10])[CH:9]=[C:2]([Cl:1])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Cl)cc(Cl)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: N#Cc1c(Cl)cc(Cl)cc1CBr
Temperature: 78 °C
Reaction time: 2 h

Procedure:
A solution of 2,4-dichloro-6-methylbenzonitrile (16.9 mmol) in 34 mL chlorobenzene was heated to 50° C. when NBS (18.6 mmol) was added. The flask was purged with Ar before AIBN (1.69 mmol) was added at once still at 50° C. The reaction mixture was then stirred at 78° C. After 2 h and 4 h, another portion of AIBN (1.69 mmol) was added and heating to 78° C. was continued overnight. The solvent was then evaporated off, the resulting residue was redissolved in Et2O and the remaining solid was removed by filtration. The filtrate was washed twice with 2N HCl solution and brine, it was dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept to EtOAc gives the desired compound as yellowish solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11](=[CH:17][N:18]([CH3:20])[CH3:19])[C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(OC)N(C)C
Reactant: CCCCc1ccc(CC(C)=O)cc1
Product: CCCCc1ccc(C(=CN(C)C)C(C)=O)cc1

Procedure:
This ketone (4.6 g) was reacted with dimethylformamide dimethyl acetal (4.0 ml) as described in Example 1 to give 3-(4-butylphenyl)-4-dimethylamino-3-buten-2-one which was used without purification to prepare ethyl 5-(4-butylphenyl)-4-oxo-4H-pyran-2-carboxylate (mp 65° C.), by the method described in Example 17.