Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1.[OH-].[Na+]>O>[C:14]([C:12]1[CH:13]=[C:8]([CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])[N:1]([C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)(C)c1cc(Nc2ccccc2)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(N(C(=O)CCCC(=O)O)c2ccccc2)cc(C(C)(C)C)c1O
Temperature: 90 °C
Yield: 56.9 %

Procedure:
12.0 g (0.038 mole) of 4-anilino-2,6-di-t-butylphenol was added to a 55° C. melt of 12.0 g (0.105 mole) of glutaric anhydride. The reaction warmed to 90° C. during the addition. The reaction was allowed to cool to 50° C., and was then maintained at that temperature for 3 hours. Thereafter, the mixture was heated briefly to 80° C. and allowed to cool to room temperature. The reaction mass was ground to a powder and the powder was heated in water. This cloudy solution was allowed to cool, and was then basified with dilute sodium hydroxide, extracted twice with diethyl ether, and acidified with dilute hydrochloric acid. The resulting precipitate was collected, dried and recrystallized from a mixture of ethanol and water to give 8.9 g of white crystalline 5-(3,5-di-t-butyl-4-hydroxy-N-phenylanilino)-5-oxopentanoic acid, m.p. 168.5°-169° C. Analysis: Calculated for C25H33NO4 :% C, 73.0; % H, 8.1; % N, 3.4; Found: % C, 73.6; % H, 8.1; % N, 3.4.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[I-].[K+].Cl[CH:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][CH2:14][CH2:13]1>CC(N(C)C)=O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][CH2:14][CH2:13]2)[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: ClC1CCSc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CN1CCCN(C2CCSc3ccccc32)CC1
Temperature: 60 °C
Yield: 98.4 %

Procedure:
A 25 ml 3-necked flask equipped with a condenser and magnetic stirring bar and under a nitrogen atmosphere was charged with a solution of N-methylhomopiperazine (0.35 ml; 2.81 mmol) in DMAC (10 ml). Potassium iodide (0.1 g) was added followed by the addition of 4-chloro-3,4-dihydro-2H-benzothiopyran (0.20 g; 1.2 mmol). This solution was then heated at 60° C. overnight, cooled, and partitioned between water and ethyl acetate which was washed with brine and dried with magnesium sulphate. Filtration and evaporation of solvent gave a yellow oil which was distilled by kugelrohr to give the title compound as an oil (0.31 g), bp (air bath temperature) 130-140° C. at 100 mtorr; essentially homogeneous by tlc (silica gel, 89:10:1 CH2Cl2:CH3OH:NH4OH), Rf 0.46; 1H nmr δ2.37 (s, 3H), 3.82-3.87 (m, 1H), 6.98-7.34 (m, 3H), 7.69-7.71 (d, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:23])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([CH3:10])([CH3:9])[CH3:8].Cl[C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][N:26]=1>O1CCCC1>[C:7]([O:11][C:12](=[O:23])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:25]2[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH2:31])=[CH:27][N:26]=2)=[CH:18][CH:17]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
Add potassium tert-butoxide (4.28 g, 36.2 mmol) to a stirred solution of [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (6.40 g, 27.0 mmol) and anhydrous tetrahydrofuran (120 mL). Stir for 30 minutes under nitrogen at room temperature. Add 6-chloronicotinamide (4.27 g, 27.2 mmol) and beat to reflux for 18 h under nitrogen. Cool to room temperature pour the reaction mixture into 150 mL), and extract with diethyl ether (3×150 mL). Dry the diethyl ether extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.7% concentrated ammonium hydroxide/7% ethanol/chloroform to yield 4.46 g (46%) of {2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester: mass spectrum (ion spray): m/z=358.1 (M+1); 1H NMR (DMSO-d6): 8.58 (d, 1H), 8.22 (dd, 1H), 8.02 (br s, 1H), 7.46 (br s, 1H), 7.23 (d, 2H), 7.06-7.02 (m, 3H), 6.92-6.89 (m, 1H), 3.17-3.12 (m, 2H), 2.69 (t, 2H), 1.35 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC1N(C)C=NC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:12]([CH3:13])[CH:14]=[N:15][CH:16]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Agent: Cn1cncc1Br
Product: Cc1ccc(-c2cncn2C)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 5-bromo-1-methyl-1H-imidazole. ESI-MS (m/z): 217 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:12].[CH2:13]=[O:14]>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:13][OH:14])=[C:5]2[OH:12]
Reactant: Oc1ccnc2ccc(F)cc12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: OCc1cnc2ccc(F)cc2c1O

Procedure:
6-Fluoro-4-hydroxyquinoline was reacted with 40% aqueous formaldehyde in aqueous sodium hydroxide solution to give the novel 6-fluoro-4-hydroxy-3-hydroxymethylquinoline m.p. 310°-315°. The product was methylated with dimethyl sulphate to give the novel 6-fluoro-1-methyl-3-hydroxymethyl-4-quinolone, m.p. 209°-212°. Reaction of this product with thionyl chloride, then sodium methanethiolate gave the novel 6-fluoro-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 114°-116° (from industrial methylated spirit).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH:23]C(C)(C)C)(=[O:22])=[O:21])(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[I-].[Na+].Cl[Si](C)(C)C>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20](=[O:22])(=[O:21])[NH:23]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1C1(O)CCN(Cc2ccccc2)C1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=S1(=O)NC2(CCN(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To a solution of 2-(1-benzyl-3-hydroxypyrrolidin-3-yl)-N-(tert-butyl)benzene sulfonamide (350 mg, 0.00090 mol) in acetonitrile (15 mL, 0.29 mol) were added sodium iodide (418 mg, 0.00279 mol) and chlorotrimethylsilane (0.354 mL, 0.00279 mol). The reaction mixture was refluxed under nitrogen for 1 hour and then cooled down to room temperature, then quenched with 10% aqueous sodium thiosulfate solution (10 mL), and then extracted with EtOAc. The organic phase was washed with water then brine, and then dried over MgSO4 followed by filteration. The filtrate was concentrated to give the desired compound (170 mg, 60% yield). MS (ESI): 315.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Fc1ccc(C2CCCN2)cc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccc(F)c(F)c1

Procedure:
The title compound, white solid, m.p. 121° C. and MS: m/e=358.1 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(3,4-difluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[NH:24]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][O:31][C:30](=[O:33])[NH:29][C@H:26]1[CH2:27][CH2:28][N:24]([C:7]2[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)[CH2:25]1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)N[C@H]1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Temperature: 65 °C
Yield: 71.1 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.16 g, 0.23 mmol, from Example 47, Step 2), methyl (3S)-pyrrolidin-3-ylcarbamate hydrochloride (0.035 g, 0.19 mmol), palladium acetate (0.87 mg, 0.0039 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (3.6 mg, 0.0058 mmol), and cesium carbonate (0.24 g, 0.74 mmol) in tetrahydrofuran (4 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated. The residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (47 mg, 70%). LCMS calculated for C17H19ClN3O3 (M+H)+: m/z=348.1; Found: 348.4.
Reaction SMILES: CS([C:4]1[N:19]=[C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=[C:11]([NH2:12])[N:6]2[N:5]=1)=O.[N:20]12[CH2:30][CH2:29][CH2:28][N:27]=C1CCCCC2.C(OC(=O)C)C.CO>N1C=CC=N1>[N:20]1([C:4]2[N:19]=[C:7]3[CH:8]=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[CH:10]=[C:11]([NH2:12])[N:6]3[N:5]=2)[CH:30]=[CH:29][CH:28]=[N:27]1
Reactant: CS(=O)c1nc2cc(-c3ccccn3)cc(N)n2n1
Reactant: C1CCC2=NCCCN2CC1
Agent: c1cn[nH]c1
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccccn2)cc2nc(-n3cccn3)nn12
Temperature: 120 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A mixture of 0.50 g (0.002 mol) 2-methanesulfinyl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 0.33 ml (0.002 mol) 1,8-diazabicyclo[5.4.0]undec-7-en in 12.5 g molten pyrazole as solvent was stirred overnight at 120° C. Destillation of the solvent and chromatography on silicagel with ethylacetate/methanol 95/5 gave 0.13 g (26%) 2-pyrazol-1-yl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine as a white solid, MS m/e (%):278 (M+H+,100).
Reaction SMILES: CC([O-])(C)C.[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH2:15][CH3:16]>C1COCC1.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:18]1([C:14](=[O:17])[CH:15]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(=O)c1ccccc1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C(=O)c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
Reaction using 0.005 mol % catalyst: Pd(OAc)2 (0.5 mg, 0.0023 mmol), tri-t-butylphosphine (0.4 mg, 0.0020 mmol) and NaOtBu (5.80 g, 60.3 mmol) were suspended in 5 mL of THF in a screw-capped test tube. Bromobenzene (6.28 g, 40.0 mmol) and propiophenone (5.90 g, 44.0 mmol) were added to the reaction mixture in the drybox. The reaction tube was sealed with a cap and the mixture was stirred for 24 h at 60° C. The reaction was diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/EtOAc=95/5) to give 8.2 g (98%) of 1,2-Diphenyl-1-propanone.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([F:25])=[CH:18][C:3]=1[CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:22][C:20]1[C:19]([F:25])=[CH:18][C:3]([CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[C:2]([F:1])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc(F)c([N+](=O)[O-])cc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(F)c(N)cc2F)CC1

Procedure:
A mixture of tert-butyl 4-(2,5-difluoro-4-nitrobenzylidene)piperidine-1-carboxylate (4.52 mmol, 1.6 g) and palladium on carbon (10%) (0.135 mmol, 0.144 g) in ethyl acetate was hydrogenated at 3 bar until the desired amount of hydrogen was consumed. The reaction was filtered through celite and concentrated under reduced pressure to give the intermediate tert-butyl 4-(4-amino-2,5-difluorobenzyl)piperidine-1-carboxylate.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH2:8][CH3:9])[C:4](=[O:7])[CH2:5][Cl:6].O.C(=O)(O)[O-].[Na+].[NH2:17][C:18]1[C:26]([CH:27]=[N:28][O:29][CH3:30])=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[Cl:31]>C(OCC)(=O)C.C(Cl)Cl>[NH2:17][C:18]1[C:26]([CH:27]=[N:28][O:29][CH3:30])=[CH:25][C:21]([C:22]([NH:2][C:3]([CH2:8][CH3:9])([CH3:10])[C:4](=[O:7])[CH2:5][Cl:6])=[O:23])=[CH:20][C:19]=1[Cl:31]
Reactant: CON=Cc1cc(C(=O)Cl)cc(Cl)c1N
Reactant: CCC(C)(N)C(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(C)(NC(=O)c1cc(Cl)c(N)c(C=NOC)c1)C(=O)CCl
Yield: 74 %

Procedure:
In a 5-liter three-necked round bottomed flask was placed 93 g of 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride and 885 mL of water. To the resulting solution were added 138.6 g of sodium bicarbonate followed by 500 mL of ethyl acetate. To the resulting well-stirred mixture was added 123.5 g of 4-amino-3-chloro-5-methoxyiminomethylbenzoyl chloride dissolved in 1000 mL of ethyl acetate at room temperature over a period of 50 minutes. After the addition was complete the reaction mixture was stirred at room temperature for 1 hour. The two phases were separated and the organic layer was washed with water (2×500 mL), brine (1×500 mL), dried over anhydrous magnesium sulfate and the solvent eliminated in a rotary evaporator yielding the crude product as a brown oil. This oil was passed through a short Silica Gel column using methylene chloride as elution solvent. Evaporation of the solvent yielded 133.3 g of the expected 4-amino-3-chloro-5-methoxyiminomethyl-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)benzamide as an off-white solid (mp 140°-141° C.).
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH2:11][N:12]([CH2:26][CH3:27])[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)[N:8]=[CH:7]1)(=O)=O.[OH-].[Na+]>Cl.C(O)C>[CH2:26]([N:12]([CH2:11][C:9]1[N:8]=[CH:7][NH:6][CH:10]=1)[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]=1)[CH3:27]
Reactant: CCN(Cc1cn(S(=O)(=O)N(C)C)cn1)c1ccnc(Oc2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(Cc1c[nH]cn1)c1ccnc(Oc2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To remove the dimethylaminosulfonyl protecting group 4-{[ethyl-(2-phenoxy-pyrimidin-4-yl)-amino]-methyl}-imidazole-1-sulfonic acid dimethylamide (65 mg, 0.16 mmol) was dissolved in hydrochloric acid in ethanol (5 N, 1 ml) and the mixture was stirred at 100° C. for 2 hours. For workup aqueous sodium hydroxide solution (0.5 ml, 1 N) was added to basic pH and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (SiO2; ethyl acetate/methanol=95:5) to yield a white solid, (0.022 g, 46%); MS (ISP): 296.3 ((M+H)+.).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[CH2:9][CH2:8][C:7]([NH:13][CH3:14])([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1.S(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:11][C:10]([C:7]1([NH:13][CH3:14])[CH2:8][CH2:9][N:4]([O:3][CH3:2])[CH2:5][CH2:6]1)=[O:12]
Reactant: CO
Reactant: CNC1(C(=O)O)CCN(OC)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CNC1(C(=O)OC)CCN(OC)CC1

Procedure:
To a suspension of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid hydrochloride salt (2.08 g, 9.26 mmol) in methanol (20 ml) at 0-5° C. was added thionyl chloride (2.41 ml, 3.97 g, 33.40 mmol) and the reaction mixture was heated at reflux for 7 days. After cooling, the mixture was concentrated, the residue diluted with ice water and neutralised with aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (4×), the combined organic layers washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (gradient ethyl acetate→ethyl acetate/methanol 20:1). Yield: 76 mg of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid methyl ester (title compound P5.4) as an oil.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([Cl:21])[C:18]([C:22]2[CH:23]=[N:24][C:25]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:27]=2[C:28]#[N:29])=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:7])(C)(C)C.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[NH:38][CH3:39].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl.CN(C=O)C>[Cl:21][C:19]1[C:18]([C:22]2[CH:23]=[N:24][C:25]([C:30]([F:32])([F:31])[F:33])=[CH:26][C:27]=2[C:28]#[N:29])=[CH:17][C:13]([C:14](=[O:16])[N:38]([C:37]2[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=2[O:35][CH3:34])[CH3:39])=[C:12]([CH:20]=1)[O:11][CH2:10][CH2:9][CH2:8][C:6]([OH:5])=[O:7]
Reactant: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)O
Reactant: CNc1ccccc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoic acid (30 mg, 0.06 mmol), 2-methoxy-N-methylaniline (9.4 mg, 0.07 mmol), triethylamine (12.5 mg, 0.12 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 35 mg, 0.09 mL) in dichloromethane (1 mL) containing DMF (0.1 mL) was stirred at rt for 16 hrs. The mixture was then partitioned in water and dichloromethane. The organic layer was washed with water, dried and concentrated to yield a crude 4-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric acid t-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].CO>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][N:10]([C:22](=[O:24])[CH3:23])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1C[C@H](C)C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
((3R,5R)-5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (0.422 g, 1.971 mmol) was dissolved in DCM. Pyridine (0.2 mL, 2.56 mmol) was added, followed by acetic anhydride (0.24 mL, 2.56 mmol). The resulting colorless solution was stirred at RT overnight. 1 mL of MeOH was added and the mixture was stirred for about 30 minutes before being evaporated. The residue was partitioned between EtOAc and aqueous 1M HCl. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and evaporated. The remaining oil was dried under high vacuum to give 0.51 g of ((3R,5R)-1-acetyl-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester as an off-white solid (>95% yield).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([CH:21]=[CH2:22])[C:7]([C:23]#[N:24])=[C:6]([Cl:25])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[Cl:25][C:6]1[CH:5]=[C:4]([CH:1]([OH:3])[CH3:2])[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[C:8]([CH:21]=[CH2:22])[C:7]=1[C:23]#[N:24]
Reactant: C=Cc1c(C#N)c(Cl)cc(C(C)=O)c1OCCNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=Cc1c(C#N)c(Cl)cc(C(C)O)c1OCCNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Tert-butyl [2-(6-acetyl-4-chloro-3-cyano-2-vinylphenoxy)ethyl]carbamate (1.6 g, 4.4 mmol) was dissolved in methanol (40 mL) cooled in an ice bath and the sodium tetrahydroborate (0.16 g, 4.4 mmol) was added. The reaction was stirred for 1 h and water was added to quench residual hydride and the reaction was concentrated to remove the methanol. The aqueous was diluted with ethyl acetate washed with brine, dried over magnesium sulfate and concentrated to give tert-butyl {2-[4-chloro-3-cyano-6-(1-hydroxyethyl)-2-vinylphenoxy]ethyl}carbamate as a glass (1.6 g, 100%). LCMS calculated for C18H23ClN2O4Na (M+Na)+: m/z=389.1; found: 389.1.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[CH:16][CH:15]=2)[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:28](O)=O)[N:8]=2)[N:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N[CH2:65][CH2:66][NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71].O>CN(C=O)C>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22](=[O:27])[C:23]([F:25])([F:26])[F:24])=[CH:18][CH:19]=2)[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:28][CH2:65][CH2:66][NH:67][C:68]([O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:74])[N:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Nc1nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)c2nc(C(=O)O)cnc2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCc1cnc2nc(N)nc(OCc3ccc(CNC(=O)C(F)(F)F)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Carboxylic acid 63 (Example 45, 0.10 g, 0.24 mmol) and PyBOP ((Benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate, 0.12 g, 0.24 mmol) are dissolved in 1 mL dry DMF and stirred at room temperature for 30 min. TEA (50 μL) and tert-butyl 2-aminoethylcarbamate (48 mg, 0.3 mmol) are added. The reaction mixture is stirred for additional 3 h and poured into 50 ml of water. The product is extracted with CH2Cl2, dried over MgSO4 and purified via flash column chromatography using CH2Cl2/MeOH (20:1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[CH2:13][CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[Mg]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(F)cc2c2c1CCC2
Agent: [Mg]
Product: O=C1Nc2ccc(F)cc2C2CCCC12
Yield: 27.8 %

Procedure:
8-Fluoro-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (1.0 g, 4.9 mmol) and magnesium (1.2 g, 49.2 mmol) are reacted to form 280 mg (28%) of product analogously to Example 7.
Reaction SMILES: [OH:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[OH:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH2:7][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C[C@H](C)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: OCc1ccccc1
Product: C[C@H](O)CC(=O)OCc1ccccc1
Reaction time: 24 h

Procedure:
A chemical reference for desired product was prepared as follows. Methyl (S)-(+)-3-hydroxybutyrate (Aldrich) was dissolved in benzyl alcohol and treated with a catalytic amount of titanium tetraisopropoxide. The mixture was aged at 60° C. for 24 hours. Partial concentration on a rotary evaporator and filtration afforded benzyl (S)-(+)-3-hydroxybutyrate and residual benzyl alcohol.