Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]([C:5]1([NH3+:8])[CH2:7][CH2:6]1)([OH:4])=[O:3].C(N(CC)CC)C.[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19]>CO>[F:16][C:17]([F:24])([F:23])[C:18]([NH:8][C:5]1([C:2]([OH:4])=[O:3])[CH2:7][CH2:6]1)=[O:19]
Reactant: [NH3+]C1(C(=O)O)CC1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Carboxycyclopropanaminium chloride (0.980 g, 7.124 mmol) was suspended in methanol (14 mL) and triethylamine (1.514 g, 14.960 mmol) was subsequently added. To this suspension was then added ethyl trifluoroacetate (1.113 g, 7.836 mmol) and allowed to stir at 25° C. After 16 hours, the reaction was quenched with 1N hydrochloric acid and extracted with ethyl acetate. The organic extract was dried with sodium sulfate, filtered and concentrated under reduced pressure to produce the title compound as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.76 (s, 1H), 9.94 (s, 1H), 1.38-1.44 (m, 2H), 1.08-1.14 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[N:14]=[C:15]([CH2:18][CH2:19][CH2:20][CH3:21])OC)=[O:8])[CH2:4][CH3:5]>C1COCC1>[CH2:18]([C:15]1[N:6]([CH2:3][CH2:4][CH3:5])[C:7](=[O:8])[C:9]2[CH:13]=[CH:12][S:11][C:10]=2[N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=Nc1sccc1C(=O)NCCC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nc2sccc2c(=O)n1CCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a sulfonation flask, 0.85 g of 2-(1-n-butyl-1-methoxymethyleneamino)-thiophene-3-carboxylicacid propylamide is dissolved in 20 ml of absolute THF and 0.15 g of a ca. 55% NaH dispersion is added in small portions. The mixture is stirred for 15 minutes at room temperature and 1 hour at reflux temperature. Then the solvent is removed in a water jet vacuum and the residue taken up in ethylacetate. The organic phase is washed twice with water and after drying of the organic phase with sodium sulfate, the solvent is removed in a water jet vacuum. The resulting crude product (yleld: 0.8 g of 2-n-butyl-3-n-propyl-3H-thieno[2,3-d]-pyrimidine-4-one in the form of a brown liquid) can be used without further purification for the halogenation step.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].C[Si](C)(C)N[Si](C)(C)C.[I:22]I.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[I:22][CH:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][C:2]1=[O:12]
Reactant: O=C1CCCc2ccccc2N1
Reactant: II
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1Nc2ccccc2CCC1I
Temperature: 30 °C

Procedure:
A suspension of 1.8 Kg (11.17 mol) of 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one in a mixture of 22.33 L of methylene chloride and 11.78 L (55.83 mol) of hexamethyldisilazane was heated at reflux for 10 minutes then cooled to 30° C. and treated with 8.503 Kg (33.5 mol) of iodine in one portion. The mixture was heated at reflux for 2.5 hours then cooled to room temperature. Aqueous sodium sulfite containing 4.926 Kg of sodium sulfite in 44 L of water was cooled to 0° C. and into it was poured the reaction mixture in several portions with vigorous stirring while maintaining the temperature below 10° C. The reaction vessel was rinsed with 22.33 L of methylene chloride and the washing transferred to the quenching mixture. The quenching mixture was stirred vigorously and the layers allowed to separate. The aqueous layer was removed and reextracted with 22.33 L of methylene chloride. The combined organic layers were washed with 11 L of water and concentrated under vacuum to a final volume of /5 L. The residue was treated with 55 L of toluene and concentrated under vacuum to a final volume of 10 L. The resulting slurry was removed by filtration and the filter cake washed with an additional 5 L of toluene and dried under vacuum at ambient temperature for 24 hours to give 1.842 Kg (6.42 mol. 57%) of product. 1H NMR (200 MHz, CDCl3): 2.6-2.8 (m,3H), 2.93 m, 1H), 4.64 (t, 8 Hz, 1H), 6.97 (d, 8 Hz, 1H), 7.10-7.35 (m, 3H), 7.55 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccccc2)ccc1N
Temperature: 85 °C
Yield: 73.3 %

Procedure:
To a solution of methyl 2-amino-5-bromobenzoate (2.0 g, 8.7 mmol) in dioxane (40 mL) were added phenylboronic acid (1.91 g, 15.7 mmol), potassium phosphate (4.08 g, 19.1 mmol) and tetrakis(triphenylphosphine)palladium (0.26 g, 0.22 mmol) under nitrogen. The mixture was heated at 85° C. for 20 h, then cooled to 0-5° C. Aqueous ammonium chloride was added and the mixture was extracted, washed with brine, dried (Na2SO4) and concentrated to dryness. Purification by chromatography gave 1.45 g of methyl 2-amino-5-phenylbenzoate.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:25])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:6][C:5]=12.[H-].[Na+].[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:25])[C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([S:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:36])=[O:35])[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)=[CH:6][C:5]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCN(S(=O)(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(piperidin-4-yl)benzamide (0.05 g, 0.150 mmol) in tetrahydrofuran (1.246 ml) was treated with sodium hydride (0.018 g, 0.449 mmol) in 3 portions. The reaction was stirred at ambient temperature for 45 minutes and became a partially homogeneous solution. Benzenesulfonyl chloride (0.021 ml, 0.164 mmol) was added and the mixture was stirred for 16 hours. The reaction was treated with 0.1 mL water and was concentrated under a stream of nitrogen. Reverse-phase chromatography provided the title compound. 1H NMR (500 MHz, methanol-d4) δ ppm 8.73 (dd, J=7.0, 0.9 Hz, 1H), 8.15 (dd, J=2.2, 0.8 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 7.89-7.75 (m, 5H), 7.73-7.59 (m, 3H), 7.46 (dd, J=7.0, 1.6 Hz, 1H), 7.37-7.31 (m, 2H), 4.75 (s, 2H), 3.96-3.88 (m, 2H), 2.67-2.52 (m, 1H), 2.48-2.37 (m, 2H), 1.95-1.72 (m, 4H); MS (ESI(+)) m/e 475 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][C:13]#[N:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CN([CH:18]=[O:19])C.C([O-])=O.[Na+]>O>[CH:18]([C:2]1[CH:3]=[C:4]([CH2:12][C:13]#[N:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)=[O:19]
Reactant: N#CCc1cc(Br)c2ncccc2c1
Reactant: CN(C)C=O
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: N#CCc1cc(C=O)c2ncccc2c1
Temperature: 80 °C

Procedure:
To a solution of (8-bromoquinolin-6-yl)acetonitrile (1 eq.) in anhydrous, deoxygenated DMF (0.08 M) was added freshly-dried sodium formate (1.5 eq.) and Pd(PPh3)Cl2 (2% loading). Through the resulting yellow suspension, was bubbled CO and then reaction was heated to 80° C. for 16 h. The now black reaction suspension was cooled to RT, diluted with water, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[CH:4][N:3]=1.[CH3:7][O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=O.[BH4-].[Na+].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH2:11][NH:1][C:2]1[S:6][N:5]=[CH:4][N:3]=1.[CH3:7][O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH2:11][NH:1][C:2]1[S:6][N:5]=[CH:4][N:3]=1
Reactant: Nc1ncns1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ncns2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
A mixture of 5-amino-1,2,4-thiadiazole (1 g; 9.89 mmol) and 2,4-dimethoxybenzaldehyde (1.81 g; 10.9 mmol) in toluene (30 ml) was refluxed under Dean and Stark conditions for 2 hours. The reaction mixture was evaporated, the residue taken up in methanol (25 ml), NaBH4 (600 mg; 15.9 mmol) added carefully in small portions (vigorous effervescence after each addition), and the reaction was left stirring overnight at ambient temperature. Aqueous HCl (2M, 1 ml) was added followed by aqueous NaOH (2M, 10 ml). The bulk of the methanol was evaporated, water (20 ml) added and extracted with ethyl acetate (2×30 ml). The combined organic was washed brine (20 ml), dried, and evaporated. The residue was purified by silica gel column chromatography (ISCO™ column 120 g; ethyl acetate:heptane 25:75 to 60:40) to furnish a semi-solid residue that was re-evaporated from heptane. 2-3 ml tBuOMe was added, then 2-3 ml heptane, the solid filtered off, washed with heptane and dried to afford 1.22 g of the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[CH2:11][NH2:12].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH:26]=O.C1(C)C=CC(S(N)(=O)=O)=CC=1>O>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH:26]=[N:12][CH2:11][C:10]1[CH:13]=[C:14]([C:17]([F:18])([F:19])[F:20])[CH:15]=[CH:16][C:9]=1[Cl:8]
Reactant: NCc1cc(C(F)(F)F)ccc1Cl
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(N)(=O)=O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cc(C=NCc2cc(C(F)(F)F)ccc2Cl)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a 100 mL round bottom flask, equipped with a Dean Start Trap was charged 50 mL of toluene, 5.0 gm of 2-chloro-5-trifluoromethyl benzyl amine and 5.8 gm of 3,5-bis(trifluoromethyl)benzaldehyde and 50 mg of para-toluenesulfonamide. The reaction was heated until water no longer distilled off about 3 hours, then cooled to ambient temperature and the solvent removed in vacuum. The crude product was used directly in the next step without further purification. 10.0 gm.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.[Li]C(C)(C)C.[Sn:11](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15].[NH4+].[Cl-]>C1COCC1>[CH2:20]([Sn:11]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]1[O:1][CH2:2][CH2:3][CH:4]=1)[CH2:21][CH2:22][CH3:23]
Reactant: C1=COCC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 108.6 %

Procedure:
A solution of 2,3-dihydrofuran (10.7 mL, 141 mmol) in anhyd THF (80 mL) was cooled to −60° C. A solution of t-BuLi (1.7 M in pentane, 100 mL, 170 mmol) was added dropwise. The yellow solution was stirred at −60° C. for 10 min then at 0° C. for 50 min. The reaction mixture was cooled down to −60° C. and Bu3SnCl (52.7 mL, 185 mmol) was added dropwise to give a colorless solution that was stirred at 0° C. for 90 min. Sat. aq NH4Cl was added dropwise and the reaction mixture was extracted with Et2O. The aqueous phase was further extracted with Et2O and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was distilled under 24 mbar vacuum at 150° C. and the residue was distilled again under 22 mbar vacuum at 154° C. to yield the title compound (55 g, 100%) as a light yellow liquid.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[O:16][C:15]3[CH:17]=[CH:18][C:19]4[C:24]([C:14]=3[CH:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)CO>[CH:13]1[C:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:15]=2[O:16][C:12]=1[CH:9]1[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCC(c2cc3c(ccc4ccccc43)o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: c1ccc2c(c1)ccc1oc(C3CCNCC3)cc12

Procedure:
7.8 g of 4-(naphtho[2,1-b]furan-2-yl)-1-piperidinecarboxylic acid ethyl ester is dissolved in 60 ml of ethylene glycol. After the addition of 40 ml of a 50% aqueous potassium hydroxide solution, the formed cloudy solution is heated, with vigorous stirring, for 15 hours at 160°. The reaction solution is thereupon cooled to 20° and extracted twice with 500 ml of ethyl acetate. The organic phases are washed five times with 1 liter of water each time, dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 400 ml of 2 N hydrochloric acid, and the acid solution extracted with toluene. The aqueous solution is then adjusted by addition of 10% sodium hydroxide solution to have a pH value of 12, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered, and concentrated by evaporation to obtain crude 4-(naphtho[2,1-b]furan-2-yl)-piperidine. The hydrochloride is prepared with hydrogen chloride in ethyl acetate, and recrystallised from ethyl acetate, whereupon it melts at 225°.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][CH2:8][CH2:9]OS(C)(=O)=O)=[CH:4][CH:3]=1.[Br-:17].[Li+]>CC(C)=O>[Br:17][CH2:9][CH2:8][O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: [Br-]
Reactant: CS(=O)(=O)OCCOCc1ccc(Cl)cc1
Agent: [Li+]
Solvent: CC(C)=O
Product: Clc1ccc(COCCBr)cc1

Procedure:
A mixture of methanesulfonic acid 2-(4-chloro-benzyloxy)-ethyl ester (Intermediate 6) (1.37 g, 5.18 mmol) and lithium bromide (1.80 g, 20.7 mmol) in acetone (15 mL) was heated at reflux overnight. The reaction mixture was concentrated to dryness and the residue partitioned between DCM and water. The organic layer was dried (MgSO4), and concentrated, and purified by column chromatography over silica using DCM/cyclohexane (1:3) as eluent to afford the product as a colourless oil.
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:18])=[CH:15][C:14]=2[F:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36].CO>ClCCl.C(N(CC)CC)C.CN(C)C1C=CN=CC=1>[C:35]([O:34][C:5]1[C:6]([CH2:31][CH2:32][CH3:33])=[C:7]([CH:29]=[CH:30][C:4]=1[C:1](=[O:3])[CH3:2])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[O:18])=[CH:15][C:14]=1[F:28])(=[O:37])[CH3:36]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)OCCCN(C)C)cc2F)ccc(C(C)=O)c1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCc1c(OCCCOc2ccc(C(=O)OCCCN(C)C)cc2F)ccc(C(C)=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-dimethylaminopropyl 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-fluorobenzoate (124 mg) in dichloromethane (1 ml), triethylamine (0.5 ml) and 4-dimethylaminopyridine (a catalytic amount) was added acetic anhydride (0.38 ml). The mixture was stirred well for 1.5 hours at room temperature. To the reaction mixture was added methanol (2 ml), and the solvents removed by evaporation under reduced pressure. The residue was dissolved in chloroform, the solution was washed with a solution of saturated sodium hydrogen carbonate and dried with sodium sulfate, and the solvent was removed by evaporation. The residue was dissolved in ether, and to the solution was added a saturated solution of oxalic acid in ether until a precipitate did not emerge any more. The precipitate was recovered by filtration and washed with ether to give a white solid of 3-dimethylaminopropyl 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-fluorobenzoate.mono-oxalate (180 mg). M.p. 166°-167° C.
Reaction SMILES: C([N:8]([C@@H:16]1[CH2:21][C:20]2[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[C:25]([F:26])[C:19]=2[O:18][CH2:17]1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.C1COCC1.[Pd]>[NH2:8][C@@H:16]1[CH2:21][C:20]2[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[C:25]([F:26])[C:19]=2[O:18][CH2:17]1
Reactant: COc1ccc(F)c2c1C[C@@H](N(Cc1ccccc1)Cc1ccccc1)CO2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c2c1C[C@@H](N)CO2
Temperature: 50 °C
Yield: 91.4 %

Procedure:
(R)-3-(N,N-Dibenzylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (13.0 g, 34.4 mmol) was dissolved in 265 mL methanol and 115 mL THF. To this was 10% Pd/C (4 g) and ammonium formate (51.5 g, 0.817 mol) added. The reaction was heated to 50° C. for 2.5 h. The reaction was filtered and the solvent was removed in vacuo, the remains were taken into a 2M solution of NaOH and then extracted twice with ether. The combined ether portions were treated with brine, dried (Na2SO4), filtered, and the solvent removed in vacuo to give 6.2 g (91% yield) of the title compound as a clear oil. [α]21D =-15.3° (C=1, CHCl3). GC-MS (70 eV) M=197 (51%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.COCCOC>[Br:9][C:10]1[CH:15]=[C:14]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(Br)nc1
Reactant: OB(O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cccc(Br)c2)nc1
Yield: 68.1 %

Procedure:
2-Bromo-5-methylpyridine (46.1 g, 267 mmol), 3-bromophenylboronic acid (35.8 g, 178 mmol), palladium(II) acetate (1.00 g, 4.4 mmol), triphenylphosphine (4.67 g, 17.8 mmol), and potassium carbonate (67.8 g, 491 mmol) were mixed with 370 mL of ethylene glycol dimethyl ether and 245 mL of water in a 1000 mL round bottom flask equipped with a temperature probe, reflux condenser, and a magnetic stir bar. The solution was heated at reflux under nitrogen for 16 hr. The cooled reaction mixture was then placed in a separatory funnel, and 100 mL of ethyl acetate was added. The aqueous layer was discarded. The organic layer was extracted twice with a saturated solution of sodium chloride, dried over magnesium sulfate, and evaporated to dryness. After the excess 2-bromo-5-methylpyridine was distilled off in vacuo at 110° C., the 2-(3-bromophenyl)-5-methylpyridine was distilled at 200° C. to give 30.1 g (68.1% yield) of a slightly orange liquid, which was used for the next step without further purification.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1>CO.O=[Pt]=O>[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NCc1cccnc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCCNC1
Reaction time: 16 h
Yield: 93.5 %

Procedure:
A cold solution of HCl in MeOH (prepared by adding acetyl chloride (13.5 mL, 14.9 g, 0.19 mol) to 1 L of MeOH) was added to a cold solution of tert-butyl pyridin-3-ylmethylcarbamate (41.0 grams, 0.20 mol) in MeOH (100 mL). The solution was transferred to a Parr hydrogenation apparatus at 12° C. PtO2 (3 g) was added, and 12 bar pressure of H2 was applied. After 16 hours 1H NMR of a concentrated sample indicated the reaction to be complete. The catalyst was filtered, and conc. aq. NaOH (20 mL) was added to neutralize the HCl. The solution was concentrated to remove the bulk of the MeOH and extracted with tert-butyl methyl ether (4×200 mL). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated to give the product (40.16 g, 0.187 mol, 95%) as a yellow oil that crystallized upon standing. 1H NMR (300 MHz, CDCl3): δ 4.62 (bs. s, 1H), 3.06-2.94 (m, 4H), 2.52 (dt, J=12 Hz, 3 Hz, 1H), 2.28 (dd, J=12 Hz, 10 Hz, 1H), 1.82-1.72 (m, 1H), 1.70-1.51 (m, 3H), 1.49-1.34 (m, 1H), 1.42 (s, 9H), 1.06 (dq, J=12 Hz, 4 Hz, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]([CH3:27])[C:19]([NH:21][C@H:22]([C:24]([OH:26])=[O:25])[CH3:23])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.C([Cl:42])(=O)OCC.[N+](=C)=[N-].CC[O:48][CH2:49][CH3:50]>O1CCCC1.Cl>[Cl:1][CH2:2][C:49]([CH2:50][Cl:42])=[O:48].[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:27])[C:19]([NH:21][C@H:22]([C:24]([OH:26])=[O:25])[CH3:23])=[O:20])=[CH:28][CH:29]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CCOCC
Reactant: CCOC(=O)Cl
Agent: C=[N+]=[N-]
Agent: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)N[C@@H](C)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)CCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-[2-{4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy}propionyl]alanine (400 mg) was dissolved in 10 ml of tetrahydrofuran, added with 0.15 ml of triethylamine and cooled to 0° C. Ethyl chlorocarbonate (0.1 ml) was added and after 5 minutes, excessive diazomethane ether solution was added, and the mixture was stirred for one hour. Then, several drops of conc. hydrochloric acid were added and, after stirring for 10 minutes, the reaction mixture was washed with water, extracted with ether, and the extract dried over anhydrous magnesium sulfate. The oily product obtained by evaporation of the solvent under a reduced pressure was subjected to silica gel medium pressure column chromatography to obtain 300 mg of the title compound as a colorless oily product.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([CH2:5][C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][Si](CC)(CC)CC)[CH:16]=3)=[C:7]2[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C@H:3]1[C@H:30]([O:32][Si:33]([CH2:38][CH3:39])([CH2:36][CH3:37])[CH2:34][CH3:35])[CH3:31].O.C(O)(=O)C.C(=O)([O-])O.[Na+]>C1COCC1>[OH:22][CH2:21][C:17]1[CH:16]=[C:15]([C:6]2[CH2:5][C@H:4]3[N:8]([C:2](=[O:1])[C@@H:3]3[C@H:30]([O:32][Si:33]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:38][CH3:39])[CH3:31])[C:7]=2[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:20]=[CH:19][CH:18]=1
Reactant: C=CCOC(=O)C1=C(c2cccc(CO[Si](CC)(CC)CC)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C1=C(c2cccc(CO)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
Allyl (5R,6S)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-3-(3-{[(triethylsilyl)oxy]methyl}phenyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (911 mg) prepared by step b) of example 4 was dissolved in THF (13 ml), and thereto water (6 ml) and acetic acid (3 ml) were added at 0° C. After stirring for 30 minutes, a saturated aqueous sodium hydrogencarbonate solution was added thereto and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give allyl (5R,6S)-3-[3-(hydroxymethyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (535 mg).