Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][CH:18]=1)(O)[C:12]([F:15])([F:14])[F:13])[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[S:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:25])=[O:26])=[CH:19][CH:18]=1)[C:12]([F:13])([F:14])[F:15])[CH3:2]
Reactant: CCOCCn1cccc1C(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOCCn1cccc1C(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 32 mg (0.07 mmol) of N-(4-{1-[1-(2-ethoxyethyl)-1H-pyrrol-2-yl]-2,2,2-trifluoro-1-hydroxyethyl}-phenyl)-N-methyl-benzenesulfonamide (see, Preparative Example A) in 2 mL of CH2Cl2 at 0° C. were added 1.05 mL (6.57 mmol) of triethylsilane followed by 167 μL (1.32 mmol) of boron trifluoride diethyl etherate dropwise. The mixture was warmed to room temperature and stirred for 1.75 h. After this time, the reaction mixture was cooled to 0° C., quenched by the addition of a saturated aqueous solution of sodium bicarbonate, allowed to warm to room temperature, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 4:1) to give the title compound.
Reaction SMILES: I[C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=2)[CH:6]=1.[F:22][C:23]([F:32])([F:31])[C:24](F)(F)[C:25]([F:28])([F:27])I.CN(C=O)C>C(OCC)(=O)C.[Cu]>[CH3:17][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[CH2:7][N:5]1[CH:6]=[C:2]([C:25]([F:28])([F:27])[CH2:24][C:23]([F:32])([F:31])[F:22])[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4]1
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Reactant: Cc1cc(Cn2cc(I)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(C(F)(F)CC(F)(F)F)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
4-Iodo-1-(3-methyl-4-nitrobenzyl)-3-trifluoromethyl-1H-pyrazole (2.06 g), copper powder (0.95 g), heptafluoro-1-iodopropane (2.96 g) and DMF (14 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 130-135° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and an insoluble matter was filtered with Celite and washed with ethyl acetate. The filtrate was concentrated under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-pentafluoropropyl-3-trifluoromethyl-1H-pyrazole (0.80 g).
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.CN(C)C=O.C(N(CC)CC)C.[C:29]([O:35][CH2:36]Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>O>[NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[N:11]=[N:12][N:13]([CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:14]=3)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCn1nnc(C2N3C(=O)C(N)[C@H]3SC2(C)C)n1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2.40 g. of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 15 ml. of N,N-dimethylformamide, is added 2.8 ml of triethylamine. Stirring is continued for a further 15 minutes, and then 2.68 g. of chloromethyl pivalate is added. The mixture is stirred at ambient temperature for 5 hours, and then it is diluted with 100 ml. of water. It is then extracted with ethyl acetate. The extract is washed with water, dried using anhydrous sodium sulfate, and then it is evaported in vacuo to give a mixture of the title compounds. The individual isomers are obtained by chromatographic separation of the crude product.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Cl:38])[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Cl:38])[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.1 g) and triethylamine (1.0 ml), and 3,4-dichlorobenzoyl chloride (1.0 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[C:4]([CH2:16][OH:17])[N:3]=1.C([O-])(=O)C.[K+].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>CN(C=O)C.O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([O:8][C:7]1[C:2]([C:24](=[CH2:25])[C:23]([O:27][CH3:28])=[O:26])=[N:3][C:4]([CH2:16][OH:17])=[CH:5][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccc(OCc2ccccc2)c(Br)n1
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C(=O)OC)c1nc(CO)ccc1OCc1ccccc1
Temperature: 120 °C
Yield: 84.1 %

Procedure:
To a solution of 2-bromo-3-benzyloxy-6-hydroxymethylpyridine (2.94 g, 10 mmol) in DMF (19 ml) and water (1 ml) were added potassium acetate (2.45 g, 10.0 mmol), tetra-n-butylammonium iodide (3.69 g. 10.0 mmol), bis(triphenyl-phosphine)palladium dichloride (281 mg, 0.4 mmol) and methyl acrylate (2.70 ml. 2.58 g, 30 mmol). The mixture was placed under nitrogen and stirred and heated at 120° C. for 5 h. The mixture was cooled and added to water (180 ml). The product was extracted into ethyl acetate (3×30 ml). The combined extracts were washed with water (3×25 ml), dried and evaporated. The residue was purified by flash column chromatography eluting with dichloromethane, then 4:1 dichloromethane:ethyl acetate to give the product (2.516 g, 84%).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH3:14][O:13][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4]2)=[O:12]
Reactant: COC(=O)c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CCN2C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.3 %

Procedure:
To a solution of methyl 2,3-dihydro-1H-indole-5-carboxylate HCl salt 55a (64.1 mg, 0.3 mmol), and benzoyl chloride 1t (0.042 mL, 0.36 mmol) in CH2Cl2 (1 mL) was added Et3N (0.13 mL, 0.9 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The resulting mixture was partitioned between CH2Cl2 and H2O. The organic solution was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography (silica gel, 10-20% EtOAc/Heptanes) gave 55g (88 mg). MS m/z (M+H+) 282.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH:11]=[CH2:12])[C:6]=2[N:7]=1.[O:19]1CCCC1.B1C2CCCC1CCC2.OO.[OH-].[Na+]>O>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][OH:19])[C:6]=2[N:7]=1
Reactant: C1CCOC1
Reactant: C=Cc1csc2c(N3CCOCC3)nc(Cl)nc12
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Product: OCCc1csc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
4-(2-chloro-7-vinylthieno[3,2-d]pyrimidin-4-yl)morpholine (170 mg, 0.6 mmol) was dissolved in tetrahydrofuran (10 mL, 100 mmol) and cooled to 0° C. under an atmosphere of nitrogen. 0.5 M 9-BBN in hexanes (3.4 mL, 2 mmol) was added and the reaction was allowed to warm up to room temperature and stir overnight. LCMS indicated mostly starting material so the reaction was cooled to 0° C. again and added 0.5 M 9-BBN in hexanes (8.0 mL, 4 mmol) and allowed to warm up to room temperature and stir overnight again. Added 20 M hydrogen peroxide (1.4 mL, 20 mmol) followed by 5 M sodium hydroxide in water (2.4 mL, 10 mmol). The reaction was diluted with water and extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo and was purified by silica gel chromatography (0 to 50% ethyl acetate/heptanes) on the CombiFlash® Rf system and concentrated in vacuo to give 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-7-yl)ethanol (110 mg, 61% yield)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH2:10][C:11]([F:14])([F:13])[CH3:12])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:69]([NH2:73])([CH2:71][CH3:72])[CH3:70]>C1(C)C=CC=CC=1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH2:10][C:11]([F:14])([F:13])[CH3:12])[N:7]=[C:6]([NH:73][C@H:69]([CH2:71][CH3:72])[CH3:70])[CH:5]=1
Reactant: CC[C@H](C)N
Reactant: COC(=O)c1cc(Cl)nc(CC(C)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(CC(C)(F)F)n1
Yield: 58 %

Procedure:
Dissolve 2-chloro-6-(2,2-difluoropropyl)-isonicotinic acid methyl ester (150 mg, 0.6 mmol), palladium (II) acetate (224.0 mg, 1.0 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (37 mg, 0.06 mmol) and cesium carbonate (293 mg, 0.9 mmol) in toluene (2 mL) in a previously degassed sealed vessel. Flush the mixture with nitrogen gas. Add (S)-(+)-sec-butylamine (0.07 mL, 0.72 mmol) to the solution under nitrogen and heat the sealed mixture overnight at 100° C. Cool the reaction to room temperature. Dilute with diethyl ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 0:100 to 5:95 ethyl acetate:hexanes) to give the title compound as an oil (58%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14]C2CCCCO2)[CH2:10][C@@H:9]1[CH3:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C=CC1C=CC=CC=1.C(C1C=CC=CC=1C=C)=C>CO>[C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][C@@H:9]1[CH3:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@H]1C[C@@H](OC2CCCCO2)CCN1C(=O)OC(C)(C)C
Agent: C=Cc1ccccc1C=C
Solvent: C=Cc1ccccc1
Solvent: CO
Product: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 14.6 g (0.04876 mol) of cis-N-BOC-2-methyl-4-[(tetrahydropyran-2-yl)oxy]piperidine in 120 ml of methanol is treated with 20 g of cationic exchanger Dowex® 50 WX8 (H+ form; 50-100 mesh (50 mesh corresponds to a granular size of c. 300 μm, 100 mesh to c. 150 μm); cationic exchanger based on a styrene/divinylbenzene polymer containing sulfonyl groups; registered trademark of Dow Chemicals Co., USA)), and the mixture is stirred for 22 hours at room temperature. After filtration, washing the ion exchanger with methanol and concentrating the filtrate under vacuum, the title compound is obtained in the form of a viscous oil, Rf =0.16 (silica gel/ethyl acetate:hexane (1:2)).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:15])[CH2:6][P:7]([CH3:14])(=[O:13])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]([OH:15])[CH2:6][P:7]([CH3:14])(=[O:13])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: [H][H]
Reactant: CC(C)COP(C)(=O)C[C@@H](O)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)COP(C)(=O)C[C@@H](O)CN

Procedure:
To a solution of 1.2 g of isobutyl P-[3-azido-2(S)- hydroxy-propyl]-P-methyl-phosphinate in 25 ml of ethanol are added 0.25 g of 5% palladium on charcoal. The resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate evaporated to give isobutyl P-[3-amino-2(S)-hydroxy-propyl]-P-(methyl)-phosphinate as a viscous oil, 31P-NMR spectrum: δ=+55.6 and +54.6 ppm (CDCl3), [α]D25 =+10.9 (c=0.50% in ethanol).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[C:16](OCC)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(O[K])(C)(C)C.Cl>C1COCC1.O>[OH:23][C:16]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[C:4]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[C:3]([NH:2][CH3:1])=[O:15]
Reactant: CNC(=O)Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccncc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=C(O)c1ccncc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-2-naphthalen-2-yl-acetamide (94 g, 470 mmol) and 71.3 g (71 ml) of ethyl isonicotinate (470 mmol) were partially dissolved in 800 mL of anhydrous THF in a 3 L, 3-necked r.b. flask equipped with a mechanical stir, temperature probe, and a 500-mL addition funnel. The flask was cooled to 0–5° C. in an ice-water bath. tBuOK (1M in THF, 470 mL) was added slowly into the heterogeneous mixture. After the addition, the resulting yellow-brown heterogeneous mixture was stirred overnight at RT. The resulting dark solution was cooled to 0–5° C. in an ice-water bath. Distilled water (800 mL) was added. The basic solution was neutralized to pH 7 using 37% HCl. The solvent was removed in vacuum at RT. The resulting solid was filtered off, washed by slurring in water (1 L) and toluene (1 L), respectively. The suspension was then filtered. The solid was dried under vacuum at 50° C. overnight and used crude in the next step.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)[NH2:2].Cl.[N:15]([O-])=O.[Na+]>C(OCC)C.O>[N:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)=[N+:2]=[N-:15]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1sc(NN)nc1C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1C
Reaction time: 0.17 h
Yield: 47.1 %

Procedure:
To a cooled (0° C.) suspension of ethyl 2-hydrazinyl-4-methylthiazole-5-carboxylate (3.00 g, 14.92 mmol) in a mixture of diethyl ether (15 mL) and water (15 mL) was added hydrochloric acid (2.72 mL) dropwise. The reaction mixture was stirred for 10 minutes, and a solution of sodium nitrite (1.21 g, 17.46 mmol) in water (2 mL) was added. The mixture was stirred for 2 hours at 0° C. and extracted with diethyl ether. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:4) to afford the title compound as a yellowish solid (1.49 g, 47%): 1H NMR (300 MHz, CDCl3) δ 4.29 (q, J=6.0 Hz, 2H), 2.62 (s, 3H), 1.33 (t, J=6.0 Hz, 3H); MS (ES+) m/z 213.2 (M+1).
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:20](=[CH:21][C:22]=1[Cl:23])[C:12]1[N:13]([CH2:16][CH:17](O)[CH3:18])[CH:14]=[CH:15][C:11]=1[CH2:10]2.C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+]>ClCCl.CN(C)C=O.O>[N:31]([CH:17]([CH3:18])[CH2:16][N:13]1[CH:14]=[CH:15][C:11]2[CH2:10][C:9]3[C:20]([C:12]1=2)=[CH:21][C:22]([Cl:23])=[C:7]([Cl:6])[CH:8]=3)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)Cn1ccc2c1-c1cc(Cl)c(Cl)cc1C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cn1ccc2c1-c1cc(Cl)c(Cl)cc1C2)N=[N+]=[N-]
Yield: 68.9 %

Procedure:
0.33 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 0.6 g of (RS)-1-(6,7-dichloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 1.1 8 ml of triethylamine in 30 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 50 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 275 mg of sodium azide and the reaction mixture was heated to 60° for 17 hours while stirring. After cooling, the solution was poured into 60 ml of water and extracted three times with 90 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.45 g (69%) of (RS)-1-(2-azido-propyl)-6,7-dichloro-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a light colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:29]2[C:24]([F:23])=[N:25][CH:26]=[C:27]([CH3:30])[CH:28]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: Cc1ccc(F)nc1
Product: Cc1cnc(F)c(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)c1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 2-fluoro-5-methylpyridine (CAS RN: [2369-19-9]) was prepared the title compound as a colorless oil, MS (ESI+): m/z=411 ([M]+, 1Br).
Reaction SMILES: Cl.Cl.[CH2:3]([NH2:8])[CH2:4][CH2:5][CH2:6][NH2:7].CN(C=O)C.[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>O>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:8][C:14](=[O:15])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NCCCCNC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 46.3 %

Procedure:
1,4-butanediamine dihydrochloride (5.96 g, 37 mmol) was dissolved in water (15 mL), and DMF (50 mL) was added. With rapid stirring, CBZ-Cl (1.0 mL, 7.0 mmol) was added dropwise over 2 minutes. The cloudy solution had pH~2.8. The pH was adjusted to 9.0 with 5 N NaOH, (clear solution) and stirred for 2 hr. 10 The reaction mixture was acidified to pH=1.25, extracted with ether (2 X), made basic (pH>10) with 5 N NaOH, and extracted with dichloromethane (2 X). The dichloromethane fractions were combined and washed with water (2 X), dried and evaporated in vacuo to provide the crude mono-CBZ amine (0.72 g, 3.24 mmol, 46%) which was used as is in the next step.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][C:28]([O:30]CC)=[O:29])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][C:28]([OH:30])=[O:29])=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a mixture of ethyl 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (1.35 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid and water were added to acidify 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 to give crystals (0.98 g, 76%) of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-154° C.
Reaction SMILES: [Mg].[CH3:2]I.C[Mg]I.[Cl:7][CH:8]([Cl:16])[C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10].[Cl-].[NH4+]>C(OCC)C>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]([CH:8]([Cl:16])[Cl:7])([OH:10])[CH3:2]
Reactant: CI
Reactant: O=C(c1cccs1)C(Cl)Cl
Agent: C[Mg]I
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)(c1cccs1)C(Cl)Cl
Temperature: 25 °C
Yield: 83 %

Procedure:
Under an argon atmosphere, 0.54 g of magnesium turnings (22 mg atom) was mixed with dry diethylether (15 ml), and 3.72 g of methyl iodide (93% purity, 24 mmol) solution in dry diethylether (15 ml) was dropped gradually thereto to prepare Grignard reagent of methylmagnesium iodide. The Grignard reagent was gradually added in drop-wise into 3.60 g of 2-(dichloroacetyl)thiophene (18.5 mmol) solution in dry diethylether (15 ml) with cooling in an ice-water bath so as to maintain a temperature below 10° C. After the dropwise addition was completed, the reaction mixture was agitated over a night at room temperature, and then, 20 ml of a saturated aqueous solution of ammonium chloride was added thereto and extracted with ether. The ether layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and the ether was distilled off. Thus, 1-(2-thienyl)-1-dichloromethylethanol was obtained in an amount of 3.22 g (yield 83%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH:13]([Br:15])[CH3:14].O>CN(C)C=O>[Br:15][CH:13]([CH3:14])[CH2:12][CH2:11][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Br)CCBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Br)CCOc1cccnc1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (1.00 g, 10.52 mmol) in N,N-dimethylformamide (DMF) (10 mL) was slowly added to a cold (0° C.), stirring slurry of sodium hydride (0.50 g of an 60% dispersion in mineral oil, 12.63 mmol) in DMF (5 mL). After stirring 30 min, 1,3-dibromobutane (2.50 g, 11.57 mmol) was slowly added drop-wise. The resulting mixture was stirred at 0-4° C. for 16 h. Cold water (10 mL) was added, and the mixture was extracted with ether (3×100 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to give 2.23 g (92.5%) of an oil.