Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:20])=[CH:3][CH2:4][O:5][C:6]1[CH:17]=[C:16]([Cl:18])[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14]O)=[C:8]([Cl:19])[CH:7]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]([Cl:20])=[CH:3][CH2:4][O:5][C:6]1[CH:17]=[C:16]([Cl:18])[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:22])=[C:8]([Cl:19])[CH:7]=1
Reactant: OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
A stirred solution of 22.3 grams (0.062 mole) of 4-[4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenoxy]butan-1-ol and 20.6 grams (0.062 mole) of carbon tetrabromide in 250 mL of methylene chloride was cooled to 10° C. and 17.9 grams (0.068 mole) of triphenylphosphine was added in one portion. Upon completion of addition the reaction mixture was warmed to ambient temperature where it stirred during an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 25% methylene chloride in hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 21.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:15]([NH2:18])([CH3:17])[CH3:16].[OH-].[Na+]>ClCCl.C(OCC)C.Cl[Ti](Cl)(Cl)Cl>[CH:15]([N:18]=[C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)[CH3:2])([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: CC(C)N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1ccc(C(C)=NC(C)C)cc1
Temperature: 25 °C

Procedure:
Tetrachlorotitanium (16.85 mL of 1 M, 16.85 mmol) in dichloromethane was added to a solution of ethyl 4-acetylbenzoate (5.4 g, 28.09 mmol) and isopropyl amine (6.644 g, 9.657 mL, 112.4 mmol) in diethyl ether (100 mL) at 0° C. and the reaction mixture allowed to warm to ambient temperature over 15 hours. The reaction mixture was poured into a biphasic mixture of aqueous 0.5 M sodium hydroxide and diethyl ether (4:1, 150 mL) and the layers separated. The aqueous phase was extracted with diethyl ether (×2) and the combined organic phases dried (MgSO4/K2CO3 10:1), filtered and concentrated in vacuo to give ethyl 4-(1-(isopropylimino)ethyl)benzoate as a pale yellow oil (6.7 g, quantitative). 1H NMR (400.0 MHz, DMSO-d6) δ 1.15 (d, J=6.3 Hz, 6H), 1.33 (t, J=7.2 Hz, 3H), 2.25 (s, 3H), 3.88 (sept, 1H), 4.33 (q, J=7.1 Hz, 2H) and 7.91-7.97 (m, 4H) ppm; LC/MS m/z 234.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2[nH]c3ccc(C(F)(F)F)cc3c2C1
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(C(F)(F)F)ccc3n2CC(O)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 3.937 mmol) in DMF (10 mL) was added sodium hydride (472 mg, 11.81 mmol) in portions at RT. After stirring at RT for 15 min, the suspension was allowed to cool to 0° C. and 4-(oxiran-2-yl)pyridine (762 mg, 6.299 mmol) was added dropwise into the reaction mixture, which was stirred at RT overnight. The reaction mixture was poured into ice-cooled water and extracted with EtOAc (3×50 mL). The organic layer was washed with water (2×50 mL), dried over anhydrous sodium sulfate and concentrated. The solid obtained was re-crystallized in DCM-diethyl ether to yield 2-(2-methyl-8-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.59 (d, 2H), 7.4 (s, 1H), 7.39 (d, 1H), 7.3 (d, 1H), 7.19 (d, 2H), 4.68 (m, 1H), 4.1 (m, 2H), 3.4 (dd, 2H), 2.82 (m, 1H), 2.74 (bs, 2H), 2.6 (m, 1H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers 6a and 6b.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.O>C(O)(=O)C>[Cl:9][C:5]1[CH:4]=[C:3]([F:10])[C:2]([N:1]2[C:14](=[O:15])[C:13]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]3[C:11]2=[O:16])=[CH:7][C:6]=1[OH:8]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(O)c(Cl)cc1F
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cc(O)c(Cl)cc1F
Yield: 92.9 %

Procedure:
5-Amino-2-chloro-4-fluorophenol (3.0 g, 18.6 mmol) and phthalic anhydride (3.3 g, 22.3 mmol) were dissolved in glacial acetic acid (60 ml) and the solution refluxed for 2 hr. Water was added and the resultant precipitate was separated by filtration. The residue was washed with water and dried to afford the title compound (5.04 g); 1H NMR (CDCl3+CD3OD, 300 MHz) 3.68 (1H, s), 6.93 (1H, d, J=6.6 Hz), 7.27 (1H, d, J=9.1 Hz), 7.84 (2H, dd, J=3.0, 5.5 Hz), dd, J=3.0, 5.5 Hz) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.C([Li])CCC.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>CCOCC.CCCCCC>[CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC1(C)COC(c2cccs2)=N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccsc1C1=NC(C)(C)CO1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4.5 g of 4,5-dihydro-4,4-dimethyl-2-(2-thienyl)-oxazole in 200 ml of anhydrous ether at -70° C. is added 11 ml of a 2.5M solution of n-butyl lithium in hexane, dropwise under a nitrogen atmosphere. The reaction mixture is stirred at -78° C. for 45 minutes and 8.3 g of tri-n-butyltin chloride in dry ether added dropwise. The reaction mixture is stirred at room temperature for 1 hour and quenched with water. The reaction mixture is extracted with ether, washed with water, dried over sodium sulfate and concentrated in vacuo to an oily residue.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]2[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]1=[O:11].C1C(=O)N([Br:19])C(=O)C1>C(#N)C>[Br:19][C:6]1[C:5]2[CH2:8][CH2:9][CH2:10][C:4]=2[C:3](=[O:11])[N:2]([CH3:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccc2c(c1=O)CCC2
Solvent: CC#N
Product: Cn1cc(Br)c2c(c1=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
The title compound of step 6 (140 mg, 1.04 mmol) was dissolved in ACN (5 mL) and NBS (188 mg, 1.06 mmol) was added. After stirring at rt for 1.5 h, purification by silica gel chromatography (PE/EtOAc=1:1) gave the title compound (196 mg, 89.5%) as a white solid. 1H NMR (CD3Cl, 300 MHz): δ 7.33 (s, 1H), 3.53 (s, 3H), 2.85-2.97 (m, 4H), 2.05-2.13 (m, 2H). LCMS: 228, 230 (M+1)+
Reaction SMILES: C([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(OC(C)(C)C)=O.ON1C2C=CC=CC=2N=N1.[ClH:33].CN(C)CCCN=C=NCC.[F:45][C:46]([F:60])([F:59])[C:47]1[CH:48]=[C:49]([CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1)[CH2:50][NH2:51]>CN(C)C=O.ClCCl.Cl>[ClH:33].[F:45][C:46]([F:59])([F:60])[C:47]1[CH:48]=[C:49]([CH:52]=[C:53]([C:55]([F:58])([F:56])[F:57])[CH:54]=1)[CH2:50][NH:51][C:20](=[O:22])[C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[NH2:8]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
To a stirred solution of N-Boc-L-tryptophan (5 g) and 1-hydroxybenzotriazole (2.48 g) in dimethyl formamide (85 ml) was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (3.15 g) at 0° C. After 30 minutes 3,5-bistrifluoromethylbenzylamine (4.43 g) was added and stirring continued for 16 hours at 25° C. The reaction mixture was diluted with dichloromethane and washed with sodium bicarbonate solution, water and dried (Na2SO4). The solvents were evaporated in vacuo to give a white solid which was dissolved in methanolic hydrogen chloride and allowed to stand for 16 hours. Concentration under reduced pressure afforded the title compound as a solid.
Reaction SMILES: [CH2:1](OC(=O)C1C=CN=C(C)C=1Cl)C.[CH3:14][O:15][N:16]=[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[C:23](Cl)[CH:24]=2)[O:19][CH2:18]1>>[CH3:14][O:15][N:16]=[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[C:23]([CH3:1])[CH:24]=2)[O:19][CH2:18]1
Reactant: CCOC(=O)c1ccnc(C)c1Cl
Reactant: CON=C1COc2cnc(Cl)cc21
Product: CON=C1COc2cnc(C)cc21

Procedure:
This compound was prepared using a method analogous to that of 3-chloro-2-methylisonicotinic acid ethyl ester (A.2.5.2), 5-chlorofuro[2,3-c]pyridin-3(2H)-one O-methyl oxime replacing 2,3-dichloroisonicotinic acid ethyl ester. Purification by prep HPLC, xbridge very polar method acidic gives the desired product as brown solid;
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.[F:6][C:7]([F:35])([CH2:30][CH2:31][C:32](Cl)=[O:33])[C:8]([F:29])([F:28])[C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15].COC>CC(C)=O>[F:6][C:7]([F:35])([CH2:30][CH2:31][C:32]([N:1]=[N+:2]=[N-:3])=[O:33])[C:8]([F:28])([F:29])[C:9]([F:26])([F:27])[C:10]([F:25])([F:24])[C:11]([F:22])([F:23])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: COC
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 2 h

Procedure:
Sodium azide (6.0 g) was put in a 250 mL round-bottom flask (2-neck) equipped with a thermometer. H2O (20 mL) was added to dissolve sodium azide. It was cooled on an ice-water bath. A solution of 3-(perfluorooctyl)propionyl chloride (12.9 g) in acetone (25 mL) was added dropwise to keep the temperature below 12° C. The mixture was vigorously stirred for 2 h. Dimethyl ether (100 mL) and water (100 mL) are added, and the mixture was vigorously stirred for 1 min. After the separation of two layers, the aqueous layer was extracted with ether (2×50 mL). The ether layers were combined, and are washed with water (3×100 mL) and brine. After drying over MgSO4, the solvent was removed under vacuum to give a mixture of white solid and liquid (12.0 g) that was immediately used for the next reaction.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH3:6][NH:7][C:8]1[C:9](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH3:13])=[O:11].[OH-].[Na+]>ClCCl.O>[Br:1][CH2:2][C:3]([N:7]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[CH3:6])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CNc1ccccc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccccc1N(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.6 %

Procedure:
A solution of bromoacetyl bromide (209 g) in dichloromethane (200 ml) was added dropwise to a cooled (ice bath) solution of methyl N-methylanthranilate (168 g) in dichloromethane (1.41). A solution of sodium hydroxide (59 g) in water (400 ml) was added dropwise and the reaction mixture was stirred at room temperature for 20 h. The organic phase was separated and washed with 1M hydrochloric acid (500 ml), brine (300 ml), saturated sodium hydrogen carbonate solution (400 ml), dried (Na2SO4) then evaporated to afford the required product (255 g). 1H NMR (360 MHz, CDCl3) δ3.23 (3H, s), 3.54 (1H, d, J=11 Hz), 3.60 (1H, d, J=11 Hz), 3.90 (3H, s), 7.40 (1H, d, J=8 Hz), 7.51 (1H, dd, J1 =J2 =8 Hz), 7.65 (1H, dd, J1 =J2 =8 Hz), 8.04 (1H, d, J=8 Hz).
Reaction SMILES: C([N:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH2:31])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:11])(=O)C.Br.O>O1CCOCC1>[NH2:31][C:25]1[C:21]2[C:22](=[O:24])[CH:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:11])=[C:13]([F:32])[CH:14]=3)[O:19][C:20]=2[C:28]([F:29])=[CH:27][C:26]=1[F:30]
Reactant: CC(=O)N(CCCCCCBr)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCCCCBr)c(F)c3)cc(=O)c12
Yield: 63.2 %

Procedure:
6.10 g (11.9 mmol) of the resulting 2-[4-[N-acetyl-N-(6-bromohexyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 60 ml of dioxane, 40 ml of 47% aqueous HBr was added and the mixture was heated at reflux for 3 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed once with 5% aqueous sodium bicarbonate and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 3.53 g (63%) of 5-amino-2-[4-(6-bromohexylamino)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[O:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7][C:6]=2[CH:13]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.Cl>CC(O)C.ClC(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: O=[N+]([O-])c1cc(F)cc2c1OC(CO)CC2
Reactant: C1=COCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(F)cc2c1OC(COC1CCCCO1)CC2
Reaction time: 3 h
Yield: 104.1 %

Procedure:
A mixture of intermediate 14-b (0.25 mol), 3,4-dihydro-2H-pyran (0.50 mol) and hydrochloric acid in 2-propanol (0.5 ml) in trichloromethane (700 ml) was stirred for 3 h on a water bath. The reaction mixture was washed with a 10% NaOH solution. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 81 g of (±)-6-fluoro-3,4-dihydro-8-nitro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran (104% crude residue) (interm. 15-b).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl>C1COCC1>[CH3:17][Si:18]([CH3:21])([CH3:20])[O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)Cl
Reactant: Nc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)OCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 945.1 %

Procedure:
To a stirred solution of 4-amino benzyl alcohol (16.0 g, 13.0 mmol, 1.0 eq) in THF (400 mL), was added triethylamine (18.9 mL, 13.6 mmol, 1.05 eq) followed by trimethylchlorosilane (17.2 mL, 13.6 mmol, 1.05 eq). The reaction mixture was stirred under a nitrogen atmosphere overnight at room temperature. THF was evaporated under vacuum and the mixture partitioned with ethyl acetate (300 mL) and water (300 mL). The organic phase was isolated and the aqueous layer re-extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (2×150 mL), dried (MgSO4), filtered and concentrated in vacuo. The product was obtained as a yellow oil (24.0 g, 95% yield) and used in stage 4 without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:19])C(=O)C1.O>CN(C=O)C>[Br:19][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][CH:10]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c[nH]nc1-c1ccccc1
Yield: 92.5 %

Procedure:
A solution of 3-phenyl-1H-pyrazole (4.08 g, 28.3 mmol) and NBS (5.04 g, 28.3 mmol) in DMF (40 mL) was stirred for 1 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (5.84 g, 93% yield) as a white solid: mp 114-116° C.; NMR (300 MHz, CDCl3): δ ppm 7.39-7.50 (31-1, m), 7.64 (1H, s), 7.77 (2H, d, J=6.8 Hz), 10.73 (1H, brs).
Reaction SMILES: [N+:1]([O-:17])([O:3][CH2:4][CH:5]([O:13][N+:14]([O-:16])=[O:15])[CH2:6][C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][OH:10])=[O:2].[C:18](=O)([O:29]C1C=CC([N+]([O-])=O)=CC=1)[O:19][C@@H:20]1[CH2:24][O:23][C@@H:22]2[C@H:25]([OH:28])[CH2:26][O:27][C@H:21]12>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:18](=[O:29])([O:19][C@@H:20]1[CH2:24][O:23][C@@H:22]2[C@H:25]([OH:28])[CH2:26][O:27][C@H:21]12)[O:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][CH:5]([O:13][N+:14]([O-:16])=[O:15])[CH2:4][O:3][N+:1]([O-:17])=[O:2]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: CC(C)(CCO)CC(CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(CCOC(=O)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O)CC(CO[N+](=O)[O-])O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-nitrophenyl carbonate (0.962 g, 3.10 mmol) in DCM (40 ml), (prepared as described in EXAMPLE 7, Step C), 6-hydroxy-4,4-dimethylhexane-1,2-diyl dinitrate (0.780, 3.10 mmol) and 4-dimethylaminopyridine (0.379 g, 3.10 mmol) were added and the mixture was stirred at room temperature for 18 hrs. Then the mixture was diluted with DCM and washed with a 5% solution of sodium dihydrogen phosphate (2×30 ml) and brine (1×30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 20 to 80%), affording the title compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]([CH3:25])[C:22]([OH:24])=O.Cl.[C:27]1([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:41][CH2:40][C@@H:39]([F:42])[C@@H:38]3[C@H:34]2[CH2:35][NH:36][CH2:37]3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.C(N(CC)CC)C>[C:43]1([C:33]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:41][CH2:40][C@@H:39]([F:42])[C@@H:38]3[C@H:34]2[CH2:35][N:36]([C:22](=[O:24])[C@H:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH3:25])[CH2:37]3)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: COc1ccccc1[C@H](C)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h
Yield: 20.8 %

Procedure:
0.32 g of carbonyldiimidazole is added to a solution, cooled to +4° C., of 0.36 g of (S)-2-(2-methoxyphenyl)propionic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.67 g of (3aR, 7R,7aR)-4,4-diphenyl- 7-fluoroperhydroisoindole hydrochloride in 20 cm3 of dry dichloromethane and 0.28 cm3 of triethylamine is added. The reaction mixture is stirred at room temperature for 20 hours, diluted with 200 cm3 of dichloromethane and then washed with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 20 cm), eluting under a nitrogen pressure of 0.4 bar with an ethyl acetate and cyclohexane mixture (60/40 by volume) and collecting fractions of 20 cm3. Fractions 10 to 15 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 0.6 cm3 of isopropyl oxide. The crystals obtained are drained, washed with isopropyl oxide, and then dried. 0.19 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoro-2-[ (S)-2-(2methoxyphenyl)propionyl]perhydroisoindole is obtained in the form of white crystals; melting point 195° C.
Reaction SMILES: FC1C=C(C#CC=C2CCN(C3C([N+]([O-])=O)=CC=CN=3)CC2)C=C(F)C=1OC.[CH:29](=[C:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)[C:30]#[CH:31].Cl[C:46]1[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][N:47]=1>>[F:52][C:50]1[CH:49]=[CH:48][N:47]=[C:46]([C:31]#[C:30][CH:29]=[C:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[CH:51]=1
Reactant: C#CC=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Fc1ccnc(Cl)c1
Agent: COc1c(F)cc(C#CC=C2CCN(c3ncccc3[N+](=O)[O-])CC2)cc1F
Product: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cc(F)ccn2)CC1
Yield: 38.5 %

Procedure:
The title compound was prepared following the procedure described for the Compound of Example 199, but using Compound 2b instead of Compound 1c and 2-chloro-4-fluoropyridine instead of 4-bromo-2,6-difluoroanisole. After the usual work-up procedure, purification was carried out by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc gradient from 95:5 to 60:40. Yield: 38.5%.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([S:3][CH2:1][CH3:2])=[CH:12][CH:11]=2)=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: CCSc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CCSc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
General procedure G was performed using 4-(ethylthio)benzoic acid and 4-chloro-3-(pyridin-2-yl)aniline to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylthio)benzamide.
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.C1COCC1.Cl[C:38]([O:40][CH3:41])=[O:39]>N1C=CC=CC=1>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([NH:1][C:38](=[O:39])[O:40][CH3:41])[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (30 mg, 71 μmol) was dissolved in a mixture of abs. THF (3 ml) and abs. pyridine (57.5 μl). At room temperature, pyridine (5×57 μl) and methyl chloroformate (5×33.6 mg, 5×356 μmol; 25 eq.) were added in a plurality of portions. The mixture was then heated at 80° C. for 12 h. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (31.1 mg, 91% of theory).