Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[C:4]2[C:5]([N:7]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:8](=[O:9])[C:3]=12)=[O:6].O>CO.[BH4-].[K+]>[F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[C:4]2[C:3]=1[CH:8]([OH:9])[N:7]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:5]2=[O:6]
Reactant: CC(C)CN1C(=O)c2c(F)ccc(F)c2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)CN1C(=O)c2c(F)ccc(F)c2C1O
Temperature: 20 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
4,7-Difluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 6.41 g of 3,6-difluoro-N-isobutylphthalimide in 70 cm3 of methanol and 1.44 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 3 hours and is then cooled to a temperature in the region of 0° C. and 45 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 30° C., followed by addition of 80 cm3 of dichloromethane. After separation of the phases by settling, the aqueous phase is extracted twice with 80 cm3 of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 5.68 g of 4,7-difluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a yellow solid melting at 129.5° C. (Rf=0.48, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[C:11]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]#[N:34]>ClCCl>[C:19]([C:11]1[CH:10]=[C:9]([Cl:8])[CH:14]=[CH:13][C:12]=1[S:15]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:28]#[N:27])(=[O:17])=[O:16])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1S(=O)(=O)Cl
Reactant: N#CCCCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
15 ml of redistilled triethylamine are added to 15.7 g of 4-chloro-2-benzoylbenzenesulphonyl chloride in 100 ml of anhydrous dichloromethane, and 5.6 g of 6-aminocapronitrile in 20 ml of dichloromethane are then added dropwise at 0° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C.CO>C(Cl)Cl.N1C=CC=CC=1>[C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(N)=O)cs2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.4 %

Procedure:
To a solution of 1-(4-carbamoyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (1.0 g, 5.02 mmol) (obtained as described in Reference Example 3(2)) in a mixture of methylene chloride (30 ml) and pyridine (5 ml) were added methanesulfonyl chloride (0.967 ml, 12.5 mmol) and triethylamine (1.75 ml, 12.5 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 2.5 hours. After checking the completion of the reaction, methanol (0.405 ml) was added to the reaction mixture in an ice bath and then the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue was added isopropyl ether, and the mixture was filtered to afford 1-(4-carbamoyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (1.30 g, yield 94%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[C:6]([F:20])[C:5]([O:21][CH2:22][CH3:23])=[C:4]([O:24][CH2:25][CH3:26])[CH:3]=1.[Cu](C#N)[C:28]#[N:29]>CN(C)C=O>[C:28]([C:2]1[C:7]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])=[C:6]([F:20])[C:5]([O:21][CH2:22][CH3:23])=[C:4]([O:24][CH2:25][CH3:26])[CH:3]=1)#[N:29]
Reactant: N#C[Cu]C#N
Reactant: CCOc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Solvent: CN(C)C=O
Product: CCOc1cc(C#N)c(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Temperature: 155 °C
Yield: 0.1 %

Procedure:
A mixture of 2-(6-bromo-3,4-diethoxy-2-fluorobenzyl)isoindol-1,3-dione (1.00 g, 2.37 mol), copper cyanide (0.42 g, 4.74 mol) and N,N-dimethylformamide (5 mL) was stirred at 155° C. for ten hours. After the reaction mixture was extracted with a 10% aqueous solution of ethylene diamine and toluene, the resultant organic layer was washed sequentially with a 10% aqueous solution of ethylene diamine and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off to give crude crystals, which were washed with ethyl acetate to give 0.52 g of the title compound (yield: 60%) as slightly green crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[CH:30]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>C1COCC1>[CH:30]1([CH2:36][NH:37][C:23]([C:14]2[C:15]3[O:19][C:18]([CH3:20])=[N:17][C:16]=3[C:21]3[NH:22][C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])=[N:11][C:12]=3[CH:13]=2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Reactant: NCC1CCCCC1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(o1)c(C(=O)NCC1CCCCC1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 32.1 %

Procedure:
The title compound was prepared following the procedure described for Example-181 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.050 g, 0.132 mmol), thionyl chloride (2.0 mL), 1-cyclohexylmethanamine (0.023 g, 0.138 mmol), THF (5.0 mL) and DIPEA (0.086 g, 0.663 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH: DCM to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 1.04-1.31 (m, 6H), 1.62-1.75 (m, 5H), 2.54 (s, 3H), 3.00 (t, J=18.6 Hz, 2H), 7.34 (s, 1H), 7.53-7.59 (m, 3H), 7.94 (s, 1H), 9.39 (s, 1H), 11.51 (s, 1H); MS [M+H]+: 472.43.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH:12]([CH3:16])[CH2:13][CH:14]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([CH2:32][CH3:33])[C:24]3[C:29]([C:30]=2[CH:31]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][NH:18][C:19]2[CH:20]=[CH:21][C:22]3[N:23]([CH2:32][CH3:33])[C:24]4[C:29]([C:30]=3[CH:31]=2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(CC=O)CC(=O)Nc1ccc(C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCn1c2ccccc2c2cc(NCCC(C)CC(=O)Nc3ccc(C#N)cc3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.2 %

Procedure:
A solution of the compound obtained in Step 2 (110 mg, 0.48 mmol) and 3-amino-N-ethylcarbazole (151 mg, 0.72 mmol) in TFA (1 mL) and toluene (1 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added sodium triacetoxyborohydride (304 mg, 1.43 mmol), and the mixture was stirred at room temperature for additional 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 80% ethyl acetate/hexane) to give the title compound (82 mg, 0.193 mmol, 40.5%) as a pale-yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])([O-])=O.P(OCC)(OCC)OCC>>[F:16][C:14]1[C:15]2[NH:1][C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:10]=2[C:11]([O:17][CH3:18])=[CH:12][CH:13]=1
Reactant: COc1ccc(F)cc1-c1ccccc1[N+](=O)[O-]
Agent: CCOP(OCC)OCC
Product: COc1ccc(F)c2[nH]c3ccccc3c12
Yield: 56.9 %

Procedure:
A mixture of 2-(2-nitrophenyl)-4-fluoroanisole (427 mg, 1.73 mmol) and triethyl phosphite (3 mL) was heated to reflux for 3.5 hours. The reaction was cooled and concentrated in vacuo. The crude product was purified via flash silica gel chromatography eluting with 2% ethyl acetate/hexanes followed by 5% ethyl acetate hexanes to give 212 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][NH2:12]>>[CH3:11][NH:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Product: CNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
1-Chloro-4-nitro-benzene (5.0 g, 31.7 mmol) was added to excess aqueous methylamine solution-(40%, 30 mL) and heated in a pressure bomb for 16 h. The reaction mass was cooled to room temperature and a solid filtered off. The filtrate was evaporated to dryness and the combined solids were purified by trituration with pentane to afford methyl-(4-nitro-phenyl)-amine (4.5 g, 93%) as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:20]2=[CH:21][CH:22]=[C:23]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)[C:24](=[O:25])[N:19]2[C:4]2([CH2:8][CH2:7][N:6](C(OCC3C=CC=CC=3)=O)[CH2:5]2)[NH:3]1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-]>[N:30]1[CH:31]=[CH:32][C:27]([NH:26][C:23]2[C:24](=[O:25])[N:19]3[C:4]4([NH:3][C:2](=[O:1])[C:20]3=[CH:21][CH:22]=2)[CH2:8][CH2:7][NH:6][CH2:5]4)=[N:28][CH:29]=1
Reactant: O=C1NC2(CCN(C(=O)OCc3ccccc3)C2)n2c1ccc(Nc1ccncn1)c2=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1NC2(CCNC2)n2c1ccc(Nc1ccncn1)c2=O
Reaction time: 4 h

Procedure:
To a stirred solution of benzyl 1,5-dioxo-6-(pyrimidin-4-ylamino)-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyridine-3,3′-pyrrolidine]-1′-carboxylate (5, 0.06 g, 0.138 mmol) in ethyl acetate:methanol (10:1, 33 mL), 20% palladium hydroxide (0.03 g) was added. The reaction mixture was hydrogenated under balloon pressure for 4 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC and repeated washing with ether to afford 6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3′-pyrrolidine]-1,5(2H)-dione (Cpd. No. 26) as a white solid. Yield: 0.025 g, 60%; MS (ESI) m/z 299.20 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.83-8.74 (m, 2H), 8.38 (d, J=5.9 Hz, 1H), 7.37 (d, J=5.9 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H), 3.67 (d, J=12.6 Hz, 1H), 3.19-3.03 (m, 2H), 2.95-2.75 (m, 2H), 2.05-1.88 (m, 1H).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[NH2:15][C:16]1[S:20][C:19]2[C:21]3[C:26]([CH2:27][C:18]=2[C:17]=1[C:28]([NH2:30])=[O:29])=[CH:25][CH:24]=[CH:23][CH:22]=3.O>ClCCl>[C:10]([OH:12])([C:9]([F:14])([F:13])[F:8])=[O:11].[NH:15]([C:16]1[S:20][C:19]2[C:21]3[C:26]([CH2:27][C:18]=2[C:17]=1[C:28]([NH2:30])=[O:29])=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6]([NH2:5])=[O:7]
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)Nc1sc2c(c1C(N)=O)Cc1ccccc1-2
Reaction time: 0.5 h
Yield: 255.9 %

Procedure:
Chlorosulfonyl isocyanate (0.025 g, 0.17 mL) was added dropwise to a stirred solution of 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide trifluoroacetate (0.040 g, 0.17 mmol) in dry dichloromethane (2 mL). The resulting reaction mixture was stirred under nitrogen for 30 min. Water (0.5 mL) was then added to the reaction mixture and the reaction mixture was allowed to stir an additional 10 minutes before the solvent was removed under vacuo. The residue was then purified on Gilson preparative HPLC (YMC HPLC column 50×20 mm I.D., s-5 μm, 120 A; gradient elution, 0.1% TFA in acetonitrile: 0.1% aqueous TFA, 10:90 to 90:10, 10 min) to give title compound as brown solid (0.020 g, 0.435 mmol, 43.5% yield). ESMS m/z: 274 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:37][CH3:38])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.FC(F)(F)S(O[CH2:56][C:57]([F:60])([F:59])[F:58])(=O)=O>O>[CH3:38][O:37][C:4]1[CH:3]=[C:2]([O:1][CH2:56][C:57]([F:60])([F:59])[F:58])[CH:7]=[CH:6][C:5]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(O)cc4OC)nccc3c2)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCC(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A vial was charged with 1-(4-hydroxy-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (from EXAMPLE 361, STEP 1; 54 mg, 0.102 mmol), cesium carbonate (100 mg, 0.306 mmol), and DMF (511 μl). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (28.0 μl, 0.204 mmol) was added and the vial was heated to 50° C. for 1 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (1 mL), and the resulting solution was stirred overnight. The mixture was diluted with MeOH and concentrated. The residue was dissolved in EtOAc and washed with saturated aq. sodium bicarbonate solution. The aq. wash was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (3.5% MeOH/DCM) to give 1-(2-methoxy-4-(2,2,2-trifluoroethoxy)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (32.7 mg, 0.067 mmol, 65.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.06 (br. s., 1H), 8.70-8.61 (m, 2H), 8.57 (s, 1H), 8.25 (d, J=5.6 Hz, 1H), 8.06 (d, J=5.8 Hz, 1H), 7.94 (dd, J=1.9, 8.9 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.03 (d, J=5.1 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.82 (dd, J=2.3, 8.4 Hz, 1H), 4.89 (q, J=8.9 Hz, 2H), 3.65 (s, 3H). m/z (ESI) 491.2 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][O:2]2.C(C=C)=[O:11].C=CC(=C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Mg]Br>>[CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH:7]1[OH:11])[CH2:4][CH2:3][O:2]2
Reactant: C1CC2CCC(CC2)O1
Reactant: C=CC=O
Agent: C[Mg]Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=CC(=C)C
Product: OC1CC2CCOC1CC2

Procedure:
When m is 1, n is 2 and p is 2, the ring system is a 2-oxabicyclo[3.2.2]nonane, another subclass of this invention. For example, compound XVp ##STR29## in which R2, R5 and R6 are methyl can be prepared by treating a Diels-Alder adduct of acrolein and isoprene with Ph3P=C(CH3)OCH3, hydrolyzing the resulting enol ether, treating the resulting ketone derivative with methyl magnesium bromide, and subjecting the resulting alcohol to epoxidation-cyclization to yield a 2-oxabicyclo[3.2.2]nonan-7-ol, which is treated with WCH2X in which X is a halogen atom to yield the desired ether, XVp. Alternatively, 4-methyl-3-cyclohexene-1-acetic acid, as obtained by the method of Kugatova-Shemyakina et al., Chemical Abstracts, 65:10504c (1966) is treated with methyl Grignard followed by epoxidation-cyclization of the resulting alcohol to yield a 2-oxabicyclo[3.2.2]nonan-7-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:40][NH:41][CH3:42].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22](=[O:23])[N:41]([CH3:42])[CH3:40])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 77 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), dimethylamine hydrochloride (44 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-dimethylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 9a (120 mg, yield 77%) as a white solid.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[I:20])[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[I:20])[C:13]([O:15][CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(I)c(Cc2ccccc2)c1
Yield: 105.5 %

Procedure:
47 ml (411 mmol) of benzyl chloride are added to a solution of 104 g (374 mmol) of methyl 3-hydroxy-4-iodobenzoate and 103 g (748 mmol) of potassium carbonate in 600 ml of methyl ethyl ketone, and the reaction medium is then refluxed for 8 hours. After cooling, the reaction medium is filtered, the precipitate is rinsed with ethyl acetate and the filtrate is evaporated to dryness. The residue is taken up in a mixture of water and ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated. 139 g (100%) of methyl 3-benzyl-4-iodobenzoate are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O=S(Cl)[Cl:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)ccc1I
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Cl)ccc1I
Temperature: 100 °C

Procedure:
To a solution of 5-chloro-2-iodobenzoic acid (3.0 g, 10.6 mmol) in toluene (150 mL), SOCl2 (7.75 mL, 106 mmol) was added and the mixture was heated at 100° C. for 3 hours. The solvent was concentrated in vacuum and the residue was co-evaporated from toluene twice to give the title compound as a grey solid. Yield (3.2 g, 100%)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH2:18])[CH:12]=1.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][CH2:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(C(=O)NCc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 77.3 %

Procedure:
In a round-bottom flask a suspension of 4-amino-benzoic acid (2 g, 14.58 mmol), C-pyridin-3-yl-methylamine (1.48 mL, 14.58 mmol), hydroxybenzotriazole (HOBt, 2.17 g, 16.04 mmol) and triethylamine (4.06 mL, 29.16 mmol) in dichloromethane (150 mL) is cooled to 0° C. and EDCI*HCl (3.08 g, 16.04 mmol) is added. The reaction mixture is stirred at room temperature for 20 hours. The solvent is removed in vacuo and ice cooled water is added. The precipitate is collected by filtration, washed once with 1 N NaOH, three times with water, two times with petroleum ether and dried in vacuo to give the title compound (2.56 g) as a solid.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:45][CH:46]([C:50]1[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=1)[CH:47]([CH3:49])[CH3:48]>CN(C=O)C>[C:1]12([C:11]([NH:45][CH:46]([C:50]3[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=3)[CH:47]([CH3:48])[CH3:49])=[O:13])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CCOC(=O)c1ccc(C(N)C(C)C)cc1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
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
Product: CCOC(=O)c1ccc(C(NC(=O)C23CC4CC(CC(C4)C2)C3)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial charged with 1-adamantylcarboxylic acid (0.031 g, 0.17 mmol) was added HATU (64.6 mg, 0.17 mmol), triethylamine (0.14 mL, 1.02 mmol) and DMF (1 mL). The solution was shaken at rt for 1 h then ethyl 4-(1-amino-2-methylpropyl)benzoate (0.038 g, 0.17 mmol) in DMF (1 mL) was added. The resulting mixture was shaken at rt for 16 h. Solvent was then evaporated. To the residue was added DCE (3 mL) and sat. NaHCO3 solution (1.5 mL). After separation, the aqueous layer was extracted with DCE twice. Combined organic layers were concentrated to give crude ethyl 4-{1-[(adamantan-1-ylcarbonyl)amino]-2-methylpropyl}benzoate as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:28][N:27]([CH3:29])[C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:26][CH:25]=1
Reactant: CN(C)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of 1-(tert-butoxycarbonyl)-4-(4-dimethylaminophenyl)piperazine (2.01 g 6.58 mmol ) in dichloromethane (20 ml) and the mixture stirred for 30 min at room temperature. The mixture was concentrated in vacuo and saturated aqueous potassium carbonate (100 ml) was cautiously added to the residue. The mixture was extracted with dichloromethane (3×100 ml), the extracts were washed with brine (50 ml), combined and dried (MgSO4). Concentration of the extracts gave 1-(4-dimethylaminophenyl)piperazine (1.14 g, 84%) as a cream solid; δH (DMSO-d6) 2.77 (6H, s, N(CH3)2), 2.79 (4H, m, 2×piperazinyl CH2), 2.86 (4H, m, 2×piperazinyl CH2), 6.68 (2H, m, ArH), and 6.82 (2H, m, ArH).