Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=2[F:22])[CH2:7][C@@H:6]1[C:23]([O:25]C)=[O:24].[OH-].[Na+].C(OC(C)C)(C)C.CCCCC>O1CCOCC1.ClCCl>[OH:1][CH:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=2[F:22])[CH2:7][C@@H:6]1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4cc(F)cc(F)c4F)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 31.7 %

Procedure:
A solution of 1.7 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 17 cm3 of dioxane to which had been added 2.58 cm3 of 5N aqueous sodium hydroxide solution was stirred for 15 hours at a temperature in the region of 60° C. After cooling to a temperature in the region of 20° C., the reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3 cm; 50 g), elution was carried out with a dichloromethane/methanol (90/10 by volume) mixture, and first a fraction of 200 cm3 was collected, followed by 23-cm3 fractions. Fractions 3 to 21 were combined and then concentrated as above. A foam was obtained, which product was subjected to a second purification by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3 cm; 70 g), elution was carried out with a dichloromethane/methanol (95/5 by volume) mixture, and first a fraction of 250 cm3 was collected, then a fraction of 100 cm3 was collected, followed by 20-cm3 fractions. Fractions 1 to 17 were combined and then concentrated as above. A foam was obtained, which product was taken up in dichloromethane and then in 20 cm3 of a 50/50 mixture of diisopropyl ether and pentane. The crystallized product formed was filtered off, washed with 2 times 10 cm3 of a diisopropyl ether/pentane (50/50 by volume) mixture and then 2 times 10 cm3 of pentane, and dried in the air. 0.524 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of a solid with a cream color melting at approximately 97° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].[CH3:9][Si:10]([CH2:13][CH2:14][O:15][CH2:16]Cl)([CH3:12])[CH3:11]>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:16][O:15][CH2:14][CH2:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(Br)c1
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a mixture of 4-bromo-1H-imidazole (1.0 g, 6.8 mmol) in THF (15 mL) was added NaH (327 mg, 8.16 mmol) at 0° C. The mixture was stirred at 0° C. to RT for 0.5 h. SEMCl (1.45 mL, 8.16 mmol) was added dropwise and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromotography (10-100% EtOAc/Heptane, then 0-15% MeOH/DCM) to afford 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.36 g, MS: 279.3 [M+H+]).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]=[C:9]3[N:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]4[CH2:15][O:14][C:10]3=[N:11][C:12]=2[CH:13]=1)([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:8]=[C:9]3[N:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]4[CH2:15][O:14][C:10]3=[N:11][C:12]=2[CH:13]=1
Reactant: O=[N+]([O-])c1ccc2nc3c(nc2c1)OCC1CCCCN31
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc2nc3c(nc2c1)OCC1CCCCN31

Procedure:
A mixture of 5.72 g. of 1,2,3,4,4a,5-hexahydro-9-nitropyrido[1',2':4,5][1,4]oxazino[2,3-b]quinoxaline, 200 ml. of dioxane and 1.5 g. of palladium on carbon catalyst is shaken in a Parr hydrogenator under 45 lb. of hydrogen pressure until reduction is complete. The mixture is filtered and the filtrate concentrated to a residue. The residue is recrystallized from ethanol to give the desired product, m.p. 229°-232° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11]>>[CH3:14][O:13][C:9]([CH2:10][CH2:11][N:1]([CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH2:11][CH2:10][C:9]([O:13][CH3:14])=[O:12])=[O:12]
Reactant: C=CC(=O)OC
Reactant: NCc1cccnc1
Product: COC(=O)CCN(CCC(=O)OC)Cc1cccnc1

Procedure:
52.06 Grams of 3-aminomethylpyridine was refluxed with 200 milliliters of methyl acrylate for 96 hours. The excess methyl acrylate was evaporated off to give 137.6 grams of 3-[N,N-di(2-methoxycarbonylethyl)aminomethyl] pyridine.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([NH2:21])[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]([CH3:35])[C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28]>C(O)(=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:21]3[C:30](=[O:29])[C:25]4[C:26](=[CH:32][CH:33]=[CH:34][C:24]=4[N:23]([CH3:22])[CH3:35])[C:27]3=[O:28])[CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)c1cccc2c1C(=O)OC2=O
Reactant: COc1ccc(C(N)CS(C)(=O)=O)cc1OC1CCCC1
Solvent: CC(=O)O
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N(C)C)c3C2=O)cc1OC1CCCC1

Procedure:
2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisoindoline-1,3-dione was prepared by the procedure of Example 8 from 1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.18 mmol) and 3-dimethylaminophthalic anhydride (608 mg, 3.18 mmol) in acetic acid (10 mL). The product was obtained as a yellow solid (780 mg, 50% yield): mp, 192.0-194.0° C.; 1H NMR (CDCl3) δ 1.61-1.64 & 1.82-2.00 (2 m's, 8H, C5H8), 2.79 (s, 3H, CH3), 3.08 (s, 6H, CH3), 3.81 (s, 3H, CH3), 3.82 (dd, J=5.5, 14.5 Hz, 1H, CHH), 4.52 (dd, J=9.8, 14.5 Hz, 1H, CHH), 4.75-4.81 (m, 1H, OCH), 5.87 (dd, J=5.0, 9.7 Hz, 1H, NCH), 6.80 (d, J=8.3 Hz, 1H, Ar), 7.03-7.26 (m, 3H, Ar), 7.47 (dd, J=7.3, 8.4 Hz, 1H, Ar); 13C NMR (CDCl3) δ 24.05, 32.75, 41.47, 43.37, 48.84, 55.36, 56.02, 80.55, 111.88, 113.74, 114.46, 114.71, 120.41, 122.04, 129.88, 134.39, 134.77, 147.91, 150.22, 150.39, 167.05, 168.13; Anal Calcd for C25H30N2O6S: C, 61.71; H, 6.21; N, 5.76. Found: C, 61.58; H, 6.06; N, 5.53.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)=[C:2]=[S:3].[H-].[Na+].[C:18]([CH:21]([CH2:27][CH2:28][C:29]([O:31]CC)=O)[C:22](OCC)=[O:23])(=[NH:20])[NH2:19].Cl>CN(C)C=O>[S:3]=[C:2]1[NH:19][C:18]2[NH:20][C:29](=[O:31])[CH2:28][CH2:27][C:21]=2[C:22](=[O:23])[N:1]1[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCC(C(=N)N)C(=O)OCC
Reactant: FC(F)(F)COc1ccc(N=C=S)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2c([nH]c(=S)n(-c3ccc(OCC(F)(F)F)cc3)c2=O)N1
Reaction time: 0.08 h
Yield: 26.6 %

Procedure:
To a solution of 1-isothiocyanato-4-(2,2,2-trifluoroethoxy)benzene (1.77 g) in N,N-dimethylformamide (25 mL) was added sodium hydride (60% in oil, 0.478 g) under ice-cooling. The reaction mixture was stirred for 5 min under ice-cooling, diethyl 2-carbamimidoylpentane-1,5-dioate (2.5 g) was added thereto, and the mixture was stirred for 30 min under ice-cooling. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (25 mL), sodium ethoxide (20% ethanol solution, 10.6 mL) was added thereto, and the mixture was stirred for 30 min. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.75 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4](=[O:29])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:31]
Reactant: CCCN1CCC(N(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(OC)c2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCN1CCC(N(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)CC1
Reaction time: 18 h
Yield: 91.7 %

Procedure:
A solution of 1.24 g (2.93 mmol) of N,N-diethyl-4-[3-methoxyphenyl(1-propylpiperidin-4-yl)amino]benzamide, Cl, in 5 mL of CH2Cl2 was cooled to −60° C. under Ar and a solution of 17.58 mL (17.58 mmol) of 1.0 M BBr3 in CH2Cl2 was added dropwise. The temperature was allowed to rise to 25° C. and the mixture was stirred for 18 h. It was partitioned between NaHCO3 solution and 25% EtOH in CH2Cl2. The organic layer was dried (Na2SO4) and the solvent evaporated. The residue was was heated under reflux in 100 mL of saturated NaHCO3 solution. The solution was cooled and extracted with CH2Cl2. The solution was dried (Na2SO4) and concentrated to give 1.1 g (92% yield) of N,N-diethyl-4-[3-hydroxyphenyl(1-propylpiperidin-4-yl)amino]benzamide as a gum. An oxalate salt was prepared in CH3CN, mp 196-197° C. MS m/z=410 (M++H). 300 MHz 1H NMR (DMSO-d6) δ7.2(m, 3H); 6.6 (m, 3H); 6.5(d, 1H); 6.4(s, 1H); 4.1(m, 1H); 3.3(q, 4H); 3.2 (m, 2H); 2.6 (m, 4H); 2.1 (d, 2H); 1.5 (m, 4H); 1.1 (t, 6H); 0.8 (t, 3H). Anal calcd. for C25H35N3O2.0.5 C2H2O4.0.25 H2O: C, 68.03; H, 8.01; N, 915; H2O, 0.98. Found: C, 67.73; H, 7.73; N, 9.11; H2O, 0.46.
Reaction SMILES: [CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@H:22]2[O:27][C:26](C)([CH3:28])[O:25][C@@H:24](CC(N(OC)C)=O)[CH2:23]2)=[C:9]([CH:37]([CH3:39])[CH3:38])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[N+]([O-])(O)=[O:41]>C(#N)C>[CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@H:22]2[O:27][C:26](=[O:41])[CH2:28][C@H:24]([OH:25])[CH2:23]2)=[C:9]([CH:37]([CH3:39])[CH3:38])[N:8]=1)[S:3]([CH3:6])(=[O:4])=[O:5]
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](/C=C/c2c(-c3ccc(F)cc3)nc(N(C)S(C)(=O)=O)nc2C(C)C)OC(C)(C)O1
Reactant: O=[N+]([O-])O
Solvent: CC#N
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H]1C[C@@H](O)CC(=O)O1
Reaction time: 3 h
Yield: 58 %

Procedure:
E-(6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide (4.0 g), acetonitrile (25.0 mL), and nitric acid (0.49 mL) were added to a reactor and then the reaction mixture was stirred at 50˜60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and then ethyl acetate (25.0 mL) and water (25.0 mL) were added thereto. The separated organic layer was dried under reduced pressure to obtain E-6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-(4R,6S)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (1.9 g, yield 58%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.C([Li])CCC.[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:25]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:26]
Reactant: O=C(Cl)C1CCCCC1
Reactant: COC(CNc1ccccn1)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(CN(C(=O)C1CCCCC1)c1ccccn1)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6 g of 2-[(2-pyridyl)amino]acetaldehyde dimethyl acetal (prepared as described in Beilstein E III/IV, 22, 3871) in 40 ml of tetrahydrofuran stirred at 0° C. was added dropwise 13.2 ml of butyl lithium (2.5 M solution in n-hexane) and the resulting mixture was stirred at room temperature for 1 h. Afterwards, to the solution was added dropwise in 5 min 4.46 ml of cyclohexanecarbonyl chloride. Stirring was continued for 5.5h, followed by in vacuo evaporation of the reaction mixture to dryness. The residue was purified by flash chromatography (chloroform-ethyl acetate 7:3) affording 13.3 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C.[NH3:30]>CO>[I:11][C:9]1[N:10]=[C:2]([NH2:30])[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=1)[C@@H:12]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([OH:19])[C@H:13]1[OH:14]
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 90 %

Procedure:
6.0 g of 6-chloro-2-iodo-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl) purine was added to 60 ml of methanol plus ammonia (saturated at 0° C.) to cause reaction at a temperature of 60° C. for 17 hours in a sealed tube. The reaction solution was cooled, then degassed, and concentrated under reduced pressure. Crystallization of the residue from water afforded 3.94 g of 2-iodoadenosine (90% yield) having a melting point of 141° C. to 144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[CH3:11]COCC.C[Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[CH:4][C:3]=1[F:10]
Reactant: CCOCC
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cl)c(F)c1
Temperature: -50 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-3-fluorobenzaldehyde (1 eq) in THF (0.3 M) at −78° C. was added 3M/Et2O MeMgBr (1.5 eq). The reaction mixture was stirred at −50° C. for 3 hrs, quenched with aqueous saturated NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give 1-(4-chloro-3-fluorophenyl)ethanol, which was used as such for the next step.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([I:25])[C:21]([NH2:22])=[N:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:26])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:27](Br)[CH:28]=[CH2:29]>C1COCC1>[CH2:29]([O:26][C@@H:13]1[C@@H:12]([CH2:11][O:10][Si:3]([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:4])[CH3:5])[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([I:25])[C:21]([NH2:22])=[N:20][C:18]2=[O:19])[CH2:14]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(N)nc2=O)C[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cc(I)c(N)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of NaH (60%, 113 mg, 2.84 mmol) in THF (26 ml) under N2 atmosphere, was slowly added a solution of the starting nucleoside (39) (669 mg, 1.43 mmol) in THF (6 ml). The mixture was stirred at room temperature for 45 minutes, cooled at 0° C. and allyl bromide (134 μL, 1.58 mmol) was slowly added. After 15 h at room temperature, the solution was cooled to 0° C. and quenched by addition of H2O (5 ml). THF evaporated under reduced pressure and the product extracted into EtOAc (3×25 ml). Combined organic extracts were dried (MgSO4) filtered and the volatiles evaporated under reduced pressure to give a residue that was purified by flash chromatography on silica gel with EtOAc affording the expected 3′-O-allyl product (40) (323 mg, 44%) as a colourless oil, together with some unreacted starting material (170 mg); 1H NMR (d6 DMSO) δ 0.00 (s, 3H, CH3), 0.01 (s, 3H, CH3), 0.79 (s, 9H, 3CH3), 1.84 (ddd, J=13.3, 8.2 and 5.5 Hz, 1H, H-2′), 2.20-2.25 (m, 1H, H-2′), 3.62-3.72 (m, 2H, H-5′), 3.88-3.93 (m, 4H, H-3′, 4′, HHC—CH═), 5.1 (dd, J=8.5, 1.7 Hz, 1H, CH═CHH), 5.16 (dd, J=17.2, 1.7 Hz, 1H, CH═CHH), 5.75-5.83 (m, 1H, CH═CHH), 5.94 (dd, J=8.4, 5.6 Hz, 1H, H-1′), 6.53 (br s, 1H, NHH), 7.74 (br s, 1H, NHH), 7.83 (s, 1H, H-6); MS (ES): m/z (%) (M−H) 506 (100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[O:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: ClCC1OCCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1OCCCCO1

Procedure:
2,6-Diethylaniline (75 grams), 2-chloromethyl-1,3-dioxepane (15 grams), potassium carbonate (34 grams) and dimethylformamide (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 18 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dioxepan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: [CH3:1][CH:2]([OH:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([Cl:15])[CH:4]=1>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:15][C:5]1[CH:4]=[C:3]([C:2](=[O:16])[CH3:1])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(O)c1ccc(-c2ccccc2)c(Cl)c1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(-c2ccccc2)c(Cl)c1

Procedure:
α-Methyl-3-chloro-4-phenylbenzyl alcohol, 28.6 g, was dissolved in 36 ml of acetone. To the resulting solution was added dropwise, with cooling and vigorous agitation, a solution of 12 g of chromium trioxide in 42 ml of 35 percent aqueous suluric acid. A large volume of acetone then was added; the aqueous layer was separated and washed with acetone. The acetone layer and acetone extracts were combined and dried over anhydrous sodium sulfate. The acetone was evaporated and the residue was distilled in vacuo to give 26.3 g of 3'-chloro-4'-phenylacetophenone, bp 132°-141°C/0.09 mm. The following elemental analysis was obtained:
Reaction SMILES: [CH3:1][NH:2][NH2:3].CN([CH:7]=[C:8]1[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]1=O)C>>[CH3:1][N:2]1[C:9]2[CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][C:13](=[O:14])[C:8]=2[CH:7]=[N:3]1
Reactant: CNN
Reactant: CN(C)C=C1C(=O)CC(C)(C)CC1=O
Product: Cn1ncc2c1CC(C)(C)CC2=O

Procedure:
Prepared analogously to Example 1 starting from methylhydrazine and 2-(dimethylaminomethylene)-5,5-dimethyl-cyclohexane-1,3-dione.
Reaction SMILES: C(OC([N:8]1[CH:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:35]=[CH:34][C:33]5[C:32]6[C:27](=[CH:28][C:29]([C:36]7[NH:37][C:38]([CH:41]8[CH2:47][C:44]9([CH2:46][CH2:45]9)[CH2:43][N:42]8[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])=[N:39][CH:40]=7)=[CH:30][CH:31]=6)[C:26]([F:60])([F:59])[C:25]=5[CH:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH:12]2[CH2:61][CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[CH3:72][O:73][C:74]([NH:76][CH:77]([CH3:81])[C:78](O)=[O:79])=[O:75].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1.CN(C=O)C.CCOC(C)=O>[CH3:57][O:56][C:54](=[O:55])[NH:53][CH:49]([C:48]([N:42]1[CH:41]([C:38]2[NH:37][C:36]([C:29]3[CH:30]=[CH:31][C:32]4[C:33]5[C:25](=[CH:24][C:23]([C:20]6[CH:21]=[CH:22][C:16]7[N:15]=[C:14]([CH:13]8[CH:12]9[CH2:61][CH:9]([CH2:10][CH2:11]9)[N:8]8[C:78](=[O:79])[CH:77]([NH:76][C:74]([O:73][CH3:72])=[O:75])[CH3:81])[NH:18][C:17]=7[CH:19]=6)=[CH:35][CH:34]=5)[C:26]([F:60])([F:59])[C:27]=4[CH:28]=3)=[CH:40][N:39]=2)[CH2:47][C:44]2([CH2:45][CH2:46]2)[CH2:43]1)=[O:58])[CH:50]([CH3:52])[CH3:51]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Reactant: COC(=O)NC(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)NC(C)C(=O)N1C2CCC(C2)C1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc(C6CC7(CC7)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc3-4)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 43.4 %

Procedure:
3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (57.6 mg, 0.068 mmol) was dissolved in DCM (1 mL) and HCl in dioxane (4M, 1 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.0 mL) and DIEA (26.4 mg, 0.204 mmol) was added. A solution of 2-(L) methoxycarbonylamino-propionic acid (9.95 mg, 0.068 mmol), HATU (25.9 mg, 0.068 mmol) and DIEA (8.8 mg, 0.068 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 45 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA) to yield the product (1-{6-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl)-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (25.4 mg) as a TFA salt.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][S:14]([C:17]1[NH:21][CH:20]=[N:19][N:18]=1)(=[O:16])=[O:15])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[CH3:11][CH:10]([CH3:12])[CH2:9][CH:8]([NH2:7])[CH2:13][S:14]([C:17]1[NH:21][CH:20]=[N:19][N:18]=1)(=[O:16])=[O:15]
Reactant: CC(C)C[C@@H](CS(=O)(=O)c1nnc[nH]1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC(N)CS(=O)(=O)c1nnc[nH]1

Procedure:
200 mg of [(S)-3-Methyl-1-(4H-[1,2,4]triazole-3-sulfonylmethyl)-butyl]-carbamic acid tert-butyl ester were dissolved in 6 ml of dioxane and reacted with 2.2 ml of 4M hydrochloric acid in dioxane at rt for 16 h. The reaction was concentrated in vacuo and the resulting crude product was used without further purification. 120 mg (100%) of S)-3-Methyl-1-(4H-[1,2,4]triazole-3-sulfonylmethyl)-butylamine-hydrochloride were obtained.