Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CO.Cl>O1CCOCC1>[F:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]3)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)([C@H]2CCCCN2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
1,1-dimethylethyl(2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (74.9 mg, 0.12 mmol) was taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane (1 mL) and the solution was stirred at room temperature for one hour. The solution was then concentrated and the residue partitioned with chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using ethyl acetate then concentrated aqueous ammonia in chloroform and methanol (0.1:10:1) as eluents afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol (57.3 mg) as a colorless amorphous solid. The free base was taken into methanol (1 mL) then brought to about pH 1 by addition of 4 N HCl in dioxane and the solution concentrated. The residue was triturated with ethyl ether to afford a suspension. The solid was collected by filtration to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol hydrochloride salt (49 mg, 72% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3): 8.43-8.39 (d, 1H), 7.41-7.38 (dd, 1H), 7.33-7.31 (dt, 1H), 7.14-7.10 (m, 1H), 6.84-6.80 (m, 1H), 6.63-6.57 (m, 1H), 4.12-3.99 (m, 4H), 3.10-3.08 (d, 1H), 2.72-2.69 (d, 1H), 2.64-2.62 (m, 1H), 1.61-1.58 (m, 2H), 1.36-1.16 (m, 4H); MS (EI) for C21H21F3IN3O2: 532 (MH+).
Reaction SMILES: [CH:1](=O)[CH3:2].[CH2:4]([O:7][CH2:8][CH:9]1[S:14](=[O:16])(=[O:15])[C:13]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:12]=2[CH:11]([NH2:24])[CH2:10]1)[CH:5]=[CH2:6].[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[CH2:4]([O:7][CH2:8][CH:9]1[S:14](=[O:16])(=[O:15])[C:13]2[S:17][C:18]([S:20]([NH2:23])(=[O:21])=[O:22])=[CH:19][C:12]=2[CH:11]([NH:24][CH2:1][CH3:2])[CH2:10]1)[CH:5]=[CH2:6]
Reactant: CC=O
Reactant: C=CCOCC1CC(N)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCOCC1CC(NCC)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Acetaldehyde, 1.5 ml. (1.19 g, 0.027 m), was added to a solution of 5,6-dihydro-6-allyloxymethyl-4-amino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide, 10.0 g. (0.028 m.), in dry tetrahydrofuran, 150 ml., and the mixture was stirred at ambient temperature for 0.75 h. under nitrogen. The solution was added over 15 min. to a stirred suspension of sodium borohydride, 5.3 g. (0.14 m.) in absolute ethanol, 150 ml., at 0° C. After stirring for an additional 15 min. at 0° C., the mixture was treated dropwise with 10% hydrochloric acid, 35 ml., until gas evolution ceased. After concentration in vacuo, the residue was distributed between 200 ml. of water containing 10 ml. of 3N hydrochloric acid and 75 ml. of ethyl acetate. The ethyl acetate layer was washed with 100 ml. of water, the combined aqueous wash and acidic water layer were basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (300 ml. and 2×200 ml.). After washing twice with brine and drying over sodium sulfate, ethyl acetate was evaporated in vacuo to yield 6.6 g. (63%) of the mixture of isomers as a yellow foam.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)C>[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])=[CH:15][CH:14]=1
Reactant: OCCCCCOc1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCCCOc1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
To a suspension of 33 g (0.15 mmol) of pyridinium chlorochromate in 450 ml of methylene chloride is added 21.4 g (0.1 mol) of 5-(4-chlorophenoxy)-1-pentanol. The mixture is maintained with stirring for 3 hours, diluted with 900 ml of ethyl ether and stirred for an additional 1 hour.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@H:27]3[CH2:30][C@H:29]([CH2:31]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:43]1[CH2:46][CH2:45][CH2:44]1>C1COCC1>[N:43]1([CH2:31][C@H:29]2[CH2:30][C@H:27]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([C:11]4[CH:20]=[C:19]5[C:14]([CH:15]=[CH:16][C:17]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)=[N:18]5)=[CH:13][CH:12]=4)=[CH:9]3)[CH2:28]2)[CH2:46][CH2:45][CH2:44]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](n3cc(-c4ccc5ccc(-c6ccccc6)nc5c4)c4c(N)ncnc43)C2)cc1
Reactant: C1CNC1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@H](CN2CCC2)C1
Reaction time: 8 h

Procedure:
A solution of toluene-4-sulfonic acid trans-3-[4-amino-5-(2-phenylquinolin-7-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl ester and azetidine (0.30 mL, 254 mg, 4.5 mmol) in THF (4 mL) was heated in a sealed tube to 50° C. overnight. More azetidine (0.30 mL, 254 mg, 4.5 mmol) was added, and heating was continued overnight. THF was evaporated, water and saturated NaHCO3 solution. were added, the mixture was extracted with CH2Cl2 (5×20 mL), and the combined CH2Cl2 extracts were washed with water and brine and dried over MgSO4. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-9)→5% MeOH in CH2Cl2 (10-31)→6.6% MeOH in CH2Cl2 (32-55)→6.6% MeOH in CH2Cl2+NH3 (0.05 M) (56-86)], yielding the title compound as a highly viscous yellow oil. This oil was dissolved in CDCl3 (0.7 mL), tBuOMe was added, and the off-white precipitate was filtered off and dried in vacuo yielding the desired product. 1H NMR (CDCl3, 400 MHz) δ 2.15 (quint, J=7.2 Hz, 2H), 2.33-2.54 (m, 4H), 2.57-2.70 (m, 3H), 2.73 (d, J=7.4 Hz, 2H), 3.33 (t, J=7.2 Hz, 4H), 5.26 (brs, 2H), 5.44 (quint, J=8.1 Hz, 1H), 7.37 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.7, 8.3 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d, J=8.6 Hz, 1H), 8.28-8.31 (m, 1H), 8.35 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135) δ 17.73 (−), 27.06 (+), 33.60 (2C, −), 46.72 (+), 55.51 (2C, −), 63.99 (−), 101.05 (Cquart), 116.12 (Cquart), 118.85 (+), 120.57 (+), 125.86 (Cquart), 127.29 (+), 127.45 (2C, +), 128.18 (+), 128.34 (+), 128.76 (2C, +), 129.41 (+), 136.31 (Cquart), 136.46 (+), 139.30 (Cquart), 148.38 (Cquart), 150.73 (Cquart), 151.83 (+), 157.07 (Cquart), 157.95 (Cquart). MS (ES+): m/z 461.2 (11) [MH+], 338.2 (14) [MH+-C4H5CH2azetidine]. HPLC: tR=2.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5].[C:15](#[N:17])[CH3:16]>>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:8]=1)[CH2:16][C:15]#[N:17]
Reactant: CC#N
Reactant: CCCCCOc1cccc(C=O)c1
Product: CCCCCOc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-pentyloxybenzaldehyde gave 3-hydroxy-3-(3-pentyloxyphenyl)propionitrile as a yellow oil. Yield (1.11 g, 67%): 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J=7.6 Hz, 1H), 6.92-6.98 (m, 2H), 6.87 (d, J=7.6 Hz, 1H), 5.02 (m, 1H), 3.98 (t, J=6.4 Hz, 2H), 2.76 (d, J=6.0 Hz, 2H), 1.75-1.83 (m, 2H), 1.32-1.49 (m, 4H), 0.92 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1]([CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O.O>[CH:1]([CH:4]1[C:9](=[O:10])[N:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(C)C1Oc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)C(C(C)C)Oc2ccccc21

Procedure:
To a solution of 2-isopropyl-2H-1,4-benzoxazin-3(4H)-one (19.1 g) in N,N-dimethylformamide (200 ml), sodium hydride (60% in oil, 4.0 g) was added and stirred at room temperature for 30 minutes, to which a solution of methyl bromoacetate (10 ml) in N,N-dimethylformamide (200 ml) was added dropwise with ice-cooling. After stirring with ice-cooling for 1 hour, the reaction mixture was diluted with water and subjected to extraction with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated to dryness, to give methyl 3,4-dihydro-2-isopropyl-3-oxo-2H-1,4-benzoxazine-4-acetate as an oil. Yield was 26.0 g (98.9%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[N:5]2[CH:32]=1.[Cl:33][C:34]([Cl:39])([Cl:38])[C:35](Cl)=[O:36].[C:40](=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:1]([C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]([F:22])([F:23])[F:24])(=[O:19])=[O:20])[N:5]2[C:32]=1[C:35](=[O:36])[C:34]([Cl:39])([Cl:38])[Cl:33])[CH3:40]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: O=C([O-])O
Reactant: Cc1cn2c(CN(CCCCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)cccc2n1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1nc2cccc(CN(CCCCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)n2c1C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a solution of 2.85 g (5.79 mmol) of 2-methyl-5-[N-tert-butoxycarbonyl-N-[5-(trifluoromethanesulfonamido)pentan-1-yl]aminomethyl]imidazo[1,2-a]pyridine and 3.53 g (28.93 mmol) of 4-dimethylaminopyridine in 35 ml of chloroform was added dropwise, for 3 minutes under stirring at room temperature, 3.2 ml (28.93 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 20 hours under reflux. After completion of the reaction, the reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with 100 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=100:1) to give 2.04 g of the desired compound (55.2%, pale yellow liquid).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([CH:27]=[O:28])=[C:11]([I:29])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:12]([C@H:27]([C:37]3[CH:38]=[CH:39][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[OH:28])=[C:11]([I:29])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC1(C)Cc2nc(C3CCOCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC(C)(C)c1ccc(I)cc1
Product: CC1(C)Cc2nc(C3CCOCC3)c([C@@H](O)c3ccc(C(C)(C)C)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-tert.-butyl-iodo-benzene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11]1([N:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]([CH2:20][NH:21][C:22](N2C=CN=C2)=[O:23])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:22](=[O:23])[NH:21][CH2:20][C:18]([N:17]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=C(CNC(=O)n1ccnc1)N(c1ccccc1)c1ccccc1
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: O=C(NCC(=O)N(c1ccccc1)c1ccccc1)Nc1cccc([N+](=O)[O-])c1
Yield: 18 %

Procedure:
3-Nitroaniline (2.8 g) is added to a solution of N-(diphenylcarbamoylmethyl)-1-imidazolecarboxamide (3.2 g) in anhydrous toluene (35 cc). The solution obtained is stirred under reflux for 4 hours. After cooling, the reaction mixture is washed with an N aqueous solution (40 cc) of methanesulphonic acid and distilled water (2×30 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is stirred for 20 minutes in dichloromethane (25 cc). The insoluble product is separated by filtration, washed with dichloromethane (5 cc) and dried in the air. After recrystallization in ethyl acetate, 2-[3-(3-nitrophenyl)ureido]-N,N-diphenylacetamide (0.7 g), m.p. 180° C., is obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br-:1].[Br-:1].[CH2:2]([N+:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N+:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccncc1
Reactant: BrCCCCCCCCCBr
Product: [Br-]
Product: c1cc[n+](CCCCCCCCC[n+]2ccccc2)cc1
Temperature: 65 °C
Yield: 87 %

Procedure:
1,9-Dibromononane (mmol) was added to a solution (30 mL) of dry pyridine, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting clear liquid was isolated in a 87% yield. 1H NMR (300 MHz, DMSO-D6) δ 9.17 (2H, d, C2&C6-H), 8.61 (1H, t, C4-H), 8.18 (2H, t, C3&C5-H), 4.63 (2H, t, C′1-CH2), 1.89 (2H, m, C′2-CH2), 1.22 (5H, m, C′3-5-CH2); 13C NMR (75 MHz, DMSO-D6) δ 145.3, 144.5, 127.9, 60.5, 30.7, 28.4, 28.2, 25.3.
Reaction SMILES: [I-:1].[K+].CS(O[CH:8]1[CH2:11][N:10]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)(=O)=O.C(OCC)(=O)C>O.COCCOC>[CH:12]([N:10]1[CH2:11][CH:8]([I:1])[CH2:9]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: IC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium iodide (530 mg, 3.14 mmol) was added to a solution of 1-benzhydrylazetidin-3-yl methanesulfonate (500 mg, 1.57 mmol) in a mixture of water (2.5 mL) and 1,2-dimethoxyethane (2.5 mL) at room temperature. The reaction mixture was then heated up to reflux and stirred for 3 hours. After cooling down to room temperature, the reaction mixture was diluted by addition of water (50 mL) and ethyl acetate (50 mL). The aqueous phase was separated and extracted with ethyl acetate (2×70 mL). The combined organic phases were washed with a saturated solution of sodium chloride (40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The title compound was obtained as a yellow solid (550 mg, 100%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(Nc1ccccc1)c1cccc(Oc2ccccc2)c1
Yield: 94.3 %

Procedure:
Prepared according to the procedure of Example 1 Step A using 3-phenoxybenzoic acid (1.2 g, 5.5 mmol), oxalyl chloride (0.55 mL, 6.3 mmol), and aniline (1.0 g, 10.7 mmol) to afford the product (1.5 g); m.p. 111-112° C. after recrystallization from ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]C(C)([O-])C.[K+].C(OP(C=[N+]=[N-])(=O)OCC)C>CCOCC>[C:6]([N:8]1[C@H:12]([C:13]#[CH:17])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Agent: CCOP(=O)(C=[N+]=[N-])OCC
Agent: [K+]
Solvent: CCOCC
Product: C#C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(R)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine was prepared according to Method X above by the treatment of tert-butyl-(S)-4-formyl-2,2-dimethyl-3-oxazolidine-carboxylate (1.00 g, 4.36 mmol) (Aldrich) with potassium tert-butoxide (730 mg, 6.54 mmol) and diazomethyl-phosphonic-acid-diethylester (1.20 g, 6.54 mmol) (see Method X, supra). The reaction was allowed to slowly warm up to room temperature and stirred for a total of 12 hrs. The product was obtained after silica gel column chromatography with 20% Et2O in hexanes. (Yield 600 mg, 61%).
Reaction SMILES: Cl[Si](C)(C)C.[I-].[K+].[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([CH:19]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[C:29]([F:36])[CH:28]=3)[CH2:20][C@@H:21]3[NH:25][C:24](=[O:26])[CH2:23][CH2:22]3)=[N:15][C:16]=2[O:17]C)[CH2:10][CH2:9]1.O>C(#N)C>[CH:8]1([C:11]2[C:16](=[O:17])[NH:15][C:14]([CH:19]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[C:29]([F:36])[CH:28]=3)[CH2:20][C@H:21]3[CH2:22][CH2:23][C:24](=[O:26])[NH:25]3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1
Reactant: CCOc1ccc(C(C[C@H]2CCC(=O)N2)c2ccc(C3CC3)c(OC)n2)cc1F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(C(C[C@H]2CCC(=O)N2)c2ccc(C3CC3)c(=O)[nH]2)cc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (0.17 mL) and potassium iodide (370 mg) were added to a solution of (5R)-5-[2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(4-ethoxy-3-fluorophenyl)ethyl]pyrrolidin-2-one (222 mg) in acetonitrile (4.4 mL) at room temperature, and then the mixture was stirred at 50° C. for one hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. One diastereomer (A) of the title compound was obtained as a white solid (71 mg, 33% (two steps)) by separating the residue by preparative HPLC (CHIRALPAK IB (20 mm i.d.×250 mm L, Daicel Chemical Industries, LTD.), 40° C., flow rate: 10 mL/min, ethanol:hexane=40:60) and concentrating the fraction eluted with a retention time of 13 minutes. The fraction eluted with a retention time of 28 minutes was concentrated to give the other diastereomer (B) of the title compound as a white solid (71 mg, 33% (two steps)).
Reaction SMILES: C([S:4][CH2:5][CH:6]([C:17]([F:20])([F:19])[F:18])[C:7]([NH:9][CH2:10][CH2:11][C:12]1[NH:16][N:15]=[N:14][N:13]=1)=[O:8])(=O)C.O.Cl>[NH4+].[OH-]>[F:19][C:17]([F:18])([F:20])[CH:6]([CH2:5][SH:4])[C:7]([NH:9][CH2:10][CH2:11][C:12]1[NH:16][N:15]=[N:14][N:13]=1)=[O:8]
Reactant: CC(=O)SCC(C(=O)NCCc1nnn[nH]1)C(F)(F)F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCc1nnn[nH]1)C(CS)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
The title compound of Example 26 (1.0 g., 3.2 mmol.) was dissolved at 0° C. under argon in 2.5 mL of a 1:1 concentrated NH4OH:H2O solution. The reaction mixture was stirred at 0° C. for 5 minutes and then acidified with 5N HCl to pH 6 at 0° C. The product was extracted with ethyl acetate containing methanol (3×) (200 mL portions). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed through 50 g of Merck silica gel using a (3:3:94) methanol:acetic acid:methylene chloride solvent system. The appropriate fractions were combined and concentrated to yield 0.56 g of the title product, m.p. 182°-184° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([N:14]=[N+:15]=[N-:16])=[O:13])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:17][N:8]1[C:7]2[C:2]([CH3:1])=[CH:3][C:4]([C:12]([N:14]=[N+:15]=[N-:16])=[O:13])=[CH:5][C:6]=2[O:10][C:9]1=[O:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)N=[N+]=[N-])cc2oc(=O)[nH]c12
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(C(=O)N=[N+]=[N-])cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
550 mg (2.50 mmol) 4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carboxylic acid azide and 400 mg (2.90 mmol) potassium carbonate were stirred in DMF for 20 min at RT. Then 0.200 mL (3.21 mmol) of methyl iodide were added and the mixture was stirred for 1.5 h at RT. Water was added to the reaction mixture, the precipitate formed was suction filtered and dried.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[ClH:10].[N:11]1([CH2:17][C:18]([OH:20])=O)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:33][C:34]1[CH:35]=[CH:36][C:37]2[N:43]3[CH:44]=[N:45][C:46]([C:47](=[N:49]O)[NH2:48])=[C:42]3[CH2:41][N:40]([CH3:51])[C:39](=[O:52])[C:38]=2[CH:53]=1>CN(C=O)C>[ClH:10].[F:33][C:34]1[CH:35]=[CH:36][C:37]2[N:43]3[CH:44]=[N:45][C:46]([C:47]4[N:48]=[C:18]([CH2:17][N:11]5[CH2:12][CH2:13][O:14][CH2:15][CH2:16]5)[O:20][N:49]=4)=[C:42]3[CH2:41][N:40]([CH3:51])[C:39](=[O:52])[C:38]=2[CH:53]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2ccc(F)cc2C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2c(-c3noc(CN4CCOCC4)n3)ncn2-c2ccc(F)cc2C1=O
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
0.38 ml (2.2 mmol) of N-ethyldiisopropylamine was added to a suspension of 0.4 g (2.2 mmol) of morpholin-4-yl-acetic acid hydrochloride in 4 ml of DMF. 390 mg (2.4 mmol) of 1,1'- carbonyldiimidazole were added portionwise at room temperature, whereupon the solution was stirred at 50° for 30 min. and then treated at room temperature with 0.58 g (2.0 mmol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime. The reaction mixture was heated to 90° for 20 hrs. The solvent was removed in a vacuum, the residue was taken up in 15 ml of water and the solution was extracted several times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on silica gel (methylene chloride/methanol 19:1). The solvent was removed in a vacuum, the residue was dissolved in 5 ml of acetonitrile and the solution was made acid by the addition of ethereal HCl solution. The white crystals were filtered off under suction and recrystallized from acetonitrile. There was obtained 0.5 g (54%) of 8-fluoro-5-methyl-3-(5-morpholin-4-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (3:5) of m.p. 198°-205° (dec.).